Table 2.

Summary of ligand–receptor signaling pathways that regulate adipocyte lipolysis and browning

Ligand	Receptor	G-protein	Cyclic nucleotide	Lipolysis	Browning/Thermogenesis
Adenosine	A1R [466,467]	Gαi	Adenosine opposes the actions of other agents that raise cAMP [468–472]. A1 R knock-out blocks the 2-chloroadenosine-evoked reduction in cAMP [473].	Adenosine opposes the actions of other agents which raise lipolysis both in vitro/ex vivo [468,469,471,472,474–480] and in vivo [481]. A1 R knock-out blocks the 2-chloroadenosine-evoked reduction in lipolysis [473,482].	Adenosine inhibits adipocyte respiration [479,483,484].
Adenosine	A2AR, A2BR [466]	Gαs	Adenosine increases cAMP in some cell lines [485]. A2AR and A2BR agonists increase cAMP [485].	Adenosine increases lipolysis in some cell lines [485]. A2AR and A2BR agonists increase lipolysis [485].	Activation of A2AR increases thermogenic gene expression in human and mouse brown and white adipocytes [485].
Adrenergic: (norepinephrine, epinephrine)	β1AR, β2AR, β3AR	Gαs	Increase cAMP [486]	Increase lipolysis [486].	Increase browning [486].
Adrenergic: (norepinephrine, epinephrine)	α1AR	Gαq/11			Augment the βAR response in brown adipocytes to increase thermogenesis [38,39].
Adrenergic: (norepinephrine, epinephrine)	α2AR	Gαi	Decrease cAMP by inhibiting adenylyl cyclase [486].	Decrease lipolysis [25,40].	Central nervous system activation of α2AR can suppress peripheral SNS activation of BAT [487]. Peripheral actions variable in literature.
Bile acids (cholic acid, chenodeoxycholic acid)	GPBAR1 (aka TGR5) [466,488–493]	Gαs	Bile acids (including cholic acid) increase cAMP in BAT cells [488].		Cholic acid and chenodeoxycholic acid both have been reported to increase adipocyte thermogenesis [488,490,491,494–496]. GPBAR1 selective agonists have similar browning effects [489,492,493,497,498].
Gastric inhibitory polypeptide (GIP)	GIPR [147,167–177,466]	Gαs	GIP raises cAMP concentrations and PKA-evoked signaling [95,167,171,174,177,188–191].	The effects of GIP on lipolysis have observed it to be increased [168,181,185,189], unaffected [193] and decreased [116,192]. GIP increased both glycerol release and fatty acid re-esterification, which resulted in an overall decrease in free fatty acid release despite the increased lipolysis [185].	Both GIP treatment and Gipr knockdown were reported to increase UCP1 in immortalized BAT cells along with an increase in their maximal oxygen consumption [204]. Similar findings were observed in Gipr−/− mice where Ucp1 mRNAwas increased in brown adipose tissue of mice fed a high fat diet [151].
Glucagon	GCGR [75,85–96,466]	Gαs	Glucagon increases intracellular cAMP in adipocytes [85,104,107,110,111,113,115,117, 118,120,124–128,284,285,469,499,500]	Glucagon increases circulating glycerol and free fatty acids in vivo [60,65,66,77–84]. Glucagon increases adipocyte lipolysis in vitro and ex vivo [75,87,89,97–103,105–110,112–114,116,118–123,126–130,501–504].	Glucagon increases body temperature, oxygen consumption, metabolic rate and thermogenic markers in vivo, but some studies indicate that this can be blocked by inhibiting β-adrenergic signaling [56–76,135]. Glucagon increases oxygen consumption and thermogenesis in vitro and ex vivo in adipocytes and adipose tissue [65,71,75,122,129–133].
Glucagon-like peptide-1 (GLP-1)	GLP1R [85,86,94,95,142–147,466]	Gαs	GLP-1 has been reported to increase [85,113,126,128] or not alter [117] intracellular cAMP in adipocytes.	GLP-1 has been reported to increase [85,113,126,128] or not alter [148,149] lipolysis.	Central administration of synthetic GLP1R agonists increase adipose tissue browning [134,152,153]. Peripheral administration of synthetic GLP1R agonists increase UCP1 in adipocytes [155–159].
Melanocyte stimulating hormones (MSH): α-MSH, β-MSH, γ-MSH etc. Adrenocorticotropic hormone (ACTH)	MC2R [228–233,236], MC5R [228,230–233,236,466] Human adipocytes lack MC2R but may express other receptors [229,239,240]	Gαs	ACTH, which binds to all melanocortin receptors, increases cAMP in adipocytes [104,107,110,115,120,219,222–224,228,230,233,234,236,284,285,292,469,499,500,505–507]. α-MSH, which does not bind to MC2R, similarly increases cAMP in adipocytes [228,230,233].	ACTH stimulates lipolysis [97–99,101,103,106,107,109,110,120, 217,218,220–223,226,227,229,231,233,234,501,502] α-MSH and β-MSH, which do not bind MC2R, stimulate lipolysis [103,226,231,233,235,241]. Lipolysis is not affected by ACTH in primates or canines [229,237,238,240], though a-MSH may have a small lipolytic effect [240].	ACTH increases oxygen consumption and thermogenic gene expression in adipocytes [59,130,133,225,232,234,236]. α-MSH, which does not bind to MC2R, increases thermogenic gene expression in adipocytes [235,236,242].
Neuropeptide Y (NPY), peptide YY (PYY), pancreatic polypeptide (PP)	YR1, YR2, YR5 [147,466,508–513]	Gαi		Both NPY and PYY inhibit lipolysis in vitro [238,241,514–516]. NPY and PYY inhibit lipolysis in vivo in sympathectomized rats [517].	NPY administration reduces [518] while global NPY knockout increases adipocyte thermogenic markers [519,520]. NPY suppress thermogenic gene expression and oxygen consumption in C3H10T1/2 adipocytes [521].
Parathyroid hormone (PTH), Parathyroid hormone-related protein (PTHrP)	PTH1R, PTH2R [236,266,268]	Gαs,Gαq/11	PTH stimulates cAMP in adipocytes [260–264].	PTH stimulates lipolysis in adipocytes [238,258–261,265,266].	Both PTH and PTHrP increase respiration and promote the expression of thermogenic genes in adipocytes [236,267,268].
Pituitary adenylate cyclase-activating peptide (PACAP), Vasoactive intestinal peptide (VIP)	PAC1, VPAC1, VPAC2 [236,466,511,522–528]	Gαs	VIP increases cAMP in adipocytes [85,111,115,264,529].	PACAP- and VIP-stimulated adipocyte lipolysis [112,116,123,149,181,226,264,524]. This can only be inhibited by a VPAC2 antagonist [524].	PACAP has been reported to stimulate Ucp1 gene expression and has a small stimulatory effect on respiration in brown adipocytes [236]. Central administration of either PACAP or VIP has been shown to promote brown adipose tissue thermogenesis [530,531].
Prostaglandin E2 (PGE2)	EP2, EP4 [236,466,532–538]	Gαs	In the absence of elevated cAMP, high concentrations of PGE2 by itself have been reported to increase cAMP in adipocytes [288,293]. Under similar circumstances, PGE1, a similar PGE analog, has also been reported to increase cAMP in adipocytes [284,539].		PGE2 has been shown to increase UCP1 [236,303,304,540]. 16,16-dimethyl-PGE2, an EP2/EP3/EP4 agonist, has been reported to also increase the expression of thermogenic gene expression in BAT in vivo [297].
Prostaglandin E2 (PGE2)	EP3 [296,466,532,533,535–538,541]	Gαi	PGE2 opposes the actions of other agents which raise cAMP [286–290,292,295,542–544]. PGE1 also lowers cAMP after it has been raised by other agents. [284,285,506,542,545–547]. In the absence of raising cAMP with other agents, PGE2 by itself lowers cAMP, but only at low concentrations [288,293]. Sulprostone, an EP1 and EP3 selective agonist, has also been shown to oppose actions of other agents that raise cAMP in adipocytes [293,544]. The EP3 antagonist, L-798,106, blocks the PGE2-evoked reduction in cAMP [295].	PGE2 opposes actions of other agents that raise lipolysis both in vitro/ex vivo [276,286,289,290,292,294,296,303,482,502,505,541,543,544,548–552] and in vivo/in situ [553,554]. PGE1 also reduces lipolysis after it has been raised by other agents both in vitro/ex vivo [434,435,500–502,505,515,542,547, 555–560] and in vivo/in situ [103,502,553,561]. Sulprostone, an EP1 and EP3 selective agonist, has also been shown to oppose actions of other agents that raise lipolysis in adipocytes [294,544]. EP3 knock-out or the antagonist L-826,266 blocks the PGE2-evoked reduction in lipolysis [296,541].
Prostacyclin (PGI2)	IP [466,532,562]	Gαs	PGI2 raises cAMP in adipocytes [279–283,563].	PGI2 increases lipolysis [276].	PGI2 and its synthetic analog carbaprostacyclin have been observed to increase Ucp1 and other thermogenic gene expression in adipocytes [298–301].
Secretin	SCTR [85,236,466,564–566]	Gαs	Secretin increases cAMP in adipocytes [85,107,111,124,125,545,564].	Secretin stimulates lipolysis both in vivo [79] and in vitro [102,106,107,112,114,116,545,564, 565,567,568].	Secretin increases oxygen consumption and thermogenic gene expression in brown adipocytes [71,236,566].
Thyroid-stimulating hormone (TSH, aka thyrotropin)	TSHR [236,466,569–582]	Gαs	TSH increases intracellular cAMP levels in adipocytes [104,285,499,570,573,574,579,580].	TSH induces lipolysis [103,501,502,577,583–589].	TSH increases Ucp1 and oxygen consumption in adipocytes in vitro [124,579,582].
Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP)	NPRA (aka GC-A) [315,383,390–396,399,402,404,406,412,418,590]	–	ANP signaling increases intracellular cGMP concentrations in adipocytes [393,404,410,418]. BNP signaling also increases intracellular cGMP concentrations in adipocytes [404].	ANP stimulates lipolysis in vitro [395,406,411,413,414,418,421,591] and in vivo [395,402,414,417,419,591]. BNP stimulates lipolysis in vitro [419] and in vivo [395,419,420].	ANP increases oxygen consumption and UCP1 expression in adipocytes in vitro [315,[404,[406,421,[422]. BNP increases UCP1 expression in vitro [404] and in vivo [315,400,423].
C-type natriuretic peptide (CNP)	NPRB (aka GC-B) [392,394,396,404]	–	CNP signaling increases intracellular cGMP concentrations in adipocytes [393,409,410].		Mice overexpressing CNP in adipose tissue have increased oxygen consumption and UCP1 in inguinal WAT [409].