Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

Abstract

The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process. Here, we review the diverse signaling mediators and mechanisms adipose tissue utilizes to relay information to other organs. We discuss recently identified adipokines (proteins, lipids, and metabolites) and briefly outline the contributions of noncoding RNAs and EVs to the ever-increasing complexities of adipose tissue inter-organ communication. We conclude by reflecting on central aspects of adipokine biology, namely, the contribution of distinct adipose tissue depots and cell types to adipokine secretion, the phenomenon of adipokine resistance, and the capacity of adipose tissue to act both as a source and sink of signaling mediators.

THE ENDOCRINE ERA OF ADIPOSE TISSUE

The roles of white adipose tissue (WAT) in long-term energy storage, thermal insulation, and mechanical protection and of brown adipose tissue (BAT) in nonshivering thermogenesis have long been appreciated (1). The concept that adipose tissue could serve as an endocrine organ, however, was only shaped after the discovery of its two most characteristic secretory products, leptin and adiponectin.

Leptin, identified in 1994, is a protein primarily produced by mature adipocytes (2, 3). It signals through the long isoform of the leptin receptor (LEPRb) and exerts the majority of its effects acting on the brain (2, 4–6). Its circulating levels reflect the filling state of adipose tissue depots and thus relate directly to the body’s long-term energy stores (7, 8). The lowering of circulating leptin levels due to a reduction in adipose tissue mass triggers behavioral, metabolic, and endocrine responses that aim at replenishing and preserving the body’s fuel reserves (9, 10). Among these responses are an increase in energy intake, a decrease in energy expenditure, and a reduction or elimination of highly energy-demanding processes, such as reproduction and immune-related processes (9, 10).

Adiponectin, originally described in 1995 as “Acrp30” with additional reports following in 1996, is a protein exclusively produced by mature adipocytes (11–15). It forms low molecular weight trimers, intermediate molecular weight hexamers, and high molecular weight dodeca- to octadecamers (16). It signals through adiponectin receptor (AdipoR)1 and AdipoR2 and binds to the nonsignaling interacting protein, T-cadherin (15). It is found in circulation and critically involved in many signaling events from the adipocyte to other cell types and tissues (11). Its circulating levels are closely tied to the functional integrity of adipose tissue and decline with obesity (17, 18). Adiponectin functions as a powerful insulin sensitizer and suppressor of cell death and inflammation, directly promoting anti-diabetic and anti-atherosclerotic outcomes (16). It acts on the liver to decrease gluconeogenesis, on skeletal muscle to increase fatty acid oxidation, and on pancreatic β-cells and cardiac muscle cells as a key anti-lipotoxic agent, exerting many of these functions on the basis of its effects on sphingolipids (19–22).

Adiponectin and leptin are clearly the two most widely studied adipocyte-derived factors with nearly 50,000 combined citations in PubMed identified with the name of these two adipokines as key search terms. Many reviews cover them extensively, so we do not want to belabor these two adipokines in detail here. However, suffice it to say that much still remains to be learned about both of these factors. While they are unquestionably important, their detailed mechanisms of action at the level of their target cells and organs, the underlying systemic resistance to the effects of these hormones, and their mutual effects on each other are yet to be better understood.

ADIPOSE TISSUE-SECRETED SIGNALING MEDIATORS

Screening endeavors undertaken in the wake of the discovery of leptin and adiponectin have revealed a vast spectrum of adipose tissue-secreted signaling mediators (see Fig. 1 and Table 1 for a compilation of central factors, some of which are portrayed in detail below) (23). The large diversity of adipose tissue secretory products may partially stem from the complex cellular composition of the tissue, which includes lipid-laden adipocytes, adipose tissue stromal cell populations of different adipogenic potentials, various immune cell populations, endothelial cells, pericytes, and neurons (24). While the term “adipokine” is commonly used to refer to adipose tissue-derived proteins exclusively, it has occasionally been used to refer to the entirety of signaling mediators secreted by adipose tissue, and it is this latter definition that will be applied here.

Fig. 1.

Adipose tissue is a highly dynamic secretory organ that employs a plethora of adipokines (proteins, lipids, metabolites), noncoding RNAs, and EVs to relay information to other organs of the body.

TABLE 1.

Collection of various adipose tissue-derived proteins, lipids, and metabolites with information on essential characteristics and several references for further reading

Class	Name (Abbreviation)	Characteristics	References
Proteins	Angiotensin II (AII)	Extracellular, generated	(453–455, 456–467)
		Generated from serine protease inhibitor A8/angiotensinogen (SERPINA8/AGT) by combined activity of renin or cathepsins and angiotensin-converting enzyme 1 (ACE1) or chymases
		Signals through G protein-coupled angiotensin receptor (ANGTR)1 and ANGTR2
		Regulates adipose tissue stromal cell adipogenesis
		Regulates adipose tissue thermogenesis
		Regulates blood pressure
		Regulates cardiac and vascular functions
		Regulates energy expenditure
		Regulates fluid homeostasis
		Regulates glucose tolerance and insulin sensitivity
		Regulates inflammation
		Regulates WAT browning
		May regulate body weight
		Increases adipocyte lipid uptake and lipogenesis
		Increases adipose tissue stromal cell proliferation
		Decreases adipocyte lipolysis
Proteins	Adiponectin (ACRP30/ADIPOQ)	Extracellular, secreted	(15, 16, 22, 156, 321, 468–476)
		May be intracellular
		Signals through AdipoR1 and AdipoR2
		Binds T-cadherin
		Improves glucose tolerance and insulin sensitivity
		Maintains cardiac and vascular functions
		Regulates angiogenesis
		Regulates ceramide metabolism
		May regulate cancer growth and metastasis
		Increases adipocyte and skeletal muscle cell glucose uptake
		Increases adipocyte lipogenesis
		Increases adipose tissue stromal cell adipogenesis
		Increases β-cell survival
		Increases energy expenditure
		Increases hepatocyte and skeletal muscle cell fatty acid oxidation
		May increase β-cell glucose-stimulated insulin secretion
		Decreases adipose tissue stromal cell proliferation
		Decreases atherosclerosis
		Decreases hepatocyte lipogenesis
		Decreases inflammation
		Decreases liver gluconeogenesis
		Decreases liver steatosis
Proteins	Angiopoietin 1 (ANG1)	Extracellular, secreted	(27, 28, 30, 33, 477–486)
		Signals through TIE2 and integrin αvβ5
		Improves glucose tolerance
		Regulates atherosclerosis
		Regulates cancer growth and metastasis
		Regulates inflammation
		Regulates vascular development and functions
		Increases angiogenesis
		Increases lymphangiogenesis
		Increases wound healing
		Decreases body weight gain
Proteins	Angiopoietin 2 (ANG2)	Extracellular, secreted	(27, 28, 31, 482, 483, 485, 487–494)
		Signals through TIE2, integrin α3β1, and integrin α5β1
		Improves glucose tolerance and lipid metabolism
		Regulates atherosclerosis
		Regulates cancer growth and metastasis
		Regulates inflammation
		Regulates vascular development and functions
		Increases angiogenesis
		Increases lymphangiogenesis
		Decreases fibrosis
Proteins	Angiopoietin-like protein 2 (ANGPTL2)	Intracellular and extracellular, secreted	(34, 35, 37, 38, 495–503)
		Signals through LILRB2 and integrin α5β1
		Binds the G protein-coupled angiotensin receptor 1 (AGTR1) (intracellular)
		Furthers glucose intolerance and insulin resistance (chronic exposure)
		Regulates vascular functions
		Regulates hematopoiesis
		Increases atherosclerosis (chronic exposure)
		Increases cancer development, growth, and metastasis
		Increases inflammation
		Increases tissue integrity (acute exposure)
		Decreases tissue integrity (chronic exposure)
Proteins	Angiopoietin-like protein 4 (ANGPTL4)	Extracellular, secreted	(39, 43, 44, 53, 54)
		Inhibits LPL and pancreatic lipase
		Cleavage fragments may have signaling functions
		May further glucose intolerance and insulin resistance
		Regulates lipid trafficking
		May increase atherosclerosis
		May increase inflammation
		Decreases lipoprotein breakdown in adipose tissue during fasting
Proteins	Angiopoietin-like protein 8 (ANGPTL8)	Extracellular, secreted	(39, 50–52)
		Acts in concert with ANGPTL3
		Inhibits LPL and endothelial lipase
		May further insulin resistance
		Regulates lipid trafficking
		Decreases lipoprotein breakdown in nonadipose tissues during feeding
Proteins	Apelin (APLN)	Extracellular, secreted	(504–506, 507–518)
		Signals through G protein-coupled APLN receptor (APLNR)
		Improves glucose tolerance and insulin sensitivity
		Maintains cardiac functions
		Regulates fluid homeostasis
		May regulate bone mass
		Increases adipocyte and skeletal muscle cell glucose uptake
		Increases adipose tissue thermogenesis
		Increases angiogenesis
		Increases energy expenditure
		Increases lymphangiogenesis
		Increases skeletal muscle cell mitochondrial biogenesis and fatty acid oxidation
		Increases white adipocyte browning
		Decreases adipose tissue stromal cell adipogenesis
		Decreases blood pressure
		Decreases body weight
		May decrease adipocyte lipolysis
		May decrease inflammation
		May decrease liver steatosis
Proteins	Autotaxin (ATX)	Extracellular, secreted	(229, 236, 240–245)
		Exhibits PLD activity
		Generates most extracellular LPAs
Proteins	Bone morphogenic protein 2 (BMP2)	Extracellular, secreted	(59, 65, 67, 519–526)
		Signals through ALK3 or ALK6 in complex with BMPR2, ACVR2a, or ACVR2b
		Maintains bone functions
		Regulates embryonic development
		May regulate cancer development, growth, metastasis, and chemoresistance
		May skew adipogenesis toward either white or brown phenotype
		Increases adipose tissue stromal cell adipogenesis
Proteins	Bone morphogenic protein 3B (BMP3B)	Extracellular, secreted	(65, 79, 80, 527–529)
		Signals through ALK4 in complex with ACVR2a or ACVR2b
		Improves glucose tolerance and insulin sensitivity
		Maintains neural functions
		Regulates bone development
		Increases activity
		Increases BAT activity
		Increases energy expenditure
		Increases food intake
		Decreases adipose tissue stromal cell adipogenesis
		Decreases body weight gain
		May decrease bone mass
Proteins	Bone morphogenic protein 4 (BMP4)	Extracellular, secreted	(59, 65, 67, 68, 76–78, 530–534)
		Signals through ALK3 or ALK6 in complex with BMPR2, ACVR2a, or ACVR2b
		Improves glucose tolerance and insulin sensitivity
		Regulates embryonic development
		May regulate cancer development, growth, metastasis, and chemoresistance
		May skew adipose tissue stromal cell adipogenesis toward either white or brown phenotype
		Increase adipose tissue stromal cell adipogenesis
		Increases angiogenesis
		Increases BAT whitening
		Increases energy expenditure
		Increases food intake
		Increases WAT browning
		Increases WAT thermogenesis
		Decreases body weight gain
		Decreases brown adipocyte lipolysis
		Decreases BAT thermogenesis
Proteins	Bone morphogenic protein 8B (BMP8B)	Extracellular, secreted	(65, 81, 82, 535–537)
		Signals through ALK2, ALK3, or ALK6 in complex with BMPR2, ACVR2a, or ACVR2b
		Maintains reproductive functions
		Increases adipocyte lipolysis
		Increases adipose tissue thermogenesis
		Increases angiogenesis
		Increases brain sympathetic output to adipose tissue
		Increases energy expenditure
		Increases WAT browning
		May increase food intake
		Decreases body weight gain
Proteins	C1q/TNF-related protein 3 (CTRP3)	Extracellular, secreted	(538, 539–550)
		May inhibit signaling of bacterial lipopolysaccharide (LPS) through toll-like receptor 4 (TLR4)
		May bind lysosomal-associated matrix protein 1 (LAMP1) and lysosome membrane protein 2 (LIMP2)
		May improve insulin sensitivity
		Maintains cardiac and reproductive functions
		May maintain vascular functions
		May regulate fibrosis
		May regulate liver size
		Increases angiogenesis
		Increases cardiac muscle cell survival
		May increase bone mass
		May increase skeletal muscle stromal cell proliferation
		Decreases adipose tissue stromal cell adipogenesis
		Decreases inflammation
		Decreases liver gluconeogenesis
		Decreases liver steatosis
		May decrease skeletal muscle stromal cell myogenesis
Proteins	Chemerin	Extracellular, secreted	(92–94, 106, 109–116)
		Signals through G protein-coupled CMKLR1 and GPR1
		Binds chemokine (C-C motif) receptor-like 2 (CCRL2)
		Acts as immune cell chemoattractant
		Impairs vascular functions
		May regulate adipose tissue stromal cell adipogenesis
		May regulate glucose tolerance and insulin sensitivity
		Increases bone mass loss
		Increases skeletal muscle cell insulin resistance
Proteins	Chemokine (C-C motif) ligand 2/monocyte chemoattractant protein 1 (CCL2/MCP1)	Extracellular, secreted	(551, 552–563)
		Signals through G protein-coupled chemokine (C-C motif) receptor 2 (CCR2)
		Binds Duffy antigen/chemokine receptor (DARC)
		May further glucose intolerance and insulin resistance
		Acts as immune cell chemoattractant
		Regulates immune cell functions
		May regulate body weight gain
		Increases angiogenesis
		Increases cancer growth and metastasis
		Increases inflammation
		Increases liver steatosis
		Increases wound healing
		Decreases adipocyte and skeletal muscle cell glucose uptake
Proteins	Complement factor D/adipsin (CFD)	Extracellular, secreted	(564, 565, 566–573)
		Cleaves complement factor B (CFB) in complex with complement factor 3b (C3b), yielding the C3 convertase (C3bBb) of the alternative pathway of complement activation
		Accelerates C3 cleavage, C3a and C3b generation, as well as C3a signaling through G protein-coupled C3a receptor (C3aR)
		Improves glucose tolerance
		Fulfills crucial functions in immune defense
		Increases adipose tissue stromal cell adipogenesis
		Increases β-cell glucose-stimulated insulin secretion
		Increases cancer stemness and growth
Proteins	Dipeptidyl peptidase 4 (DPP4)	Extracellular, membrane-bound and secreted	(574, 575, 576–587)
		Exhibits serine protease activity, processing a variety of other Proteins
		Binds and/or signals through adenosine deaminase (ADA), caveolin 1 (CAV1), caspase recruitment domain-containing protein 11 (CARD11), dipeptidyl peptidase fibroblast activation protein α (FAPα), and others (membrane-bound)
		Binds and/or signals through mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) and G protein-coupled protease-activated receptor 2 (PAR2) (secreted)
		Binds different extracellular matrix components
		Furthers glucose intolerance and insulin resistance
		Alters gastrointestinal microbiome
		Impairs β-cell functions
		Impairs gastrointestinal functions
		May impair cardiac and vascular functions
		Regulates immune cell functions
		May regulate bone mass
		Increases adipose tissue stromal cell proliferation
		Increases atherosclerosis
		Increases body weight gain
		Increases cancer development
		Increases fibrosis
		Increases inflammation
		Increases liver steatosis
		Decreases adipocyte, skeletal muscle cell, and vascular smooth muscle cell insulin sensitivity
		Decreases adipose tissue thermogenesis
		Decreases energy expenditure
		Decreases white adipocyte browning
Proteins	endotrophin (ETP)	Extracellular, generated	(118, 123–129, 588)
		C-terminal cleavage fragment of COL6A3
		Furthers glucose intolerance and insulin resistance
		Increases angiogenesis
		Increases cancer growth, metastasis, and chemoresistance
		Increases fibrosis
		Increases inflammation
		Increases liver steatosis
		May increase adipose tissue stromal cell adipogenesis
		Decreases energy expenditure
		May decrease adipocyte lipolysis
Proteins	Fatty acid binding protein 4 (FABP4)	Intracellular and extracellular, secreted	(589, 590, 591–602)
		Binds diverse lipids
		Binds hormonse-sensitive lipase (HSL), PPARγ, and keratin 1 (KRT1) (intracellular)
		Furthers glucose intolerance and insulin resistance
		May maintain brown adipocyte thermogenesis
		Regulates immune cell functions
		Regulates lipid trafficking
		Regulates lipolysis
		Increases angiogenesis
		Increases atherosclerosis
		Increases β-cell glucose-stimulated insulin secretion
		Increases cancer growth and metastasis
		Increases cardiac dysfunction
		Increases inflammation
		Increases liver steatosis
		Decreases adipose tissue stromal cell adipogenesis
Proteins	Fibroblast growth factor 21 (FGF21)	Extracellular, secreted	(130, 134–136, 140, 141, 147, 151–155, 158)
		Signals through FGFR1c and FGFR3c in complex with β-klotho
		Binds FGFR4 in complex with β-klotho
		Improves glucose tolerance and insulin sensitivity (not in humans)
		Regulates circadian rhythm
		Regulates brain sympathetic output to different tissues
		Increases adipose tissue glucose and fatty acid uptake, mitochondrial activity, and thermogenesis
		Increases β-cell glucose-stimulated insulin secretion (acute exposure)
		Increases bone mass loss
		Increases energy expenditure
		Increases hepatocyte fatty acid oxidation
		Increases life span
		Increases liver gluconeogenesis (acute exposure)
		Decreases β-cell glucose-stimulated insulin secretion (chronic exposure)
		Decreases body weight
		Decreases bone mass
		Decreases circulating triglycerides
		Decreases food intake
		Decreases growth
		Decreases hepatocyte lipogenesis
		Decreases liver gluconeogenesis (chronic exposure)
		Decreases liver glycogenolysis
		Decreases sugar and alcohol intake
Proteins	Intelectin 1/omentin (INTL1/OMT)	Extracellular, secreted	(603, 604–615)
		Scarcely expressed in mouse adipose tissue
		Binds bacterial glycans
		Binds lactoferrin (LF)
		May partake in bacterial surveillance
		Maintains bone mass
		Maintains cardiac and vascular functions
		Increases adipocyte insulin sensitivity
		Increases adipose tissue stromal cell proliferation and survival
		May increase cancer cell death
		Decreases angiogenesis
		Decreases atherosclerosis
		Decreases inflammation
		May decrease cancer growth
Proteins	Interleukin 1β (IL1β)	Intracellular and extracellular, secreted or generated	(616–618, 619–630)
		Generated from pro-IL1β by the NLRP1, NLRP3, NLR family CARD domain-containing 4 (NLRC4), and absent in melanoma 2 (AIM2) inflammasomes
		Alternatively generated from pro-IL1β by various proteases such as proteinase 3 (PRTN3), granzyme A (GZMA), cathepsin G (CG), elastases, chymases, or chymotrypsin
		Signals through IL1 receptor α (IL1Rα) in complex with IL1 receptor accessory protein (IL1RAP)
		Binds IL1 receptor β (IL1Rβ) either alone or in complex with IL1RAP
		Binds soluble IL1Rα
		Binds soluble IL1β either alone or in complex with IL1RAP
		Furthers glucose intolerance and insulin resistance
		Impairs β-cell functions
		Regulates immune cell functions
		May regulate brain sympathetic output to different tissues
		Increases activity
		Increases adipocyte insulin resistance and lipolysis
		Increases β-cell death
		Increases body temperature
		Increases BAT activity
		Increases energy expenditure
		Increases inflammation
		Increases liver steatosis
		May increase adipose tissue stromal cell proliferation
		Decreases adipocyte glucose uptake
		Decreases adipose tissue stromal cell adipogenesis
		Decreases body weight
		May decrease adipose tissue lipid uptake
		May decrease gastrointestinal lipid uptake
Proteins	Interleukin 4 (IL4)	Extracellular, secreted	(631, 632–643)
		Signals through IL4 receptor α (IL4Rα) in complex with IL2 receptor γ (IL2Rγ) or IL13 receptor α1 (IL13Rα1)
		Binds soluble IL4Rα
		Improves glucose tolerance and insulin sensitivity
		Skews adipose tissue stromal cell adipogenesis toward brown phenotype
		Regulates adipocyte lipolysis
		Regulates adipose tissue and skeletal muscle stromal cell adipogenesis
		Regulates body weight gain
		Regulates immune cell functions
		Regulates inflammation
		May regulate atherosclerosis
		Increases WAT browning
		May increase adipose tissue stromal cell proliferation
		May increase energy expenditure
Proteins	Interleukin 6 (IL6)	Extracellular, secreted	(198, 644–654)
		Signals through glycoprotein 130 (GP130) in complex with membrane-bound or soluble IL6 receptor (IL6R)
		Binds soluble GP130 and soluble IL6R
		Regulates α- and β-cell functions
		Regulates body weight
		Regulates glucose tolerance and insulin sensitivity
		Regulates immune cell functions
		Regulates inflammation
		Regulates liver steatosis
		Increases adipocyte lipolysis
		Increases body temperature
		Increases cancer development, growth, metastasis, and chemoresistance
		Increases energy expenditure
		Increases skeletal muscle cell fatty acid oxidation
		Increases WAT browning
		Decreases activity
		Decreases food intake
Proteins	Interleukin 10 (IL10)	Extracellular, secreted	(558, 645, 650, 655, 656–664)
		Signals through through IL10 receptor α (IL10Rα) in complex with IL10 receptor β (IL10Rβ)
		Maintains cardiac functions
		Regulates glucose tolerance and insulin sensitivity
		Regulates immune cell functions
		Regulates liver steatosis
		May regulate body weight gain
		May increase cancer stemness, growth, and chemoresistance
		Decreases fibrosis
		Decreases inflammation
		May decrease adipose tissue stromal cell adipogenesis
		May decrease adipose tissue thermogenesis
		May decrease energy expenditure
		May decrease WAT browning
Proteins	Leptin (LEP)	Extracellular, secreted	(5, 9, 665, 666, 667–677)
		Signals through leptin receptor isoform b (LEPRb)
		Binds short and soluble leptin receptor isoforms (e.g. LEPRa)
		Informs brain on long-term energy stores
		Regulates body weight gain
		Regulates bone mass
		Regulates brain sympathetic output to different tissues
		Regulates food intake and energy expenditure
		Regulates glucose tolerance and insulin sensitivity
		Regulates immune cell functions
		Regulates reproduction
		May regulate body temperature
		May regulate hematopoiesis
		Increases adipocyte lipolysis
		Increases adipocyte, hepatocyte, and skeletal muscle cell fatty acid oxidation
		Increases angiogenesis
		Increases BAT activity
		Increases inflammation
		Increases skeletal muscle cell glucose uptake
		Increases wound healing
		May increase adipose tissue stromal cell proliferation
		May increase blood pressure
		May increase WAT browning
		Decreases adipocyte glucose uptake
		Decreases adipocyte, hepatocyte, and skeletal muscle cell lipogenesis
Proteins	Lipocalin 2 (LCN2)	Intracellular and extracellular, secreted	(167, 173, 174, 178, 183–187, 190, 192–194)
		Binds iron-chelating siderophores
		Binds LCN2 receptor and LRP2
		Regulates intracellular iron stores
		May regulate adipose tissue stromal cell adipogenesis
		May regulate adipocyte glucose uptake
		May regulate body weight gain
		May regulate BAT activity
		May regulate fibrosis
		May regulate glucose tolerance and insulin sensitivity
		May regulate liver steatosis
		May regulate vascular functions
Proteins	Neuregulin 4 (NRG4)	Extracellular, membrane-bound and secreted	(200, 201, 203–205, 212, 213, 678, 679)
		Signals through ErbB4
		Improves glucose tolerance and insulin sensitivity
		Maintains neural functions
		May regulate immune functions
		Increases angiogenesis
		May increase BAT activity
		May increase hepatocyte survival
		Decreases body weight gain
		Decreases hepatocyte lipogenesis
		Decreases inflammation
		Decreases liver steatosis
		May decrease fibrosis
Proteins	Nicotinamide phosphoribosyltransferase/visfatin (NAMPT)	Intracellular and extracellular, secreted	(680–682, 683–694)
		Generates nicotinamide mononucleotide (NMN) for NAD synthesis (intracellular)
		Acts as immune cell chemoattractant (extracellular)
		Regulates body weight gain
		Regulates food intake
		Regulates glucose tolerance and insulin sensitivity
		Regulates inflammation
		Increases β-cell glucose-stimulated insulin secretion
		Increases brown adipocyte thermogenesis
		Increases cancer growth and chemoresistance
		Increases immune cell survival
		Increases physical activity
		Decreases fibrosis
		Decreases liver steatosis
Proteins	Resistin (RETN)	Extracellular, secreted	(695, 696–707)
		May bind and/or signal through TLR4, cleaved decorin (cDCN), receptor tyrosine kinase-like orphan receptor 1 (ROR1), and adenylyl cyclase-associated protein 1 (CAP1)
		Expressed in mouse adipocytes, but scarcely expressed in human adipocytes
		May be expressed in human immune cells
		Furthers glucose intolerance and insulin resistance (not in humans)
		May regulate brain sympathetic output to different tissues
		Increases adipocyte lipolysis
		Increases angiogenesis
		Increases atherosclerosis
		Increases inflammation
		May increase adipose tissue stromal cell proliferation
		Decreases adipocyte and skeletal muscle cell glucose uptake
		Decreases adipocyte insulin sensitivity
		Decreases adipose tissue stromal cell adipogenesis
Proteins	Retinol-binding protein 4 (RBP4)	Extracellular, secreted	(708, 709–720)
		Binds retinol
		Binds and signals through stimulated by retinoic acid 6 (STRA6)
		Binds RBP4 receptor 2 (RBPR2)
		Signals through TLR4
		May further glucose intolerance and insulin resistance
		Regulates adipose tissue stromal cell adipogenesis
		Regulates immune cell functions
		Increases cancer stemness and growth
		Increases inflammation
		May increase blood pressure
		May increase liver steatosis
		May increase mitochondrial dysfunction
		Decreases adipocyte insulin sensitivity
Proteins	Secreted frizzled-related protein 5 (SFRP5)	Extracellular, secreted	(721, 722–731)
		Inhibits wingless-related integration site (WNT)5a, WNT5b, and WNT11
		May exhibit additional signaling capacities
		May bind different extracellular matrix components
		Maintains cardiac and vascular functions
		May regulate adipocyte insulin sensitivity
		May regulate adipocyte mitochondrial function
		May regulate adipose tissue stromal cell adipogenesis
		May regulate body weight gain
		May regulate glucose tolerance and insulin sensitivity
		Increases angiogenesis
		Decreases β-cell proliferation
		Decreases inflammation
		Decreases liver steatosis and fibrosis
Proteins	Serine protease inhibitor A12/vaspin (SERPINA12/VASP)	Extracellular, secreted	(732, 733–744)
		Inhibits kallikrein 7 (KLK7)
		May inhibit acetylcholine esterase (AChE)
		Signals through GRP78 in complex with DnaJ heat shock protein family member C1 (DNAJC1) and/or voltage-dependent anion channel (VDAC)
		Binds different extracellular matrix components
		Improves glucose tolerance and insulin sensitivity
		Maintains vascular functions
		Maintains β-cell functions
		Increases adipose tissue stromal cell adipogenesis
		Increases skeletal muscle cell glucose uptake and insulin sensitivity
		Increases β-cell glucose-stimulated insulin secretion
		May increase bone mass
		Decreases atherosclerosis
		Decreases food intake
		Decreases ER stress
		Decreases inflammation
		Decreases liver steatosis
Proteins	Serine protease inhibitor E1/plasminogen activator inhibitor 1 (SERPINE1/PAI1)	Extracellular, secreted	(278, 745, 746, 747–757)
		Inhibits tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA)
		Signals through LRP1
		Binds and signals through uPA in complex with uPA receptor (uPAR) and LRP1
		Binds vitronectin and inhibits its binding and signaling through integrin αVβ3, integrin αVβ5, and uPAR
		May further glucose intolerance and insulin resistance
		Maintains cellular senescence
		Regulates angiogenesis
		Regulates cancer growth and metastasis
		Regulates cell migration
		Regulates wound healing
		May regulate adipose tissue stromal cell adipogenesis
		May regulate bone mass
		May regulate ceramide metabolism
		Increases atherosclerosis
		May increase body weight gain
		May increase inflammation
		Decreases fibrinolysis
		Decreases hematopoiesis
		Decreases life span
		May decrease adipocyte glucose uptake
Proteins	Serine protease inhibitor F1/pigment epithelium-derived factor (SERPINF1/PEDF)	Extracellular, secreted	(758, 759, 760–771)
		May be intracellular
		No known protease inhibitory functions
		Binds and/or signals through PEDF receptor/adipose tissue triglyceride lipase (PEDFR/ATGL), laminin receptor (LAMR), LRP6, and plexin domain-containing protein (PLXDC)1 and PLXDC2
		Inhibits cell surface F1-ATPase
		May regulate PPARα (intracellular)
		Binds different extracellular matrix components
		Maintains neuronal functions
		Regulates fibrosis
		Regulates immune cell functions
		Regulates inflammation
		May regulate glucose tolerance and insulin sensitivity
		Increases adipocyte, hepatocyte, and skeletal muscle cell lipolysis
		Increases cancer cell death and differentiation
		Decreases adipose tissue stromal cell adipogenesis
		Decreases angiogenesis
		Decreases cancer growth and metastasis
		Decreases liver steatosis
Proteins	Serum amyloid A3 (SAA3)	Extracellular, secreted	(772, 773–783)
		Not expressed in humans
		Signals through TLR2 and TLR4
		May bind to HDL
		Acts as immune cell chemoattractant
		May regulate immune cell functions
		May increase body weight gain
		May increase inflammation
		May increase liver steatosis
Proteins	Transforming growth factor β (TGFβ)	Extracellular, secreted	(784–786, 787–793)
		Signals through ALK1, ALK2, ALK3, or ALK5 in complex with TGFβ receptor 2 (TGFBR2)
		Binds connective tissue growth factor (CTGF)
		Binds different extracellular matrix components
		Furthers glucose intolerance and insulin resistance
		Increases adipose tissue stromal cell proliferation
		Increases fibrosis
		Increases inflammation
		Increases liver steatosis
		Decreases adipocyte fatty acid oxidation
		Decreases adipose tissue stromal cell adipogenesis
		Decreases adipose tissue thermogenesis
Proteins	TNF ligand superfamily member 10/TNF-related apoptosis-inducing ligand (TNFSF10/TRAIL)	Extracellular, membrane-bound and secreted	(794, 795, 796–807)
		Signals through TRAIL receptor (TRAILR)1 and TRAILR2
		Binds TRAILR3, TRAILR4, and osteoprotegerin (OPG)
		Improves glucose tolerance and insulin sensitivity
		Regulates adipocyte metabolism
		Regulates immune cell functions
		Increases adipose tissue stromal cell proliferation
		Increases adipose tissue stromal cell and adipocyte inflammation
		Decreases adipose tissue stromal cell adipogenesis
		Decreases atherosclerosis
		Decreases body weight
		Decreases liver steatosis
		Decreases systemic inflammation
Proteins	TNF ligand superfamily member 2/TNFα (TNFSF2/TNFA)	Extracellular, membrane-bound and secreted	(802, 808–810, 811–821)
		Signals through TNF receptor (TNFR)1 and TNFR2
		Furthers glucose intolerance and insulin resistance
		Regulates immune cell functions
		Increases adipocyte lipolysis
		Increases adipose tissue stromal cell proliferation
		Increases atherosclerosis
		Increases body weight loss
		Increases ER stress
		Increases inflammation
		Increases mitochondrial dysfunction
		Decreases adipose tissue stromal cell adipogenesis
		Decreases adipose tissue thermogenesis
Proteins	TNF ligand superfamily member 6/Fas ligand (TNFSF6/FASL)	Extracellular, membrane-bound and secreted	(802, 822, 823–827)
		Signals through FAS
		Furthers glucose intolerance and insulin resistance
		Regulates immune cell functions
		Increases adipocyte insulin resistance
		Increases adipose tissue stromal cell proliferation
		Increases body weight
		Increases brown adipocyte lipolysis
		Increases inflammation
		Increases liver steatosis
		Increases mitochondrial dysfunction
Proteins	Vascular endothelial growth factor A (VEGFA)	Extracellular, secreted	(828, 829, 830–841)
		Maybe intracellular
		Signals through VEGF receptor (VEGFR)1 and VEGFR2
		May bind to neuropilin 1 (NRP1)
		May bind different extracellular matrix components
		Regulates glucose tolerance and insulin sensitivity
		Regulates vascular permeability
		May regulate adipose tissue stromal cell osteogenesis and adipogenesis
		Increases adipose tissue stromal cell proliferation
		Increases angiogenesis
		Increases brown adipocyte mitochondrial function and survival
		Increases energy expenditure
		Increases vasculogenesis
		Increases white adipocyte browning
		Increases white adipocyte lipolysis
		Increases WAT sympathetic innervation
		Increases WAT vascularization
		May increase inflammation
Proteins	Vascular endothelial growth factor D (VEGFD)	Extracellular, secreted	(828, 829, 842–845)
		Signals through VEGFR2 and VEGFR3
		Acts as immune cell chemoattractant
		Regulates glucose tolerance and insulin sensitivity
		Regulates lymphangiogenesis
		Regulates WAT inflammation
		May regulate liver steatosis
		May regulate vascular permeability
		May increase angiogenesis
		May increase vasculogenesis
Proteins	Xanthine oxidoreductase (XOR)	Intracellular and extracellular, secreted	(371, 372, 376, 379, 384, 403, 404, 405, 409–414)
		Exhibits dehydrogenase and oxidase activities
		Interconvertible dehydrogenase and oxidase forms (XDH and XO)
		Generates uric acid
		Can generate reactive oxygen and nitrogen species
		Regulates adipose tissue stromal cell adipogenesis
Lipids	12,13-Dihydroxy-9Z-octadecenoic acid (12,13-diHOME)	Intracellular and extracellular	(846–849)
		Generated from linoleic acid by combined activity of cytochrome P450 oxidases (CYPs) and epoxide hydrolase (EH)1-4
		May act as peroxisome PPARγ ligand (intracellular)
		Regulates immune cell functions
		Increases brown adipocyte and skeletal muscle cell fatty acid uptake and oxidation
		Increases BAT and skeletal muscle lipid uptake
		Decreases atherosclerosis
Lipids	2-Arachidonoylglycerol (2-AG)	Intracellular and extracellular	(850, 851, 852–863)
		Generated from arachidonic acid (AA)-containing diacylglycerols (DAG) by DAG lipases (DAGL)
		Signals through G protein-coupled cannabinoid receptor (CB)1 and CB2, GPR55, and transient receptor potential cation channel subfamily V member 1 (TRPV1)
		Binds to FABP3, FABP5, and FABP7
		May act as PPARα and/or PPARγ ligand (intracellular)
		Acts as immune cell chemoattractant
		Regulates brain sympathetic output to different tissues
		Regulates glucose tolerance and insulin sensitivity
		Regulates immune cell functions
		Regulates social and food reward
		Increases adipocyte insulin sensitivity and glucose uptake
		Increases adipose tissue stromal cell adipogenesis
		Increases atherosclerosis
		Increases β-cell glucose-stimulated insulin secretion
		Increases body weight
		Increases food intake
		Increases gastrointestinal energy absorption
		Increases liver steatosis
		Decreases adipose tissue thermogenesis
		Decreases energy expenditure
		Decreases mitochondrial biogenesis
		Decreases white adipocyte browning
		Decreases WAT, liver, and skeletal muscle glycogenesis
Lipids	4-Hydroxynonenal (4-HNE)	Intracellular and extracellular	(864–866, 867–878)
		Generated from unsaturated lipid acyl chains by reactive oxygen species-mediated peroxidation followed by nonenzymatic decomposition
		Strong electrophile that covalently modifies lipids, Proteins, and nucleic acids
		May further glucose intolerance and insulin resistance
		Increases apoptosis
		Increases autophagy
		Increases body weight gain
		Increases ER stress
		Increases mitochondrial dysfunction
		Increases mitophagy
		Increases oxidative stress
		Decrease β-cell glucose-stimulated insulin secretion
		Decreases adipose tissue and skeletal muscle insulin sensitivity
		Decreases adipose tissue stromal cell adipogenesis
		Decreases adipose tissue stromal cell proliferation
Lipids	Ceramide-1-phosphates (C1Ps)	Intracellular and extracellular	(251, 296, 345, 879–886)
		Generated from ceramides by CERK
		Stimulate AA-releasing cytosolic PLA2α
		Inhibit TNF-releasing TACE
		Inhibit acid SMase
		Bind to C1P transfer protein (CPTP)
		Further glucose intolerance
		Regulate immune cell functions
		Regulate inflammation
		Increase body weight gain
		Increase inflammation
Lipids	Ceramides	Intracellular and extracellular	(251, 256, 261, 264, 268, 273, 290, 296, 297, 299, 301–304, 316)
		Generated by multiple mechanisms, de novo synhesis and salvage
		Stimulate PP1, PP2A, and PP2C
		Stimulate PKCζ
		Stimulate the NLRP3 inflammasome
		Bind ceramide transfer protein (CERT)
		Further glucose intolerance and insulin resistance
		Increase cancer development
		Increase ER stress
		Increase inflammation
		Increase liver steatosis
		Increase mitochondrial dysfunction
		Increase cell death (various cell types)
		Decrease adipose tissue stromal cell adipogenesis
		Decrease adipose tissue thermogenesis
		Decrease β-cell glucose-stimulated insulin secretion
		Decrease insulin sensitivity (various cell types)
		Decrease WAT browning
Lipids	cis-Palmitoleic acid	Intracellular and extracellular	(311, 887–889, 890–900)
		Generated from palmitate by stearoyl-CoA desaturase 1 (SCD1)
		Alternatively generated from stearate or cis-oleate by desaturation and/or chain shortening
		Inhibits SCD1
		Improves glucose tolerance and insulin sensitivity
		Maintains cardiac and vascular functions
		May regulate liver steatosis
		Increases β-cell proliferation and glucose-stimulated insulin secretion
		Increases hepatocyte and skeletal muscle cell insulin sensitivity
		Increases hepatocyte, skeletal muscle cell, and β-cell survival
		May increase adipocyte and skeletal muscle cell glucose uptake
		May increase adipose tissue stromal cell proliferation and survival
		May increase cancer growth
		Decreases atherosclerosis
		Decreases inflammation
Lipids	Glucosylceramides	Intracellular and extracellular	(251, 337–344)
		Generated from ceramides by GCS
		Bind pleckstrin homology domain-containing family A member 8 (PLEKHA8)
		Substrate for complex glycosphingolipid synthesis
		May further glucose intolerance and insulin resistance
		May increase fibrosis
		May increase inflammation
Lipids	Lysophosphatidic acids (LPAs)	Intracellular and extracellular	(223, 224, 226, 227, 229–231, 233, 236, 238, 239)
		Generated by multiple mechanisms
		Signal through G protein-coupled LPAR1–6 (extracellular)
		May act as PPARγ ligands (intracellular)
		Intermediates of glyceroplipid synthesis
		Further glucose intolerance and insulin resistance
		Increase adipose tissue stromal cell proliferation
		Decrease adipose tissue stromal cell adipogenesis
		Decrease β-cell glucose-stimulated insulin secretion
Lipids	Palmitic acid	Intracellular and extracellular	(628, 901–903, 904–914)
		Taken up from ingested food (exogenous)
		Also generated by multiple mechanisms (endogenous)
		Signals through GPR40
		Signals through TLR4 (high exposure)
		Also stimulates different PKC isoforms (e.g., PKCε and PKCθ) (likely indirect, high exposure)
		Also stimulates PKR (likely indirect, high exposure)
		Also stimulates the NLRP3 inflammasome (likely indirect, high exposure)
		Binds diverse FABPs, fatty acid transport proteins (FATPs), and fatty acid translocase (FAT)
		Affects lipid membrane properties (e.g., fluidity and permeability)
		Prime substrate for ceramide synthesis
		Substrate for energy generation
		Substrate for structural component and signaling mediator synthesis
		Regulates glucose tolerance and insulin sensitivity
		Regulates immune cell functions
		May regulate adipose tissue stromal cell proliferation and adipogenesis
		May regulate atherosclerosis
		May regulate body weight gain
		May regulate energy expenditure
		May regulate food intake
		May regulate liver steatosis
		Increases β-cell glucose-stimulated insulin secretion (low exposure)
		Increases cell death (various cell types, high exposure)
		Increases ceramide generation (high exposure)
		Increases enteroendocrine cell hormone release (low exposure)
		Increases ER stress (high exposure)
		Increases inflammation (high exposure)
		Increases mitochondrial dysfunction (high exposure)
		Increases oxidative stress (high exposure)
Lipids	Palmitic acid ester of 5-hydroxystearic acid (5-PAHSA)	Intracellular and extracellular	(215–221, 222)
		Produced by unknown mechanisms
		May signal through GPR40 and GPR120
		May improve glucose tolerance and insulin sensitivity
		May increase adipose tissue stromal cell adipogenesis
		May increase adipocyte glucose uptake
		May increase β-cell glucose-stimulated insulin secretion
		May increase L-cell GLP1 secretion
		May decrease inflammation
Lipids	Palmitic acid ester of 9-hydroxystearic acid (9-PAHSA)	Intracellular and extracellular	(215–221, 222)
		Produced by unknown mechanisms
		May signal through GPR40 and GPR120
		May improve glucose tolerance and insulin sensitivity
		May increase adipose tissue stromal cell adipogenesis
		May increase adipocyte glucose uptake
		May increase β-cell glucose-stimulated insulin secretion
		May increase L-cell GLP1 secretion
		May decrease inflammation
Lipids	Prostaglandin E2 (PGE2)	Intracellular and extracellular	(915, 916–927)
		Generated from AA by combined activity of cyclooxygenase (COX)1 and COX2 and PGE synthase (PGES)1, PGES2, or PGES3
		Signals through G protein-coupled PGE receptor (EP)1-4
		May improve glucose tolerance and insulin sensitivity
		Regulates atherosclerosis
		Regulates fibrosis
		Regulates immune cell functions
		Regulates inflammation
		Regulates liver steatosis
		May regulate lipid trafficking
		Skews adipose tissue stromal cell adipogenesis toward brown phenotype
		May increase activity
		May increase BAT activity
		May increase WAT browning
		Decreases adipose tissue stromal cell adipogenesis
		Decreases white adipocyte lipolysis
		May decrease body weight gain
		May decrease food intake
Lipids	Sphingomyelins	Intracellular and extracellular	(251, 262, 289, 331–334, 335, 336)
		Generated from ceramides by SMSs
		May regulate adipose tissue development
		May regulate glucose tolerance and insulin sensitivity
		May regulate liver steatosis
		May regulate mitochondrial functions
Lipids	Sphingosine-1-phosphate (S1P)	Intracellular and extracellular	(251, 276, 296, 348–350, 353, 355–357, 360, 361, 363, 365)
		Generated from sphingosine by sphingosine kinases
		Signals through G protein-coupled S1PR1–5
		Also stimulates CIAP2
		Also stimulates TRAF2
		Also inhibits HDAC1 and HDAC2
		May regulate glucose tolerance and insulin sensitivity
		May regulate vascular functions
		May regulate liver steatosis
		May increase adipose tissue stromal cell proliferation
		May increase β-cell glucose-stimulated insulin secretion
		May increase hepatocyte and skeletal muscle cell glucose uptake
		May increase hepatocyte and β-cell survival
		May increase hepatocyte lipogenesis
		May increase inflammation
		May decrease adipose tissue stromal cell adipogenesis
Metabolites	Uric acid	Intracellular and extracellular	(371, 372, 376, 379, 385, 393, 395–402)
		Product of purine base degradation
		Acts as anti-oxidant (extracellular)
		Acts as pro-oxidant (intracellular)
		Stimulates the NLRP3 inflammasome (intracellular)
		Stimulates NOX (intracellular)
		Furthers glucose intolerance and insulin resistance
		Impairs vascular and kidney functions
		Increases blood pressure
		Increases inflammation
		Increases liver steatosis
		Increases mitochondrial dysfunction
Metabolites	Uridine	Intracellular and extracellular	(418, 419, 421, 424–429)
		May require metabolism for signaling
		Substrate for RNA and DNA synthesis
		Substrate for glycogen deposition
		Substrate for protein and lipid glycosylation
		Improves glucose tolerance (acute exposure)
		May regulate glucose tolerance and insulin sensitivity (chronic exposure)
		Essential for fasting-induced decrease in body temperature (acute exposure)
		Increases body weight gain (chronic exposure)
		May increase body temperature (low concentration exposure)
		May increase cancer development (chronic exposure)
		May increase liver steatosis (chronic exposure)
		Decreases body temperature (high concentration)
		Decreases energy expenditure (acute exposure)

References in bold indicate reviews.

Adipose tissue forms circumscribed depots in the body that differ in their cellular composition and character (24, 25). Whereas dermal, subcutaneous, and visceral depots exist in both humans and mice, the occurrence of depots in the bone marrow, skeletal muscle, and pancreas depends on several factors, including species, sex, age, and nutritional state (25). While the cellular differences between these adipose tissue depots immediately suggest quantitatively and possibly even qualitatively distinct patterns of adipokine secretion, thorough assessments of depot-specific production have been carried out for only few adipose tissue-derived factors.

Adipose tissue is highly dynamic and able to respond to changes in nutritional state (e.g., during feeding or fasting or with obesity) with acute and chronic adjustments in both its metabolism and cellularity (26). These metabolic and cellular adjustments are usually accompanied by pronounced shifts in adipokine secretion with immediate effects on systemic homeostasis (26). With obesity, such shifts in adipokine secretion may directly contribute to the development of insulin resistance, hepatic steatosis, type 2 diabetes, and cardiovascular disease (26).

PROTEINS

Angiopoietins and angiopoietin-like proteins

The family of angiopoietins (ANGs) and ANG-like proteins (ANGPTLs) consists of several structurally similar but functionally distinct proteins.

ANG1 and ANG2 regulate angiogenesis and vascular function and exert their effects by signaling through the tyrosine kinase with Ig and epidermal growth factor (EGF) homology domains 2 (TIE2) expressed by endothelial cells and certain populations of monocytes and macrophages, as well as integrins αvβ5, α3β1, and α3β1 expressed by a variety of cells (27, 28). Obesity and fasting decrease ANG1 and ANG2 expression in WAT, while cold exposure increases ANG2 expression in BAT (29–31). Overexpression of ANG1 from injected plasmid DNA slows the body weight gain in obese leptin-deficient ob/ob mice, whereas overexpression of a stabilized ANG1 variant from a viral vector reduces diabetic nephropathy and improves glucose tolerance in obese leptin receptor-deficient db/db mice (30, 32, 33). Inducing adipocyte-specific overexpression of ANG2 in mice elicits increased WAT angiogenesis and an anti-inflammatory secretion profile, offering protection from high-fat diet-induced obesity and improving glucose and lipid metabolism (31). Treating mice with an ANG2-neutralizing antibody conversely decreases WAT angiogenesis, increases WAT inflammation and fibrosis, and results in metabolic deterioration (31). ANG1 and ANG2 thus appear to have beneficial effects on systemic metabolism.

ANGPTL2 also affects vascular function, but does so in a TIE2-independent fashion by engaging integrin α5β1 and the leukocyte Ig-like receptor B2 (LILRB2) (34). ANGPTL2 expression in WAT and BAT is increased with hypoxia, ER stress, and obesity (35, 36). Its circulating levels correlate positively with adiposity and markers of inflammation and insulin resistance (35, 36). In mice, endothelial cell-specific overexpression of ANGPTL2 results in vascular dysfunction and facilitates vascular inflammation and atherosclerosis when combined with ApoE deficiency, whereas adipocyte-specific overexpression causes increased WAT inflammation, glucose intolerance, and insulin resistance (35, 37). ANGPTL2-deficient mice, in turn, exhibit improved insulin sensitivity and are protected from high-fat diet-induced metabolic and vascular deterioration (35, 37, 38). ANGPTL2 thus has detrimental effects on systemic metabolism, at least under the conditions tested.

ANGPTL3, ANGPTL4, and ANGPTL8 regulate triglyceride trafficking and metabolism (39). ANGPTL3 and ANGPTL8 act in concert to inhibit LPL and endothelial lipase, while ANGPTL4 acts alone to inhibit LPL and pancreatic lipase (39–41). ANGPTL3 and ANGPTL4 also undergo proteolytic cleavage, generating C-terminal fragments that may exert alternative signaling functions (42–44). ANGPTL3 is primarily produced by the liver, ANGPTL4 primarily by WAT and BAT, and ANGPTL8 by WAT and BAT as well as the liver (45–47). Fasting increases ANGPTL4 expression in WAT and BAT, suppressing local LPL activity and thus hydrolytic release of fatty acids from triglyceride-rich lipoproteins, redirecting them to other energy-demanding tissues (47). Conversely, upon feeding, ANGPTL3 and ANGPTL8 mediate the suppression of lipases in energy-demanding tissues, allowing white and brown adipocytes to replenish their lipid reserves (39). ANGPTL3- and ANGPTL8-deficient mice display improved triglyceride clearance, but no or only slight improvements in insulin sensitivity, even upon high-fat challenge (48–52). In line with its role in redirecting triglyceride-rich lipoproteins from WAT and BAT to other organs, mice lacking ANGPTL4 exhibit increased fatty acid uptake into WAT during fasting (47). Adipocyte-specific deletion of ANGPTL4 in mice improves triglyceride clearance and glucose tolerance with increased triglyceride uptake into WAT, BAT, and liver (53). In the setting of a high-fat diet, adipocyte-specific deletion of ANGPTL4 improves glucose tolerance and insulin sensitivity, while curbing inflammation and atherosclerosis (53). Specific overexpression of ANGPTL4 in adipocytes, in turn, causes dyslipidemia and exacerbates the detrimental metabolic effects of a high-fat diet (54). Similarly, humans harboring loss-of-function alleles of ANGPTL3, ANGPTL4, or ANGPTL8 display decreased triglyceride levels and increased triglyceride clearance (55–58).

Bone morphogenic proteins

The bone morphogenic protein (BMP) family belongs to the transforming growth factor β (TGFβ) superfamily, and its members have central functions in the development and maintenance of many tissues (59). They signal through complexes of one of seven different type I receptors, the activin receptor-like kinases 1–7 (ALK1–7), with one of three different type II receptors, the BMP receptor 2 (BMPR2) and the activin receptor (ACVR)2a and ACVR2b, that are expressed by a wide range of cells (59). In mice, the specific deletion of ALK3 in brown adipocyte progenitors impairs BAT formation, while its deletion in mature white adipocytes alleviates high-fat diet-induced WAT inflammation and insulin resistance (60, 61).

BMP2 and BMP4 regulate the commitment and differentiation of adipose tissue stromal cells and the maintenance of adipocytes. They signal through ALK3 or ALK6 in conjunction with BMPR2, ACVR2a, or ACVR2b (62–65). BMP2 and BMP4 are expressed in WAT and BAT, and the expression of BMP4 correlates positively with adiposity and adipocyte size (66–68). Both promote the commitment of adipose tissue stromal cells to the adipogenic lineage, which involves the repression of the anti-adipogenic zinc finger protein 521 (ZFP521) and activation of the pro-adipogenic zinc finger protein 423 (ZFP423) (69–73). They also appear to skew adipogenesis toward either a white or brown adipocyte phenotype, although in vitro experiments have been unsuccessful to determine what combination of factors (e.g., dose, time, and duration of treatment, or cell type) determines the exact outcome (66, 68, 74–77). Adipocyte-specific overexpression of BMP4 in mice results in decreased WAT and increased BAT weights, increased WAT angiogenesis and browning, BAT whitening, yet overall increased energy expenditure and improved glucose tolerance and insulin sensitivity (66, 78). Intriguingly, the specific deletion of BMP4 in adipocytes causes increased WAT and BAT weights, decreased WAT angiogenesis, and BAT whitening, as well as disturbed glucose tolerance and insulin sensitivity (66, 78). Similar effects are observed using viral vectors to overexpress BMP4 either systemically or locally in BAT (68, 77).

Another member of the BMP family that is implicated in the regulation of adipose tissue stromal cell adipogenic differentiation is BMP3B. It signals through ALK4 and ACVR2a or ACVR2b, and its production in WAT and BAT increases with obesity (65, 79). Suppressing BMP3B expression in adipose tissue stromal cells increases their adipogenic potential, while overexpressing BMP3B decreases it (79). On a high-fat diet, mice with adipocyte-specific overexpression of BMP3B display decreased WAT weight and adipocyte size, increased BAT thermogenic marker expression, food consumption, activity, and energy expenditure, and improved glucose tolerance and insulin sensitivity (80).

BMP8B is a BMP family member that may particularly regulate BAT function. It signals through a combination of ALK2, ALK3, or ALK6 and BMPR2, ACVR2a, or ACVR2b (65). It is expressed in WAT and BAT, and its expression in BAT is decreased during fasting and increased during feeding and with obesity, as well as upon cold exposure (67, 81). Mice lacking BMP8B display decreased body temperature and impaired cold-induced thermogenesis with reduced oxygen consumption and BAT sympathetic input (81). On a high-fat diet, these mice furthermore exhibit increased body weight gain, but also decreased food intake (81). Apart from directly acting on adipocytes to increase their lipolytic capacity, BMP8B augments the vessel density and neuronal innervation of adipose tissue and prompts the brain to increase the sympathetic output to it (81, 82).

BMP2, BMP3B, BMP4, and BMP8B thus appear to have favorable effects on metabolic homeostasis.

While BMP7 has also been described to have a role in the regulation of BAT formation and function, it has, to our knowledge, never been unambiguously established that it is produced by adipose tissue (67, 74, 76, 83–86).

Chemerin

Chemerin acts as a chemokine and is produced as a pro-protein that undergoes stepwise C-terminal proteolytic processing to generate multiple variants differing greatly in their respective activity (87–90). Chemerin signals through the chemokine-like receptor 1 (CMKLR1) and the G protein-coupled receptor (GPR)1 and also binds to the nonsignaling C-C chemokine receptor-like 2 (CCRL2), all of which are expressed by a variety of cells (91–94). It circulates mostly in its pro-form, and its total circulating levels correlate positively with age, adiposity, triglycerides, and blood pressure (95–102). Apart from its role in immune cell chemotaxis, in vitro experiments implicate chemerin to act on endothelial and vascular smooth muscle cells, promoting vascular dysfunction on skeletal muscle cells fueling insulin resistance and on osteoclasts instigating bone resorption (98, 103–108). A direct action of chemerin on adipose tissue stromal cell adipogenic differentiation or on adipocyte function has remained controversial though (91, 109–111). Chemerin-deficient mice display increased skeletal muscle but decreased WAT insulin sensitivity, as well as mild glucose intolerance; whereas mice overexpressing chemerin specifically in the liver exhibit improved glucose tolerance (112). In contrast, treatment with chemerin exacerbates the obesity-associated glucose intolerance in ob/ob mice, db/db mice, and mice fed a high-fat diet (113). The deletion of CMKLR1 was reported to either not affect or, in another study, decrease glucose tolerance in mice on regular or high-fat diets, while the deletion of GPR1 decreases glucose tolerance in mice on a high-fat diet (110, 111, 114–116). More advanced mouse models may need to be used to clarify the effects of this signaling axis on metabolic homeostasis, such as overexpression or deletion of chemerin or its receptors in a time- and cell type-controlled manner. Such approaches are essential to effectively deconvolute developmental effects from effects on mature cells and tissues (38, 117).

Endotrophin

Endotrophin (ETP) constitutes a C-terminal cleavage fragment of the collagen VI α3 chain (COL6A3) that is released from mature collagen VI (COL6) following secretion (118). While diverse integrins and the chondroitin sulfate proteoglycan 4 (CSPG4) may act as receptors for COL6, a specific receptor for ETP has not yet been identified (118, 119). ETP levels are strongly associated with adipose tissue dysfunction. Similarly, COL6A3 expression in WAT correlates positively with adiposity and with markers of WAT inflammation and is decreased upon anti-diabetic thiazolidinedione treatment (120, 121). Following this pattern, the circulating ETP levels correlate positively with adiposity and markers of insulin resistance, and actually predict the therapeutic response to thiazolidinedione treatment (121). Adipocytes have the unique ability to support the growth of breast cancer cells not only in vitro but also in vivo in the local microenvironment of the mammary gland. COL6A3-derived ETP was singled out as one of the key adipokines involved in this process (122, 123). Studies in the mouse mammary tumor virus/polyomavirus middle T antigen (MMTV-PyMT) model of breast cancer highlighted ETP as a major driver of tumor growth, metastasis formation, and chemoresistance (123–125). In MMTV-PyMT mice, functional elimination of COL6 or treatment with an ETP-neutralizing antibody or with thiazolidinediones decreases tumor growth, metastasis, and chemoresistance (123–125). Mammary epithelial cell-specific overexpression of ETP, in turn, increases tumor inflammation, angiogenesis, and fibrosis, while it also decreases tumor hypoxia and promotes tumor metastasis by initiating epithelial-mesenchymal transition (123–125). Intact TGFβ signaling is required for ETP’s effects on tumor epithelial-mesenchymal transition and is partially required for its effect on tumor fibrosis (124). It is, however, not required for its effects on inflammation and angiogenesis (124). The negative impact of ETP on tumor progression and chemoresistance is in fact highly relevant for human breast cancer as well (126). ETP has more recently also been demonstrated to aggravate the inflammatory and fibrotic consequences of liver damage and advance the development of liver cancer (127). COL6A3 and ETP, moreover, act as drivers of metabolic deterioration in obesity (128). COL6-deficient ob/ob mice and mice fed a high-fat diet exhibit increased WAT adipocyte size and decreased WAT inflammation and liver steatosis, as well as improved triglyceride clearance, glucose tolerance, and insulin sensitivity (128). Consistent with ETP being the key constituent of COL6, adipocyte-specific overexpression of ETP aggravates WAT inflammation and fibrosis, enhances dyslipidemia, liver steatosis, and impaired glucose tolerance and insulin sensitivity in mice fed a high-fat diet, while antibody neutralization of ETP results in the opposite effects (129). ETP thus exerts unfavorable effects on systemic metabolism.

Fibroblast growth factor 21

Fibroblast growth factor (FGF)15/19, FGF21, and FGF23 form the endocrine subgroup of the FGF family (130). They generally have a low heparin- and heparan sulfate-binding capacity, allowing them to leave their place of production and enter circulation (130). FGF21 signals through complexes of FGF receptor (FGFR)1c or FGFR3c with β-klotho as a coreceptor, and binds to, but does not signal through, complexes of FGFR4 with β-klotho (131–133). FGF21 is primarily produced by the liver, but is also expressed in WAT, BAT, and the brain, and possibly skeletal muscle, cardiac muscle, and the pancreas [reviewed in (130)]. Under most conditions, circulating FGF21 primarily derives from the liver where its production increases upon fasting and exercise as well as with high carbohydrate or low protein intake (130). Possible extra-hepatic contributions to the circulating FGF21 levels may occur from BAT upon cold exposure or from skeletal and cardiac muscle upon disturbances of cellular metabolism or mitochondrial function (130). The exact contributions of WAT to circulating pools of FGF21 remain to be clarified. Circulating FGF21 levels are increased with obesity, lipodystrophy, and pancreatitis (130). FGF21 has been extensively studied in mice, monkeys, and humans. Its main effects may relate to decreasing body weight (134–139), sugar and alcohol consumption (140, 141), circulating triglycerides and insulin (134–139), and bone mass (139, 142, 143), while in parallel increasing WAT and BAT glucose uptake, mitochondrial activity, and thermogenesis (136, 144–154) as well as circulating adiponectin (138, 139, 155–157). FGF21 also decreases circulating glucose and improves glucose tolerance and insulin sensitivity in mice (134–136), but may not do so in non-human primates and humans (137–139). Effects on dyslipidemia seem to be preserved in all cases. While FGF21 may exert many of its effects by direct action on the brain, local effects on WAT and BAT nonetheless occur and could be physiologically relevant (140, 141, 147, 150, 158–161). Direct FGF21 signaling was reported to increase white and brown adipocyte glucose uptake (134, 153, 162, 163), thermogenic marker expression (144, 146, 150), and adiponectin secretion (153, 155–157), decrease white adipocyte lipolysis (153, 164), and promote white adipocyte-initiated cold-induced WAT beiging (154), partly through autocrine and paracrine effects of adipocyte-produced FGF21 (146, 154, 157). Other studies failed to demonstrate such effects of direct FGF21 signaling or adipocyte-produced FGF21 (148, 153, 165, 166). Adipocyte-specific deletions of either FGFR1 or β-klotho abolish FGF21’s acute effects on glucose tolerance and insulin sensitivity in mice (137, 145, 153, 155, 161). Adiponectin has been identified as a crucial mediator of FGF21’s glucoregulatory actions (156, 157). We had proposed a direct linear relationship between the activation of PPARγ by thiazolidinediones, local production of FGF21, and local production as well as systemic release of adiponectin, eventually resulting in an effective reduction in blood and tissue ceramide levels with associated improvements in insulin sensitivity (156). It may thus be the absence of the FGF21-triggered adiponectin surge that explains how defects in adipose tissue FGF21 signaling impact its effects on glucose tolerance and insulin sensitivity. Taken together, FGF21 has mostly beneficial effects on systemic metabolism, some of which may, however, not fully translate from rodents to man.

Lipocalin 2

The lipocalin (LCN) family encompasses several structurally similar proteins that bind and transport small hydrophobic molecules, such as retinol, fatty acids, and steroids (167). LCN2 binds iron-chelating siderophores produced by bacterial and mammalian cells, including 2,3-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, and catechol (168–172). LCN2 binds to the LCN2 receptor (LCN2R) and the LDL receptor-related protein (LRP)2, which either increases or decreases intracellular iron stores depending on whether LCN2 is loaded with iron or not (168–172). Human LCN2 can also form covalent homodimers as well as heterodimers with matrix metallopeptidase 9 (MMP9), while murine LCN2 lacks the cysteine residue required for these interactions (173). The circulating LCN levels correlate positively with adiposity, markers of inflammation, and markers of insulin resistance (174–182). Studies with LCN2-deficient mice on either a regular or high-fat diet yielded variable results in that these mice were reported to have increased, decreased, or unchanged body weight gain, altered WAT, BAT, and endothelial cell function, cold intolerance, liver steatosis, and improved, worsened, or unchanged glucose tolerance and insulin sensitivity (178, 183–191). Studies involving either the overexpression of LCN2 or treatment with LCN2 have equally failed to paint a clearer picture of LCN2’s effects on adipose tissue stromal cell adipogenic differentiation, adipocyte function, and metabolic homeostasis (167, 174, 182, 184, 189–194). Surprisingly, despite the central role that iron plays in adipocyte function, the vast majority of these studies on LCN2 did not address iron homeostasis (167, 174, 182, 184, 189–196). As in the case of chemerin, the use of more advanced mouse models enabling an inducible tissue-specific overexpression or deletion of LCN2 or its receptors may be required to refine our assessment of LCN2’s effects on systemic metabolism. We should not be surprised by the wide array of effects reported. This range of phenotypes seen under different conditions is characteristic of what has been observed for many factors involved in inflammatory responses, where beneficial and detrimental effects are in a tug of war, and the net effects differ between acute and chronically challenged states (197–199).

Neuregulin 4

The neuregulin (NRG) family belongs to the EGF superfamily and its members are mostly known for their functions in the development and maintenance of the nervous system (200). Akin to other NRGs, NRG4 is produced as a transmembrane pro-protein that undergoes N-terminal proteolytic processing to release a soluble ligand (201). It signals through the EGF receptor 4 (ErbB4) that is expressed by a wide range of cells (200, 201). NRG4 is expressed in WAT and BAT where its production increases upon cold exposure and decreases with obesity (201–205). Its circulating levels were reported to correlate positively, negatively, or not at all with adiposity and markers of insulin resistance (206–211), yielding a rather unclear picture of its behavior. NRG4-deficient mice fed a high-fat diet display increased body weight gain, decreased WAT and BAT vessel density, increased WAT inflammation, liver steatosis, and impaired glucose tolerance and insulin sensitivity (201, 204, 205). While similar effects occur in high-fat-challenged ErbB4-deficient mice, opposite effects can be achieved by adipocyte- or hepatocyte-specific overexpression of NRG4 (201, 203, 204, 212, 213). This argues for beneficial effects of NRG4 on metabolic homeostasis. Of note though, humans harboring loss-of-function alleles of NRG4 display reduced to nearly absent fasting C-peptide levels, but no apparent alterations of glucose homeostasis, calling for further studies addressing the translatability of above findings (214).

LIPIDS

Fatty acid esters of hydroxy fatty acids

Fatty acid esters of hydroxy fatty acids (FAHFAs) are produced by still poorly understood enzymatic and nonenzymatic processes (215, 216). Differences in acyl chain length, saturation, and hydroxylation of the constituent fatty acids allow for the generation of more than a hundred distinct FAHFA species of which palmitic acid esters of 5- and 9-hydroxystearic acid (5-PAHSA and 9-PAHSA) are the best studied ones (215, 216). 9-PAHSA and possibly also 5-PAHSA signal though the GPR40 and GPR120 expressed by a variety of cells (215, 217, 218). They are produced by BAT and WAT where their production increases with glucose uptake, de novo lipogenesis, and possibly lipid oxidation, and they may be found in food (215, 216, 219, 220). Low circulating 5-PAHSA levels are moreover associated with markers of insulin resistance (215). Administration of 5- and 9-PAHSA to lean or obese mice increases glucagon-like peptide 1 (GLP1) and insulin secretion, decreases circulating glucose levels, and improves glucose tolerance and insulin sensitivity (215, 218). 5-PAHSA and 9-PAHSA may directly act on adipose tissue stromal cells to promote adipogenic differentiation, and in adipocytes to increase insulin-stimulated glucose uptake, in L-cells to increase GLP1 secretion, in β-cells to increase glucose-stimulated insulin secretion, and in macrophages to decrease activation and pro-inflammatory cytokine release (215, 219–221). Of note though, another study featuring both in vitro and in vivo experiments was unable to confirm any of the above-mentioned effects of 5- and 9-PAHSA (217). Whether central aspects of the experimental setups used by individual studies may have contributed to different outcomes remains to be addressed though (222).

Lysophosphatidic acids

Lysophosphatidic acids (LPAs) consist of a glycerol backbone, a phosphate group, and an ester-bound acyl chain of differing length and saturation (223). They are generated both intra- and extracellularly and their circulating levels increase with obesity (223, 224). They can be produced by acylation of glycerol 3-phosphate by glycerol-3-phosphate acyltransferases (GPATs), phosphorylation of monoacylglycerol by acylglycerol kinases (AGKs), head group modification of other lysophospholipids involving phospholipase (PL)D activity, or deacylation of phosphatidic acids involving PLA1 or PLA2 activity (223). LPAs can subsequently be degraded by deacylation involving PLA1 or PLA2 activity, dephosphorylation by lipid phosphate phosphatases (LPPs), or acylation by acylglycerol-3-phosphate acyltransferases (AGPATs) (223). Intracellular LPAs are crucial intermediates of glycerolipid synthesis and may possibly function as endogenous PPARγ ligands, while extracellular LPAs act as lipid mediators signaling through six widely expressed G protein-coupled LPA receptors (LPAR1–6) (223). Administration of LPAs to mice diminishes glucose-stimulated insulin secretion and glucose tolerance (224). LPAs may also directly increase adipose tissue stromal cell proliferation, decrease adipose tissue stromal cell adipogenic differentiation by downregulation of PPARγ2, increase hepatocyte glycogenolysis, and decrease β-cell glucose-stimulated insulin secretion (224–236). Mice deficient in LPAR1 display pronounced developmental defects and delays with a reduced body size and weight, but also increased adipose tissue mass and adipocyte size, enhanced adipocyte glucose transporter 4 (GLUT4) expression, and elevated circulating leptin levels (237–239). Furthermore, when fed a high-fat diet, these mice do not gain body weight or adipose tissue mass and also do not exhibit the expected increase in food intake (238). Chemical inhibition of LPAR1 and LPAR3 in high-fat diet-fed mice increases adipose tissue mass, adipose tissue PPARγ2 expression, and adipocyte size, skeletal muscle glucose utilization, liver glycogen storage, and pancreatic islet mass, and improves glucose tolerance and insulin sensitivity (224, 239). Circulating LPAs are mainly generated from lysophosphatidylcholines by the PLD activity of autotaxin (ATX), an enzyme primarily produced by adipocytes (229, 240–244). ATX secretion by WAT and BAT and circulating ATX levels are increased with obesity and correlate positively with markers of glucose intolerance and insulin resistance (229, 243–249). While a homozygous loss of ATX is embryonically lethal in mice, a heterozygous loss of ATX is tolerated and, upon high-fat feeding, results in decreased circulating LPA levels, body weight gain, and adipose tissue accrual as well as improved glucose tolerance and insulin sensitivity (240–242, 250). Mice with adipocyte-specific deletion of ATX also display decreased circulating LPA levels and improved glucose tolerance, but intriguingly increased adipose tissue accrual, adipose tissue PPARγ2 expression, and adipocyte size (244). Mice overexpressing ATX conversely display increased circulating LPA levels, body weight gain, and adipose tissue accrual, yet no alterations of glucose homeostasis (236).

Taken together, LPAs appear to have mostly detrimental effects on systemic metabolism.

Sphingolipids

The sphingolipid superfamily is characterized by a sphingoid backbone (e.g., sphingosine) and, depending on the respective subfamily, a specific head group, an amide-bound acyl chain, and, in certain cases, also an ester-bound acyl chain (251). Their de novo synthesis begins with the generation of 3-ketodihydrosphingosine from serine and palmitoyl-CoA by serine palmitoyltransferases (SPTs) (251). This is succeeded by a reduction to dihydrosphingosine by 3-ketodihydrosphingosine reductase (KDSR), an acylation to dihydroceramides by (dihydro)ceramide synthases (CERSs), and a conversion to ceramides by (dihydro)ceramide desaturases (DEGSs) (251). Ceramides can be modified further by addition of different head groups, such as phosphatidylcholine by sphingomyelin synthases (SMSs) or glucose by glucosylceramide synthase (GCS) (251). They can alternatively be acylated to acylceramides by diacylglycerol acyltransferases (DGATs), deacylated to sphingosine by ceramidases (CDases), or phosphorylated to ceramide-1-phosphates (C1Ps) by ceramide kinase (CERK) (251). Sphingosine too can be phosphorylated by sphingosine kinases (SPHKs) yielding sphingosine-1-phosphate (S1P) (251). Additional “salvage pathways” exist for ceramide generation from sphingomyelins, glucosylceramides, sphingosine, and C1P that involve SMases, glucosylceramidases (GlcCDases), CERSs, and C1P phosphatases, respectively (251).

While a near-complete reduction of SPT activity due to a homozygous loss of either SPT long chain subunit 1 or 2 (SPTLC1 or SPTLC2) is embryonically lethal in mice, a partial reduction due to heterozygous loss of SPTLC2 or by chemical SPT inhibition alleviates glucose intolerance, insulin resistance, WAT inflammation, liver steatosis, and atherosclerosis, as well as cardiac and vascular dysfunction in different mouse and rat models of obesity, diabetes, and cardiovascular disease (252–269). Highlighting the importance of balanced de novo sphingolipid synthesis for adipose tissue function, mice with adipocyte-specific deletion of SPTLC1 or SPTLC2 display age-dependent lipodystrophy and metabolic deterioration (270, 271). This is, however, a complex pathway, as another study demonstrates that adipocyte-specific deletion of SPTLC2 can also result in protection from high-fat diet-induced metabolic disturbances (268).

Ceramides form a pivotal sphingolipid subfamily that is implicated in causing many of the metabolic sequelae of excessive saturated fatty acid intake (272, 273). Circulating ceramides associate with VLDLs and LDLs, extracellular vesicles (EVs), and possibly also albumin (272). Their levels in circulation as well as in tissues, such as WAT, skeletal muscle, and liver, increase with obesity and correlate positively with markers of inflammation and insulin resistance (268, 274–295). Ceramides can activate protein phosphatase (PP)1, PP2A, and PP2C, protein kinase (PK)Cζ, and the NLR family pyrin domain-containing (NLRP)3 inflammasome, suppress mitochondrial β-oxidation, and promote ER stress (273, 296). They directly decrease the insulin sensitivity of adipose tissue stromal cells, adipocytes, skeletal and cardiac muscle cells, endothelial cells, vascular smooth muscle cells, and kidney cells (256, 261, 264, 297–308). They also decrease adipose tissue stromal cell adipogenic differentiation, white adipocyte browning, and β-cell insulin production, increase adipocyte inflammatory marker expression, and promote β-cell, cardiac muscle cell, and kidney cell death (268, 276, 308–315). Ceramides differ in the length and saturation of their amide-bound acyl chains, mostly resulting from the acyl-CoA preference of the CERS isoform involved in their synthesis (251). CERS1 prefers C18, CERS2 C20–26, CERS5 C16, and CERS6 C14–16 acyl-CoA (251). Mice deficient in either CERS1, CERS5, or CERS6 display improved glucose homeostasis upon high-fat feeding, whereas mice (partially) deficient in CERS2 not only display impaired glucose homeostasis upon high-fat feeding, but also develop liver steatosis and cancer (290, 294, 316–320). Comparable metabolic improvements are seen in high-fat diet-fed mice with either brown adipocyte- or hepatocyte-specific deletions of CERS6 (290). This implicates ceramides with rather short amide-bound C14–C18 acyl chains as prime mediators of saturated fatty acid-induced glucose intolerance and insulin resistance.

Similar to upstream SPT activity, a near-complete reduction of downstream DEGS activity due to a homozygous loss of DEGS1 results in incompletely penetrant embryonic lethality in mice (255). Mice with a heterozygous loss of DEGS1 are viable and display increased insulin sensitivity (255). In line with these observations, chemical DEGS1 inhibition offers partial protection from glucose intolerance and insulin resistance upon high-fat feeding (307).

Ceramide degradation is intimately connected to adiponectin signaling, as the engagement of AdipoR1 and AdipoR2 is associated with increased ceramidase activity, which may stem from the receptors themselves (117, 321–324). Adiponectin-deficient mice display not only impaired glucose tolerance and insulin sensitivity, but also increased ceramide and decreased sphingosine and S1P levels in WAT and liver as well as exacerbated responses upon experimental induction of β-cell and cardiac muscle cell death (117, 321). Treatment with adiponectin or overexpression of it decreases tissue ceramide levels, normalizes glucose homeostasis upon high-fat feeding, and restrains β-cell and cardiac muscle cell death, likely through induction of ceramide degradation and S1P production (321). In mice, WAT-, liver-, or skeletal muscle-restricted overexpression of AdipoR1 or AdipoR2 decreases local ceramide levels and increases local insulin sensitivity (321, 322, 325). When either WAT or liver is targeted, not only local but also distant tissue ceramide levels diminish and glucose tolerance and insulin sensitivity improve, suggesting a dynamic inter-tissue exchange of ceramides (322). In agreement, overexpression of acid ceramidase in either WAT or liver decreases tissue and circulating ceramide levels and augments systemic metabolism (326). Intriguingly, adiponectin itself may play a role in this exchange of ceramides by stimulating the release of ceramide-rich EVs from cells following T-cadherin but not AdipoR1 or AdipoR2 engagement (327). In addition, consistent with adaptor protein containing PH domain, PTB domain, and leucine zipper motif 1 (APPL1) being a key downstream mediator of adiponectin signaling, global APPL1 overexpression decreases cardiac ceramide accumulation, insulin resistance, and damage, and improves systemic metabolism upon high-fat feeding (328).

Sphingomyelins are ceramide derivatives whose circulating levels increase with obesity and, dependent on the length of their amide-bound acyl chain, correlate positively with markers of insulin resistance (251, 276, 287, 288, 291, 329, 330). Mice deficient in SMS1 display incompletely penetrant neonatal lethality, age-dependent lipodystrophy, and disturbed glucose tolerance with pronounced mitochondrial dysfunction and oxidative stress in WAT and pancreas (331, 332). In contrast, mice deficient in SMS2 display augmented glucose tolerance and insulin sensitivity and partial protection from high-fat diet-induced obesity and metabolic deterioration (262, 333, 334). These differences may arise not only from the differential expression of SMS1 and SMS2 in specific tissues, but also from the distinct subcellular localizations of both enzymes, and thus may be due to subcellular differences in sphingomyelin generation (335). Alterations of sphingomyelin synthesis can furthermore influence the levels of ceramides and ceramide derivatives such as glucosylceramides (335). The loss or chemical inhibition of acid SMase, for instance, decreases liver ceramide levels and steatosis, glucose intolerance, and insulin resistance in mice fed a high-fat diet (289, 336).

Glucosylceramides are also ceramide derivatives and themselves form the basis for the synthesis of more complex glycosphingolipids (251). Not much is known about whether and how glucosylceramide levels in circulation and in tissues change with obesity, glucose intolerance, and insulin resistance. A homozygous loss of GCS results in embryonic lethality in mice, and the metabolic consequences of a heterozygous loss of GCS have not yet been studied (337, 338). While hepatocyte-specific deletion of GCS is without apparent impact on systemic metabolism, not even upon high-fat challenge, chemical inhibition of GCS curtails WAT inflammation and liver steatosis, fibrosis, and inflammation and improves glucose tolerance and insulin sensitivity in ob/ob mice and mice fed a high-fat diet (339–344). Thus, while there appears to be an involvement, much remains to be uncovered concerning the role of glucosylceramides and glycosphingolipids in obesity and obesity-associated diseases.

C1Ps and S1P are lipid mediators formed by the phosphorylation of ceramides and sphingosine, respectively (251). C1Ps stimulate the enzymatic activity of the arachidonic acid-releasing cytosolic PLA2α and inhibit those of TNF-releasing TNF-converting enzyme (TACE) and acid SMase (251, 296). Arguing for mostly detrimental effects of C1Ps on systemic metabolism, CERK-deficient mice exhibit decreased body weight gain and decreased WAT adipocyte size, as well as reduced macrophage infiltration and inflammation (345). As a consequence, they show improved glucose tolerance upon high-fat feeding (345).

S1P not only signals through five widely-expressed G protein-coupled S1P receptors (S1PR1–5), but also stimulates the enzymatic activities of TNF receptor-associated factor 2 (TRAF2) and cellular inhibitor of apoptosis 2 (CIAP2) and inhibits those of histone deacetylase (HDAC)1 and HDAC2 (251, 296). In circulation, S1P associates with ApoM on HDL and with albumin (251, 296). Its circulating levels increase with obesity as well as upon fasting and correlate positively with markers of insulin resistance and inflammation (276, 283, 346–351). S1P directly acts on adipose tissue stromal cells to increase proliferation and decrease adipogenic differentiation, prompts adipocytes to increase inflammatory marker expression, triggers hepatocytes to increase inflammatory marker expression, survival, glucose uptake, and lipid accumulation, and leads to an overall decrease in insulin sensitivity (276, 348, 350, 352–361). It also triggers skeletal muscle cells to increase glucose uptake, β-cells to increase survival and glucose-stimulated insulin secretion, vascular smooth muscle cells to increase tone, and endothelial cells to increase immune cell adhesion and permeability (276, 348, 350, 352–361). SPHK1-deficient mice display decreased circulating S1P levels and are variably reported to exhibit either decreased WAT inflammation, liver inflammation and steatosis, and improved glucose tolerance and insulin resistance or increased β-cell death and worsened glucose tolerance and insulin sensitivity (349, 356, 357, 359). While chemical inhibition of SPHK1 has yielded similarly inconsistent results, SPHK1 overexpression from an integrated transgene or from viral vectors was uniformly reported to have beneficial metabolic effects (346, 349, 353, 355, 362). In contrast, not only overexpression but also deletion of SPHK2 results in increased circulating S1P levels and improved glucose tolerance and insulin resistance in mice (361, 363, 364). Targeting S1P signaling rather than S1P production has provided more consistent results. To this end, either combined chemical modulation of S1PR1 and S1PR3–5, chemical inhibition of S1PR2, or deletion of S1PR2 results in augmented glucose homeostasis in different mouse models of obesity and diabetes (348, 350, 360, 365–370).

As in the case of other signaling mediators, more sophisticated models and methods may be required to disentangle acute and chronic effects of altered C1Ps and S1P production and signaling on different cells and tissues.

METABOLITES

Uric acid

Uric acid is a product of purine base degradation, a process that begins with the conversion of adenine and guanine nucleotides to hypoxanthine and xanthine, respectively, and concludes with the conversion of hypoxanthine to xanthine to uric acid (371, 372). Uric acid is produced by adipose tissue, the liver, and skeletal muscle and excreted primarily by the kidneys and secondarily by the liver (372). It is also degraded by uricase, an enzyme that is present in mice and rats, but absent in humans, resulting in overall higher circulating and tissue uric acid levels in the latter (371, 372). The circulating uric acid levels increase with obesity, liver steatosis, type 2 diabetes, and kidney disease and may predict the development of the metabolic syndrome (373–389). Uric acid exerts anti-oxidant effects in the extracellular environment where it can scavenge reactive oxygen and nitrogen species, including superoxide anions (O₂⁻), peroxynitrite anions (ONOO⁻), and NO, but pro-oxidant effects in the intracellular environment where it can activate the NLRP3 inflammasome and NADPH oxidase (NOX) (379, 385, 390–395). NADPH oxidase activation by uric acid triggers its translocation to the mitochondria, induces mitochondrial oxidative stress, suppresses β-oxidation, and promotes de novo lipogenesis (379, 393, 394). Uric acid directly increases adipocyte and hepatocyte inflammatory marker expression, hepatocyte lipid accumulation, and vascular smooth muscle cell proliferation, and decreases hepatocyte and endothelial cell insulin sensitivity as well as endothelial cell proliferation (376, 379, 385, 393, 395–402). Chemical inhibition of uricase in mice and rats results in elevated circulating uric acid levels, raised blood pressure, diminished WAT, liver skeletal muscle, and vessel insulin sensitivity, evident liver steatosis and inflammation, kidney dysfunction, as well as disturbed glucose tolerance and insulin sensitivity (394, 395, 400, 401).

The final steps of purine base degradation, the conversion of hypoxanthine to xanthine to uric acid, are carried out by the multifunctional enzyme, xanthine oxidoreductase (XOR), that occurs in two distinct forms, a dehydrogenase form (XDH) and an oxidase form (XO) (403, 404). XOR is produced as XDH and can be converted to XO either reversibly by cysteine residue oxidation or irreversibly by limited proteolysis (403, 404). Secreted XDH undergoes rapid turnover to XO, which then binds to the surface of endothelial cells (403, 404). XOR can utilize a wide range of substrates (403, 404). While substrate oxidation by XDH consumes NAD⁺ to produce NADH, substrate oxidation by XO consumes oxygen (O₂) to produce mainly hydrogen peroxide (H₂O₂) but also O₂⁻ (403, 404). Depending on pH, O₂ tension, and substrate availability, XDH can also utilize O₂ as an electron acceptor and thus act as a source of reactive oxygen species (403, 404). Moreover, both XDH and XO can generate reactive nitrogen species by substrate or NADH oxidation with concomitant reduction of nitrate (NO₃⁻) to nitrite (NO₂⁻) to NO (403, 404). XOR is expressed in WAT, liver, and skeletal muscle, and its production and activity in WAT and liver increase with obesity (382, 385, 405, 406). XOR partakes in the regulation of adipogenesis, and mice with a homozygous loss of XOR display decreased fat mass and early lethality, although comparable XOR deficiency in humans is nonlethal (405, 407, 408). Mice with a heterozygous loss of XOR display age-dependent body and WAT weight gain and WAT dysfunction with increased oxidative stress and inflammation, as well as glucose intolerance and insulin resistance, all of which are exacerbated on a high-fat diet (409). Chemical inhibition of XO, in contrast, not only lowers the circulating uric acid levels, but also preserves WAT and liver function and augments glucose homeostasis in db/db mice as well as mice fed a high-fat diet (376, 379, 384). The outcome of manipulating XOR thus appears to depend on which aspects of XOR biology are targeted.

Uric acid production is tightly linked to fructose intake (371, 372). Following cellular uptake, fructose can undergo unrestrained phosphorylation by ketohexokinase (KHK), which yields fructose-1-phosphate and consumes cellular ATP (371, 372). The accompanying depletion of cellular phosphate triggers an activation of AMP deaminase (AMPD), degradation of adenine nucleotides, XOR-dependent production of uric acid, and uric acid-mediated inhibition of AMP-dependent protein kinase (AMPK) (371, 372). High-fructose feeding of mice and rats causes elevated circulating uric acid levels, cardiac, vascular, and kidney dysfunction with increased oxidative stress, inflammation, and fibrosis, as well as disturbed glucose homeostasis, all of which can be mitigated by chemical XO inhibition (383, 399, 410–414).

Taken together, this argues for mostly detrimental effects of elevated uric acid levels on systemic metabolism.

Uridine

Uridine is the nucleoside of the pyrimidine base, uracil, and provides the basis of substrates that are essential for RNA and DNA synthesis, glycogen deposition, and protein and lipid glycosylation (415). Its de novo synthesis usually begins with the formation of dihydroorotate from glutamine, bicarbonate (HCO₃⁻), ATP, and aspartate by the tri-functional enzyme, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD2), followed by the conversion of dihydroorotate to orotate by dihydroorotate dehydrogenase (DHODH), of orotate to UMP by the bi-functional enzyme, UMP synthase (UMPS), and of UMP to uridine by 5′-nucleotidase (5NT) (415). Its degradation, in turn, is carried out by uridine phosphorylases (UPPs) (415). Uridine is produced by the liver and WAT and cleared by the liver (416–419). Both endogenous and exogenous uridine (introduced either orally or intraperitoneally) undergo continuous and rapid clearance by the liver, mostly through degradation by Kupffer cells and endothelial cells, but also through biliary excretion by hepatocytes (416–419). The circulating uridine levels are tightly regulated, increase with obesity and upon fasting, exercise, and ingestion of ethanol, glucose, and fructose, and decrease with lipodystrophy and upon ingestion of amino acids (418–421). Strikingly, while the liver produces most of the circulating uridine in the fed state, adipose tissue is doing so in the fasted state (418, 419). Not much is known about how uridine signals and no dedicated uridine receptor has been identified yet. Uridine may indeed exert most of its effects by being metabolized to either UDP, UDP-glucose, or UTP, which can signal through different G protein-coupled purinoreceptors (i.e., P2YR2, P2YR4, P2YR6, and P2YR14) or to UDP-hexosamines and UDP-N-acetyl-hexosamines, which can alter the glycosylation and thus the activity of distinct proteins and lipids (422, 423).

Acute treatment of humans, rats, and mice with a high dose of uridine results in a transient decrease in body temperature, while a low dose may cause a slight increase instead (418, 424, 425). In extension, the fasting-associated decrease in body temperature was found to be critically dependent on uridine production by adipose tissue (418). In mice, uridine treatment also increases the circulating leptin level, decreases the metabolic rate, and improves glucose tolerance in aged and in high-fat diet-fed animals (418). Uridine’s effects on both body temperature and glucose homeostasis apparently involve active leptin signaling, as uridine treatment of ob/ob mice evokes an exacerbated decrease in body temperature, but unexpectedly also worsens glucose homeostasis (418).

Prolonged disturbances of uridine homeostasis in either direction appear to be mostly detrimental. As such, dietary supplementation of uridine in mice for several days to weeks promotes body weight gain, alters liver protein acetylation and glycosylation, stimulates liver glycogen and lipid accumulation, blunts liver insulin sensitivity, and disturbs glucose homeostasis (426–428). Intriguingly, lowering uridine levels by chemical inhibition of DHODH or overexpression of UPP1 also induces liver lipid accumulation and blunts liver and systemic insulin sensitivity, but improves glucose tolerance (426, 427). Elevating uridine levels by UPP1 deletion, in turn, does not affect liver insulin sensitivity, but similarly blunts systemic insulin sensitivity, improves glucose tolerance, and may furthermore promote spontaneous tumorigenesis (427, 429).

The ER stress response, specifically the mRNA splicing-dependent production of the short isoform of X-box binding protein 1 (XBP1s), plays a central role in uridine metabolism (430). In the fed state, XBP1s levels are high in hepatocytes and pro-opiomelanocortin neurons of the arcuate nucleus and low in adipocytes, whereas the opposite can be observed in the fasted state (419, 431, 432). XBP1s upregulation in adipose tissue seems to be tied to active lipolysis with higher XBP1s levels detectable not only upon fasting, but also with obesity and cancer-associated cachexia (419). XBP1s acts as a transcription factor that stimulates uridine de novo synthesis by inducing CAD2 as well as uridine conversion to UDP-hexosamines and UDP-N-acetyl-hexosamines by inducing both glutamine/fructose-6-phosphate aminotransferase 1 (GFPT1) and UDP-glucose 4-epimerase (GALE) (419, 431–433). Highlighting its role in promoting uridine production, adipocyte-specific deletion of XBP1s abolishes the fasting-induced increase in uridine (419). Mice with adipocyte-specific overexpression of XBP1s display elevated circulating and adipose tissue uridine levels, increased activity, energy expenditure, and body heat loss, decreased body weight and body temperature, and protection from obesity upon high-fat feeding or with leptin deficiency (419). Suggesting mostly favorable effects of XBP1s induction, hepatocyte- or pro-opiomelanocortin neuron-specific XBP1s overexpression augments glucose homeostasis, and cardiac muscle cell-specific XBP1s overexpression alleviates ischemia-reperfusion damage in mice (431–433).

Much remains to be learned about how short- and long-term disturbances of uridine homeostasis impact systemic metabolism and about whether manipulations of uridine metabolism may yield therapeutic benefits.

NONCODING RNAs

Long noncoding RNAs

Contrary to lasting assumptions, the majority of the genome is transcribed, at least under some conditions (434). Long noncoding RNAs (lncRNAs) originate from the transcription of intergenic and genic portions of the genome, both in the sense and antisense direction (434). They are, by definition, over 200 nucleotides long, not translated into proteins, and may regulate gene transcription and nuclear domain organization as well as RNA and protein function (434). Most lncRNAs are localized in the nucleus, lowly abundant, and poorly conserved (434). Only a small fraction (hundreds to thousands) of the predicted 20,000–100,000+ lncRNAs in humans may indeed have specific functions (434). lncRNAs are found in EVs, raising the possibility that EV-associated lncRNAs released from adipose tissue function as regulators of distant tissue function (435). Recent reviews provide an excellent overview of the role of lncRNAs in the regulation of adipose tissue function and systemic metabolism (436–438).

MicroRNAs

MicroRNAs (miRNAs) either originate from introns or are transcribed from dedicated genes (439). They are released from pri- and pre-miR precursors by successive processing involving the microprocessor complex in the nucleus as well as DICER in the cytoplasm (439). At the end of their processing, they are 20–24 nucleotides long and incorporated into the RNA-induced silencing complex (RISC). As a RISC component, they regulate mRNA translation and stability, usually resulting in a repression of protein expression (439). They are more conserved than lncRNAs and show a wide range of abundance (439). Strikingly though, only less than 100 of the adipose tissue-expressed miRNAs appear to be regulated by obesity in either humans or mice (439). Distinct populations of miRNAs are released from cells associated mostly with components of the RISC, but also associated with lipoproteins and EVs (440–442). Adipose tissue is a major source of circulating EV-associated miRNAs, and recent reviews offer much insight into how adipose tissue-derived miRNAs shape metabolic homeostasis (439).

EVs

EVs are an eminent means of intercellular communication (435, 443–445). They carry a large variety of cargo, including organelle parts, proteins, and lipids, as well as small coding and noncoding RNAs (e.g., mRNAs, lncRNAs, and miRNAs), delivering them from one cell to another. Cells secrete EVs in an orderly process that is controlled by intra- and intercellular signals, including nutrient-related cues (435, 443–445). Determined by their biogenesis, ectosomes (also called microvesicles) with a diameter of 50–1,000 nm and exosomes with a diameter of 50–150 nm can be distinguished (435, 443–445). While ectosomes bud directly from the plasma membrane, exosomes are generated by inward budding of endosomal membranes to create multivesicular bodies (MVBs) containing intraluminal vesicles (ILVs, i.e., unreleased exosomes) followed by either degeneration through fusion of the ILVs with the MVB membrane, degradation through fusion of the MVBs with lysosomes, or release through fusion of the MVBs with the plasma membrane (435, 443–445). Accordingly, ectosomes are released in an immediate fashion and exosomes in a delayed fashion (435, 443–445). EVs are capable of delivering their cargo to specific cells and tissues by binding to and rolling on target cell surfaces, which subsequently allows for receptor interaction and fusion by fusogenic interactions, endocytosis, macropinocytosis, or phagocytosis (435, 443–445).

Obesity alters the cargo and increases the release of EVs from WAT, while cold exposure does so in BAT and browning WAT (446, 447). Establishing a role for adipose tissue-derived EVs in the regulation of systemic metabolism, EVs collected from WAT of high-fat diet-fed mice elicit glucose intolerance and insulin resistance when injected into wild-type mice and exacerbate atherosclerosis when injected in ApoE-deficient mice (447, 448). Highlighting the contribution of macrophages to these effects, WAT macrophage EVs from high-fat diet-fed mice are sufficient to disrupt glucose homeostasis when injected into wild-type mice, whereas WAT macrophage EVs of regular diet-fed mice are capable of augmenting glucose homeostasis instead (449). WAT EVs of high-fat diet-fed mice may also induce monocyte homing to adipose tissue and the liver, promote local monocyte proliferation and differentiation, and increase macrophage pro-inflammatory cytokine production (447, 448, 450). Taken together, these observations allude to a vicious cycle of obesity-associated shifts in the adipose tissue EV secretion profile, immune cell infiltration, and inflammation.

EVs serve as a means of communication not only between adipose tissue and other organs but also between different cell populations within adipose tissue itself. Regarding this aspect of adipose tissue biology, we recently uncovered an extensive EV-mediated local exchange of cellular components between adipocytes and endothelial cells that is governed by the nutritional state (451). In WAT of mice, the cellular origin and destination as well as the cargo of the transferred EVs changes upon fasting, feeding, and with obesity (451). Fasting, for instance, results in an increased EV-mediated transfer of cellular components from WAT endothelial cells to adipocytes as well as an enrichment of WAT EVs in proteins involved in central cellular signaling pathways, mitochondrial respiration, oxidative stress defense, and hypoxia response and a depletion of WAT EVs in proteins involved in lipid and amino acid metabolism (451). The highly dynamic character of this EV-mediated local exchange alludes to the possibility that it might primarily serve to rapidly and efficiently redistribute cellular components between different cell populations within WAT, thus lending heightened metabolic flexibility to the tissue as a whole.

Altogether, EVs released from adipose tissue into circulation may exert mostly beneficial effects on systemic metabolism in the lean state but detrimental effects in the obese state. Related to this, much remains to be learned about exactly how adipose tissue communicates with other organs by means of EV exchange, the sending cells, and the receiving cells, as well as the nature of the transmitted message.

PERSPECTIVE

There is clearly a wide variety of signaling mediators and mechanisms that adipose tissue utilizes to communicate with other organs of the body. At the systemic level, we deal with adipose tissue as a whole, distributed throughout the body in the form of discrete depots.

The contribution of specific depots and cell populations within them to the overall production frequently remains to be defined for many adipose tissue-derived factors. Likewise, the manner in which physiological and pathophysiological states, such as fasting, aging, and obesity, affect the production of certain factors by distinct depots and cell types awaits elucidation. Particularly with respect to fibrosis and inflammation, it has become clear that the effects observed commonly involve a cross-talk of multiple different cell types with net output from all participating populations. A fundamental impediment to more refined studies of adipose tissue-emergent signals is the present dearth of methods to measure and manipulate the production of distinct signaling mediators by specific adipose tissue depots and cell populations in vivo.

There are several signaling molecules, such as leptin and FGF21, which exert mostly beneficial effects on systemic metabolism, yet also display elevated circulating levels in pathophysiological states tightly associated with metabolic disturbances. The mechanistic basis by which certain pathophysiological states alter the signaling capacity and character of distinct factors is of immense interest. Reduced responsiveness to the metabolically favorable actions of leptin and FGF21 in the obese state, for instance, evoked still controversial ideas of leptin and FGF21 resistance that have been probed in numerous studies, altogether providing no coherent model (130, 452). To reliably define the role that a specific signaling mediator plays in metabolic disease remains challenging. It requires careful modulation of the abundance and/or activity of the respective factor and its receptor(s), while concomitantly monitoring systemic metabolism and cellular signaling. At the same time, focusing unduly on either individual cell types and tissues or isolated signaling pathways has to be avoided. More sophisticated in vivo models that enable these types of modifications are likely to make crucial contributions to such efforts.

Above, we solely discussed signaling mediators that are actively produced by adipose tissue. Adipose tissue is, however, also capable of degrading signaling mediators that derive from or that are destined for other organs (Fig. 2). It thus partakes in inter-organ communication as a source as well as a sink of signals. Future endeavors should thus consider not only the anabolism but also the metabolism and catabolism of signals by adipose tissue when evaluating its contributions to systemic metabolic and cellular homeostasis.

Fig. 2.

Adipose tissue partakes in inter-organ communication by producing new signaling mediators (“signal anabolism”) as well as by converting or degrading signaling mediators reaching it from other organs (“signal metabolism” and “signal catabolism”).