The evolving view of thermogenic adipocytes — ontogeny, niche and function

Farnaz Shamsi; Chih-Hao Wang; Yu-Hua Tseng

doi:10.1038/s41574-021-00562-6

. Author manuscript; available in PMC: 2022 Feb 4.

Published in final edited form as: Nat Rev Endocrinol. 2021 Oct 8;17(12):726–744. doi: 10.1038/s41574-021-00562-6

The evolving view of thermogenic adipocytes — ontogeny, niche and function

Farnaz Shamsi ^1,^2,⁵, Chih-Hao Wang ^1,^3,⁵, Yu-Hua Tseng ^1,^4,^✉

PMCID: PMC8814904 NIHMSID: NIHMS1774853 PMID: 34625737

Abstract

The worldwide incidence of obesity and its sequelae, such as type 2 diabetes mellitus, have reached pandemic levels. Central to the development of these metabolic disorders is adipose tissue. White adipose tissue stores excess energy, whereas brown adipose tissue (BAT) and beige (also known as brite) adipose tissue dissipate energy to generate heat in a process known as thermogenesis. Strategies that activate and expand BAT and beige adipose tissue increase energy expenditure in animal models and offer therapeutic promise to treat obesity. A better understanding of the molecular mechanisms underlying the development of BAT and beige adipose tissue and the activation of thermogenic function is the key to creating practical therapeutic interventions for obesity and metabolic disorders. In this Review, we discuss the regulation of the tissue microenvironment (the adipose niche) and inter-organ communication between BAT and other tissues. We also cover the activation of BAT and beige adipose tissue in response to physiological cues (such as cold exposure, exercise and diet). We highlight advances in harnessing the therapeutic potential of BAT and beige adipose tissue by genetic, pharmacological and cell-based approaches in obesity and metabolic disorders.

Adipose tissue has a major role in the regulation of whole-body energy homeostasis and impairments in adipose tissue function directly link to the aetiology of type 2 diabetes mellitus and cardiovascular diseases. White adipose tissue (WAT) depots, which contain lipid-filled white adipocytes, are distributed throughout the body and are major energy storage sites. In addition, two other functionally distinct types of adipocytes exist that are energy-burning (that is, thermogenic). These are brown adipocytes, which are present in brown adipose tissue (BAT), and related beige or brite adipocytes (hereafter referred to as beige adipocytes), which appear in certain WAT depots in response to cold acclimation, exercise training or pharmacological activation of β-adrenergic receptors¹.

Adipose thermogenesis is mainly ascribed to a high density of mitochondria and uncoupling protein 1 (UCP1) expression in brown and beige adipocytes. UCP1 is located on the inner mitochondrial membrane and shuttles protons from the mitochondrial intermembrane space back to the mitochondrial matrix without generating ATP. This process uncouples the metabolism of glucose and fatty acids from ATP generation and results in energy dissipation as heat². Stemming from their high energy expenditure, brown and beige adipocytes have a remarkable capacity to take up and utilize fuels, and therefore function as a metabolic sink for glucose and free fatty acids³. Furthermore, BAT and beige adipose tissues play major parts in the regulation of whole-body metabolism through their secretory function, releasing different endocrine signalling molecules, including proteins, lipids and microRNAs, into the circulation that exert regulatory effects on the target tissues or organs^4,5.

In humans, UCP1-positive adipose tissue has been found in several depots, including the cervical–supraclavicular, perirenal–adrenal and paravertebral regions, and around the major arteries^6–9. The activity of BAT in humans negatively correlates with BMI^6,8–10, which suggests that BAT is an attractive target for anti-obesity therapies. Additionally, studies in humans and mice have shown that the amount of active BAT positively correlates with insulin sensitivity^11,12. Therefore, any strategy that increases the amount and activity of BAT can potentially be applied to the treatment of obesity and its comorbidities.

In this Review, we provide a comprehensive discussion of the ontogeny of thermogenic adipocytes and we integrate the existing literature on the role of niche factors and intercellular communications in the regulation of BAT and beige adipose tissue function and remodelling. Furthermore, we focus on the endocrine functions of BAT and beige adipose tissue and discuss their contributions to whole-body metabolism via long-range inter-organ crosstalk. Finally, we review the translational implications of these findings and propose strategies to optimize these processes towards the development of novel therapies for obesity and metabolic diseases.

Origin of thermogenic adipocytes

Lineage tracing studies have revealed the heterogeneity of adipocyte lineages between and within adipose depots. Early histological examination of mouse embryonic development identified the mesoderm layer to be the primary origin of most adipocytes¹³. However, the cephalic adipocytes can be traced with the neural crest marker Sox10-Cre and are therefore thought to have a neural crest origin¹⁴.

Origin of brown adipocytes

Early lineage tracing studies in mice using En1-CreER, which marks somites and somite-derived tissues, revealed that the majority of adipocytes in the interscapular BAT are derived from progenitors in dermomyotome¹⁵. Later studies showed that brown adipocytes in the interscapular and perirenal BAT arise from Pax3⁺Pax7⁺Myf5⁺ progenitors, but that white adipocytes in the gluteal, inguinal and epididymal WAT depots do not arise from these cells^16–18. These findings led to the assumption that brown and white adipocytes arise from completely distinct embryonic progenitors, and that functional and phenotypical distinctions between these two types of adipocytes can therefore be attributed to their ontogenetic differences^18–20. However, further examination of other adipose depots using the Myf5-Cre lineage tracing system revealed that the Myf5-expressing progenitors not only give rise to the brown adipocytes present in the BAT depots originated from the somitic mesoderm (that is, interscapular, subscapular and cervical BAT), but they also contribute to adipocytes in some minor WAT depots, such as the anterior WAT (interscapular and axillary) and the retroperitoneal WAT²¹.

Somites.

Segmental axial structures located on either side of the neural tube in the developing vertebrate embryo that contain the precursor populations of cells, which give rise to vertebral column, ribs, skeletal and smooth muscles, dermis, tendons, ligaments, cartilage and adipose tissue.

Lineage tracing studies using multiple Cre drivers that label the progenitors in different mesodermal subcompartments have shed light on the exact regions in the somites that contribute to each adipose depot²². Tracing the Meox1-expressing progenitors in the somite revealed that both brown and white adipocytes of the dorsoaxial adipose depots (including retroperitoneal WAT, and interscapular BAT and WAT) arise from somitic mesoderm. Interestingly, more than half of perigonadal white adipocytes in male mice, but not female mice, are also derived from Meox1-expressing progenitors²². However, contrary to the previous observation that indicated Pax7-expressing progenitors in the central dermomyotome as the source of all brown adipocytes in the interscapular BAT¹⁷, the 2018 Pax7-Cre:mTmG lineage tracing study suggested that the majority of brown adipocytes originate from Pax7-negative progenitors in the epaxial dermomyotome²². The discrepancy between the results of two Pax7 lineage tracings might have been due to differences in the targeting strategies (for example, Pax7 heterozygote knockout versus Cre knock-in without disruption of the endogenous gene) and the use of different reporter mouse strains (for example, LacZ versus Rosa26-mTmG) in these studies. Of note, disruption of one copy of Pax7 locus in the earlier work by Lepper and Fan¹⁷ could potentially affect lineage specification; thus, it seems more likely that the Pax7-negative progenitors in the epaxial dermomyotome are the origin of most adipocytes in the interscapular BAT.

In rodents, chronic cold exposure increases BAT mass and activity through both de novo recruitment of brown adipocytes and enhancing the thermogenic capacity of pre-existing brown adipocytes²³. Genetic lineage tracing using platelet-derived growth factor receptor-α reporter mice (Pdgfra-CreER^T2/tdTomato mice) combined with BrdU labelling revealed the contribution of Pdgfra-expressing adipocyte progenitors to brown adipocytes; Pdgfra-expressing adipocyte progenitors are recruited mostly to the dorsal edges of BAT in the first week of cold acclimation²⁴. Additionally, a single-cell RNA sequencing analysis of mouse BAT published in 2021 identified the transient receptor potential cation channel subfamily V member 1 (Trpv1)-expressing vascular smooth muscle-derived adipocyte progenitors as the origin of cold-induced brown adipogenesis. Cold exposure in mice induced the proliferation of Trpv1-expressing progenitors, which was followed by their differentiation to brown adipocytes²⁵.

Origin of beige adipocytes

In adult humans, gene expression analysis of BAT from the supraclavicular region revealed the expression of markers of both classic brown and beige adipocytes, indicating that human BAT is a heterogeneous pool of brown and beige adipocytes²⁶. Numerous studies in rodents have demonstrated the beneficial metabolic effects of WAT browning, therefore substantiating the contribution of beige adipocytes to whole-body metabolism. Importantly, some of the beneficial effects of these adipocytes are mediated through their secretory function and might be independent of thermogenic activity.

WAT browning.

The formation of thermogenic beige adipocytes within the white adipose tissue depots.

Two possible models of beige adipocyte recruitment.

The origin of beige adipocytes remains somewhat controversial. Two possible models for beige adipocyte recruitment have been proposed. First, beige adipocytes can form via reprogramming of white adipocytes: white to beige trans-differentiation. Second, beige adipocytes arise through de novo differentiation from tissue-resident adipocyte progenitors. The first model was originally supported by electron microscopy (EM) analysis of adipocytes in WAT of mice exposed to cold. One study found the presence of two types of UCP1-expressing cells: paucilocular adipocytes, which have a central large lipid droplet and several small lipid droplets in the periphery of the cytoplasm; and multilocular adipocytes, which have the typical morphology of the classic brown adipocytes with several small lipid droplets in the cytoplasm²⁷. EM analysis of UCP1-expressing paucilocular adipocytes showed that they have a mixture of ‘brown’ mitochondria (large with numerous transverse cristae) and elongated ‘white’ mitochondria²⁷, consistent with the presence of intermediate steps in the process of direct trans-differentiation of white into beige adipocytes. Consistently, genetic labelling of white adipocytes in mice with adiponectin-CreER^T2 and tracing their outcome upon 7 days of cold exposure has revealed that all of the UCP1-expressing multilocular beige adipocytes are derived from pre-existing white adipocytes²⁴. This interconversion process of beige and white adipocytes seems to be reversible. For example, transfer of animals from a cold environment to a warmer one results in the conversion of beige adipocytes into cells with the morphology and gene expression pattern of white adipocytes²⁸.

By contrast, another study showed that the majority of beige adipocytes formed in mouse inguinal WAT (ingWAT) upon 3 days of cold exposure are the result of de novo adipogenesis from adipocyte progenitors. In that study, ‘AdipoChaser’ mice were used to enable doxycycline-inducible permanent labelling of adiponectin-expressing adipocytes, which were tracked upon cold exposure or treatment with β₃-adrenergic receptor agonist CL316,243 (REF.²⁹). Another study using the AdipoChaser mice combined with the Rosa26-mTmG reporter (a dual fluorescent reporter mouse strain) showed the contribution of both the trans-differentiation and de novo adipogenesis to beige adipocyte recruitment in ingWAT upon cold exposure in mice³⁰.

The opposing findings of the above-mentioned studies could have been the result of differences in the lineage-tracing strategy used (tamoxifen versus doxycycline induction or LacZ reporter versus membrane tagged fluorescent proteins), as well as key differences in the experimental design of each study. Notably, tamoxifen was shown to be retained in adipose tissue for a long period following initial injection, essentially extending the ‘Pulse’ experimental period into the ‘Chase’ period. Another confounding variable is the housing temperature in which mice are raised before the experiments. A 2019 study³¹ examined the effects of housing temperatures early in life on beige adipogenesis. Using AdipoChaser mice, the researchers demonstrated that the majority of beige adipocytes formed upon transferring the mice from thermoneutrality (30 °C) to cold (6 °C) are the result of de novo adipogenesis. However, if the mice are raised at room temperature (22 °C) and then transferred to cold, only half of the beige adipocytes are formed through de novo adipogenesis and the rest originate from the pre-existing adipocytes. These findings indicate that beige adipocytes are predominantly derived from adipocyte progenitors during the first exposure of mice to cold. These beige adipocytes are converted to inactive ‘dormant’ thermogenic adipocytes, which are indistinguishable from white adipocytes, when the animals are returned to warm temperatures. Upon future exposures to cold, the dormant adipocytes can be activated to form the beige adipocytes. Of note, room temperature presents a mild cold exposure in mice and results in the appearance of the first wave of beige adipocytes observed in mice born and raised at room temperature.

One study also addressed the effect of the type of stimulus (cold versus β₃-adrenergic receptor agonist CL316,243) on beige adipogenesis³². Compared with cold exposure, the administration of CL316,243 activated the conversion of dormant beige adipocytes more potently. This phenomenon probably occurs because adipocytes express the β₃-adrenergic receptor; however, their progenitors do not. In humans, dormant BAT is found throughout the perirenal depot, especially in the region most distant to the adrenal gland³².

A role for mural progenitors.

Several studies have demonstrated the presence of white and beige adipocyte progenitors in the vessel-associated mural component of WAT^25,33–37. Lineage tracing studies using Cre drivers that mark the vascular smooth muscle lineage (Pdgfrb, Acta2, Tagln, Cspg4, Myh11 and Trpv1) have shown the contribution of smooth muscle lineage to the white and beige adipocyte pool. Although different studies have shown varying extents to which vascular smooth muscles contribute to cold-induced beige adipogenesis, together they provide convincing evidence that progenitors derived from mural lineage are the key contributors to the browning of WAT depots. Impairing the adipogenic differentiation of these mural progenitors through the deletion of the key adipogenic transcription factor, Pparg, impedes browning of WAT in adult mice^36,37.

Heterogeneity in adipocyte progenitors.

A remaining question is whether beige and white adipocytes derive from distinct types of adipocyte progenitors present in WAT, or if cold exposure stimulates the thermogenic differentiation of the common beige–white progenitors. Clonal analysis of adipocyte progenitors in ingWAT of mice identified a group of adipocyte progenitors with the potential to differentiate into beige adipocytes in vitro³⁸. Such heterogeneity in adipocyte progenitors has also been observed in human neck adipose tissue³⁹. One study identified Ebf2⁺PDGFRA⁺ progenitors present in mouse BAT and adult mouse ingWAT as beige adipocyte progenitors and showed that cold exposure increases the number of Ebf2⁺PDGFRA⁺ progenitors⁴⁰. Furthermore, genetic deletion of Ebf2 in mice results in severe loss of thermogenic gene expression in BAT without any alteration in the expression of pro-adipogenic genes⁴¹.

Single-cell RNA sequencing was used to identify a population of Lin⁻Sca1⁺CD142⁺Abcg1⁺ adipocyte progenitor in mouse ingWAT that was refractory to adipogenesis in vitro. Of note, Lin⁻Sca1⁺CD142⁺Abcg1⁺ adipocyte progenitors inhibited adipogenesis of other adipocyte progenitors in a paracrine manner during co-culture, therefore suggesting a regulatory function of these cells in reducing adipogenesis in the whole adipose depot⁴². Another study⁴³ identified three subpopulations of Sca1⁺PDGFRA⁺ adipocyte progenitors and used computational trajectory analysis to determine the hierarchical relationship between the cells in these populations. Such analysis combined with in vitro and in vivo characterization demonstrated that cells expressing dipeptidyl peptidase 4 are highly proliferative, multipotent progenitors that give rise to both committed pre-adipocytes (Icam1⁺) and CD142⁺ adipocyte progenitors. Contrary to the observation reported by Schwalie et al.⁴², the CD142⁺ cells were shown to be adipogenic in vitro and in vivo^42,43. Another study used single-cell RNA sequencing to examine the effect of the β₃-adrenergic agonist CL316,243 on lineage-negative cells from mouse ingWAT⁴⁴. The analysis revealed that administration of CL316,243 for 3 days does not result in proliferation or differentiation of adipocyte progenitors to beige adipocytes. This finding supports the notion that the CL316,243-induced recruitment of beige adipo cytes in ingWAT mostly results from white to beige adipocyte conversion. By contrast, CL316,243 treatment stimulates the proliferation of PDGFRA⁺ adipocyte progenitors in perigonadal WAT (pgWAT), followed by induction of the adipogenic gene programme⁴⁴. These studies provide strong evidence for the presence of depot-specific pathways involved in WAT browning induced by β₃-adrenergic agonists or cold exposure.

Intercellular crosstalk in the adipose niche

Although the developmental origin of adipocytes could partially explain the functional differences between adipocytes, the depot-specific microenvironment also plays a key part in directing adipocyte development and function. Adipose tissue is composed of mature adipocytes, adipocyte progenitors, immune cells, endothelial cells, smooth muscle cells, pericytes, neurons and Schwann cells. Adipocytes have a major role in maintaining energy balance, but other cell types form the adipocyte niche and regulate adipose tissue function through extensive cellular crosstalk. Such communication axes are essential for the regulation of adipose tissue turnover, expansion and remodelling, in response to external stimuli such as ambient temperature and diet. Numerous studies have demonstrated that healthy remodelling and expansion of adipose tissue is essential for adipose tissue function and metabolic health⁴⁵. Impairment in the capacity of adipose tissue to remodel is a hallmark of obesity and its sequelae.

Cold exposure is a robust stimulus of BAT activity². This stimulus increases BAT cellularity by recruitment of new brown adipocytes, as well as via expansion and remodelling of other cell types in BAT. Under conditions of increased thermogenic demand, a coordinated expansion of brown adipocyte progenitors, endothelial cells and nerve terminals occurs, as well as changes in the composition of BAT-resident immune cells, to enable maximal thermogenic activity^46,47.

Here we focus on cellular crosstalk within adipose tissue mediated through ligand–receptor interactions. We summarize our current understanding of the role of paracrine niche factors in regulating the thermogenic function of brown and beige adipocytes and how their coordinated functions contribute to the adaptation of adipose depots to environmental stimuli (BOX 1).

Box 1 |. Different mechanisms for intercellular communication in the adipose tissue microenvironment.

Multicellular organisms have developed three main ways to establish intercellular communications over short or long distances. These include direct physical cell–cell contact between adjacent cells, ligand–receptor interactions, and extracellular vesicle (EV)-mediated cellular crosstalk. All three of these communication modes have been shown to mediate intercellular crosstalk in the adipose tissue microenvironment by integrating internal and external stimuli, which maintains tissue function and homeostasis. Direct cell–cell contacts between beige adipocytes are mediated by connexin 43 gap junction channels and are essential for propagation of sympathetic nerve signals in the sparsely innervated white adipose tissue²¹⁵. Multiple ligand–receptor interactions between adipose-resident cells are discussed in this Review. EVs such as exosomes and microvesicles transport various cargoes, including proteins, lipids, DNA, RNA and other signalling molecules, between cells and tissues. For example, endothelial-derived EVs are taken up by adipocytes and are used to inform adipocytes about the systemic nutritional status²¹⁶. Adipocyte-derived EVs have also been identified as a lipase-independent pathway for lipid transport to adipose tissue macrophages²¹⁷. A 2021 study showed that mitochondria are transferred from adipocytes to macrophages in a heparan sulfate-dependent manner²¹⁸. Although the mechanism involved in the transfer of mitochondria from adipocytes to macrophages is unclear, previous studies have identified EVs as a potential vehicle for intercellular transfer of mitochondria²¹⁹. Thus, it is possible that adipocyte-derived EVs contain intact or fragmented mitochondria that are taken up by macrophages or other cells.

Neurons

BAT is innervated by an extensive network of sympathetic nerve projections that transmit signals from the central nervous system (CNS) to BAT, as well as afferent sensory neurons that convey inputs from BAT to the brain⁴⁸. The sympathetic stimulation has a crucial role in BAT thermogenesis and energy expenditure through modulating noradrenaline production and secretion from sympathetic nerve terminals. In humans, the level of BAT innervation correlates with BAT activity⁴⁹. In animals, cold exposure increases sympathetic activity in BAT and WAT by elevating the rate of noradrenaline turnover and increasing the density of sympathetic arborizations^50,51. Dynamic communication between nerve fibres, brown adipocytes and other cell types in BAT enables the appropriate growth of neurites to provide the necessary network for noradrenaline-mediated activation of brown adipocytes and to transmit afferent signals from BAT to the CNS (FIG. 1).

Fig. 1 | — Extensive communication between the neurons, thermogenic adipocytes and other cell types in adipose tissue is essential for brown adipose tissue (BAT) thermogenesis and cold-induced browning of white adipose tissue (WAT). The central nervous system (CNS) stimulates the release of neurotransmitters (pale blue), including noradrenaline (NE), neuropeptide Y (NPY) and ATP, from the sympathetic nerve terminals in BAT and WAT upon exposure to cold temperatures. Thermogenic adipocytes (here shown in beige and brown) release lipids and neurotrophic factors (pale yellow) that affect the growth, survival and function of sympathetic nerves in the adipose niche. These factors, whose production and release are stimulated by sympathetic nerve activity, promote the coordinated expansion of sympathetic innervation that is essential for maintaining tissue responsiveness to CNS signals. Both axon growth and angiogenic sprouting are regulated through a common array of attractive and repulsive cues. Nerve terminals release signalling molecules to guide and promote angiogenesis. Blood vessels also secrete factors (red) that attract and direct axons to innervate the vasculature. Sympathetic nerves regulate the development and function of immune cells by releasing neurotransmitters, such as NE and NPY. Several cytokines (grey) produced by adipose-resident immune cells also positively or negatively impact the survival and growth of sensory and sympathetic nerves. BMP, bone morphogenetic protein; NGF, nerve growth factor; NRG4, neuregulin 4; S100b, S100 calcium binding protein B; TGFβ1, transforming growth factor-β 1; VEGFA, vascular endothelial growth A factor.

Crosstalk between sympathetic nerves and adipocytes.

Sympathetic nerve terminals release factors such as noradrenaline, neuropeptide Y (NPY) and ATP to regulate adipocyte function⁴⁸. Noradrenaline stimulates adipocytes mainly through activation of the β_1–3-adrenergic receptors to promote lipolysis, increase the expression of thermogenic genes and facilitate adipose tissue remodelling⁵². Conversely, the secretion of NPY from sympathetic nerves antagonizes the function of noradrenaline and promotes adipogenesis and lipid accumulation⁵³. Noradrenaline also increases the proliferation of adipocyte progenitors in BAT and pgWAT depots. This proliferative response seems to be considerably impaired in the absence of β₁-adrenergic receptors^24,54. However, the underlying molecular pathway leading to noradrenaline-induced proliferative responses has remained undefined.

Adipocytes produce fatty acids and other bioactive lipids, such as endocannabinoids, with potential effects on sympathetic nerves. Evidence from mouse models suggests that the endocannabinoid system has negative regulatory effects on adipose sympathetic innervation and thereby inhibits BAT thermogenesis and promotes WAT accumulation⁵⁵. Whether these effects are mediated via direct action of endocannabinoids on sympathetic nerve activity in adipose tissue or through central mechanisms needs to be investigated.

Studies in mouse models have shown that, in addition to lipids, adipocytes secrete several neurotrophic factors including neuregulin 4 (REF.⁵⁶), nerve growth factor^57,58 and S-100 protein β-chain⁵⁹ that promote neurite outgrowth. Furthermore, BMP8b secreted from adipocytes was shown to improve sympathetic innervation by upregulating neuregulin 4 expression in BAT and WAT in mice⁵⁶. Cold exposure increases the expression of these neurotrophic factors in brown and beige adipocytes. Furthermore, loss or reduction in the expression of these factors is associated with impairment in BAT thermogenic capacity in mice, which results from reduced sympathetic innervation and activity^56,58,59.

Crosstalk between sympathetic nerves and adipose vasculature.

The close anatomical and functional relationship between the vasculature and peripheral nerve fibres ensures the interrelated growth and remodelling of the neurovascular network in several tissues. Both axon growth and angiogenic sprouting are regulated through a common array of attractive and repulsive cues and a substantial overlap exists between the factors that direct these processes. Blood vessels secrete factors that attract and direct axons to innervate the vasculature. Conversely, nerves also release signalling molecules to guide and promote angiogenesis⁶⁰.

Sympathetic activation of BAT in mice results in the rapid upregulation of vascular endothelial growth factor A (VEGFA) expression in brown and beige adipocytes⁶¹. Additionally, vascular cells also secrete VEGFA, which acts on the VEGFR2 receptor expressed on sympathetic nerves and promotes axon growth⁶². Transient overexpression of VEGFA in mouse WAT increases sympathetic innervation and promotes lipolysis, leading to WAT browning⁶³.

Crosstalk between sympathetic nerves and immune cells.

Pro-inflammatory and anti-inflammatory cytokines produced by adipose-resident macrophages influence the survival and growth of sensory and sympathetic nerves. In conditions of chronic tissue inflammation, the accumulation of inflammatory cytokines might lead to the repulsion of sympathetic fibres and could even result in nerve damage⁶⁴. Other evidence supporting the direct role of BAT-resident macrophages on sympathetic nerve activity emerged from a mouse model of macrophage-specific mutation in Mecp2, a gene mutated in the rare neurological disorder Rett syndrome. Mice lacking Mecp2 in CX3CR1-expressing macrophages gain more weight than their wild-type littermates on chow or high-fat diets. The macrophage-specific Mecp2-knockout mice show reduced BAT innervation and impaired thermogenesis⁶⁵.

Sympathetic neurotransmitters such as noradrenaline and NPY have been shown to directly affect human immune cells⁶⁶. Immune cells such as macrophages and T cells express the adrenergic receptor, suggesting the potential for direct communication axes between sympathetic nerves and immune cells⁶⁷.

Vascular cells

BAT is one of the most vascularized tissues in the body⁶⁸. Several external stimuli including cold, nutritional status, diet and exercise promote angiogenesis and vascular remodelling in adipose tissue. The reciprocal interactions between adipocytes and vascular cells are crucial for providing the optimal supply of oxygen, nutrients, hormones and other bioactive molecules for adipocytes.

In WAT, induction of angiogenesis is essential for the healthy expansion of adipose tissue. In individuals with obesity, the excessive and rapid expansion of WAT mass is usually not coordinated with the expansion of vasculature, resulting in tissue hypoxia and eventually leading to inflammation, fibrosis and insulin resistance. In mouse BAT, the triggering of angiogenic processes elevates thermogenesis and improves whole-body metabolism⁶⁹.

Here we discuss the interactions between adipocytes, endothelial cells and other cell types in the adipose niche that have been shown to contribute to adipose function (FIG. 2).

Fig. 2 | — Accumulation of pro-angiogenic factors combined with reduced levels of angiogenic inhibitors in the adipose niche promotes the expansion and remodelling of the vascular network in response to thermogenic stimuli. Thermogenic adipocytes (shown in beige and brown) and their progenitors secrete several angiogenic factors (pale yellow) to guide vascular cells to expand, regress or remodel depending on the requirements of the adipose tissue microenvironment. Reciprocally, endothelial cells release factors (red), such as endothelin1 (EDN1) and nitric oxide (NO), that promote the thermogenic function of brown and beige adipocytes. EDN1 and platelet-derived growth factor C (PDGF-C) also regulate adipogenesis in progenitors. Pro-angiogenic and anti-angiogenic cytokines (grey) and growth factors secreted by immune cells regulate vasculature function and remodelling. ANGPT1, angiopoietin 1; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; NPY, neuropeptide Y; TGFβ1, transforming growth factor-β 1; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.

Cellular crosstalk between adipocytes and vascular cells.

Adipocytes secrete angiogenic factors including members of the VEGF family, angiopoietins (ANGPT1, ANGPT2) and hepatocyte growth factor (HGF)⁷⁰.

In mice, VEGFA is the key factor responsible for the angiogenic response of BAT to cold exposure or β₃-adrenergic stimulation⁷¹. VEGFA is a highly specific and potent angiogenic factor that promotes proliferation, migration and survival of vascular endothelial cells⁷². Specific overexpression of VEGFA in brown adipocytes enhances mitochondrial respiration and thermogenesis. This effect is associated with an increase in energy expenditure that protects mice against diet-induced obesity and improves their glucose and lipid metabolism⁶⁹. Another member of the VEGF family, VEGFB, also has a role in adipose tissue vascular remodelling. VEGFB also acts on endothelial cells to enhance proliferation and fatty acid utilization⁷³. Members of the VEGF family bind to two tyrosine kinase receptors, VEGFR1 and VEGFR2 (REF.⁷²), and VEGF-induced angiogenesis is mediated through VEGFR2. By contrast, evidence from in vivo mouse studies suggests that VEGFR1 acts as a decoy receptor and limits the binding of VEGF ligands to VEGFR2 (REF.⁷⁴). Together, these findings provide strong support for the contribution of the VEGF–VEGFR axis in the regulation of adipose tissue angiogenesis and thermogenic function. However, future studies are required to provide the mechanistic link between increased angiogenesis and the activation of the thermogenic programme in WAT.

Endothelial cells regulate adipocyte function through the secretion of endothelin 1 (EDN1) and nitric oxide. EDN1 inhibits differentiation of human and mouse adipocyte progenitors⁷⁵. In mature adipocytes, EDN1 stimulates lipolysis through binding to endothelin receptor type A, but not endothelin receptor type B⁷⁶. Nitric oxide triggers the relaxation of vascular smooth muscle to promote vasodilation⁷⁷, which enables nutrients to influx into BAT, a process that is required for enhanced thermogenesis. Additionally, nitric oxide directly acts on brown and beige adipocytes to induce mitochondrial biogenesis and the thermogenesis process⁷⁸.

Cellular crosstalk between adipocyte progenitors and vascular cells.

Adipocyte progenitors can also secrete several angiogenic factors, including VEGFA, HGF, fibroblast growth factor 1 (FGF1), FGF2, transforming growth factor-β1 (TGFβ1) and PDGFs⁷⁰, to guide vascular cells to expand, regress or remodel depending on the requirements of the adipose tissue microenvironment. FGFs are suggested to indirectly modulate neovascularization and angiogenesis by inducing the production of other pro-angiogenic factors such as VEGFs and HGF⁷⁹. PDGFs are ligands that bind to and signal through their cognate tyrosine kinase receptors (PDGFRA and PDGFRB)⁸⁰. In addition to their role in the regulation of tissue vasculature, one study demonstrated the role of PDGFs in thermogenic adipocyte formation. Genetic deletion or pharmacological inhibition of PDGF-C in mice statistically significantly abrogated CL316,243-induced beige adipocyte formation in WAT, a phenotype that was rescued by overexpression of PDGF-C. Furthermore, PDGF-C treatment of both undifferentiated and differentiated PDGFRA-expressing progenitors induced thermogenic gene programme⁸¹. However, since the level of Pdgfra expression in adipocytes is much lower than in progenitors, in vivo PDGF-C probably acts on adipocyte progenitors to direct their differentiation towards beige adipocytes.

Cellular crosstalk between adipose immune cells and vasculature.

Adipose tissue immune cells secrete several cytokines and growth factors with pro-angiogenic and anti-angiogenic potential⁸². Macrophages can regulate angiogenic processes and this regulation plays a key part in wound healing and tissue repair^83,84. Macrophage infiltration in adipose tissue has been shown to promote angiogenesis in humans and animal models through secretion of factors such as tumour necrosis factor, IL-8, WNT and PDGF^85–87. Adipose tissue macrophages were also shown to be a major source of PDGF, which is at least partially responsible for hypoxia-induced angiogenesis observed in adipose tissues of obese mice⁸⁶.

Adipose immune cells

Adipose tissue depots house a wide array of immune cells including macrophages, dendritic cells, lymphocytes, neutrophils, eosinophils and mast cells. These resident immune cells have crucial roles in the maintenance of adipose tissue homeostasis. Emerging evidence demonstrates that multiple adipose-resident immune cell types are dysregulated in obesity and are associated with its progression and related metabolic complications. Obesity-induced adipose inflammation, which occurs as a result of chronic nutritional overload, mediates insulin resistance in type 2 diabetes mellitus⁸⁸.

Over the past decade, studies have found unexpected roles for multiple immune cells in the development and function of BAT and beige adipose tissue. Although recruitment of M1 macrophages and other inflammatory immune cells is associated with suppression of thermogenesis⁸⁹, a type 2 immune response is shown to promote BAT activation and WAT browning in mice^90–95.

M1 macrophages.

Macrophages that secrete pro-inflammatory cytokines and chemokines and mediate host defence against pathogens.

Type 2 immune response.

An immune response characterized by infiltration of alternatively activated (or M2) macrophages, eosinophils and innate lymphoid type 2 cells.

Here we focus on reviewing the role of different immune cells in regulating thermogenic adipocytes (FIG. 3).

Crosstalk between immune cells, adipocytes and adipocyte progenitors.

At the onset of obesity, the release of pro-inflammatory cytokines from adipocytes combined with the presence of other stressors favours polarization of macrophages in WAT to a M1-like phenotype. The recruitment of these activated M1-like macrophages facilitates the infiltration of other inflammatory immune cells into the adipose depot, which further exacerbates chronic inflammation and impairs insulin-regulated adipocyte metabolism in obesity⁹⁶. In mice, obesity is associated with increased expression of pro-inflammatory cytokines in BAT and the recruitment of several immune cell types, albeit with less intensity than in WAT⁹⁷. Similar to the processes occurring in WAT, the pro-inflammatory environment in BAT in rodents and individuals with obesity disturbs glucose metabolism and causes insulin resistance in brown adipocytes⁹⁸. Additionally, pro-inflammatory cytokines can directly suppress thermogenic gene expression and hamper thermogenic function in vitro and in vivo^89,99. These findings led to the conclusion that obesity produces a self-sustained inflammatory response in adipose tissue that suppresses beige adipogenesis¹⁰⁰.

Although M2 macrophages have been reported to contribute to sustaining adaptive thermogenesis, the specific mechanism remains to be elucidated. Loss of IL-4 and IL-13 cytokine signalling, which is required for alternative activation of M2 macrophages, impairs cold-induced BAT thermogenesis and WAT lipolysis in mice^90,91. Myeloid cell-specific deletion of tyrosine hydroxylase, which is the rate-limiting enzyme of noradrenaline biosynthesis, decreased noradrenaline content in ingWAT of cold-acclimated mice, suggesting that alternatively activated M2 macrophages are a source of catecholamine in WAT⁹¹. However, these findings were not reproduced by another study using a mouse model of inducible adult-onset loss of tyrosine hydroxylase in myeloid lineage¹⁰¹. This study detected no tyrosine hydroxylase expression in the macrophage populations isolated from BAT or ingWAT either at room temperature or following cold exposure¹⁰¹. Although the reasons for the striking discrepancies between these studies remain unclear, the use of different animal models (congenital versus adult-onset) might partially explain the differences.

A 2017 study identified a population of sympathetic neuron-associated macrophages that mediate the clearance of extracellular noradrenaline and thereby negatively regulate noradrenaline availability and thermogenic activity of BAT and beige adipose tissue¹⁰². Consistent with this finding, another group observed a higher frequency of sympathetic neuron-associated macrophages in two mouse models of obesity, indicating the role of these macrophages in regulating adipose tissue function and energy balance¹⁰².

Several adipocyte-derived factors have been shown to contribute to promoting the M2 macrophage phenotype in adipose tissue. For example, CXCL14 is a chemokine secreted from brown adipocytes that induces macrophages to favour M2 polarization¹⁰³. Cold exposure increases both expression and release of CXCL14 protein from BAT. CXCL14-null mice display a substantial reduction of the number of M2 macrophages in interscapular BAT and ingWAT, accompanied by reduced thermogenesis and impaired glucose tolerance. Furthermore, systemic administration of recombinant CXCL14 in these mice promotes recruitment of M2 macrophages to WAT and induces WAT browning¹⁰³. Adiponectin is another adipokine that was found to promote the proliferation of M2 macrophages in ingWAT of mice upon cold exposure⁹³. Additionally, in vitro treatment of RAW 264.7 macrophages with the conditioned medium from brown adipocytes repressed the expression of inflammatory genes, and knocking down GDF15 in brown adipocytes reduces the anti-inflammatory effects of the brown adipocyte secretome. These findings suggest that GDF15 is a potential anti-inflammatory brown adipokine¹⁰⁴.

Eosinophils seem to be the major source of IL-4 in ingWAT of mice^91,105. Eosinophil-derived IL-4 acts through two key mechanisms to promote beige adipocyte formation. First, IL-4 induces alternative activation of macrophages through the secretion of type 2 cytokines within the adipose niche. For example, meteorin-like (METRNL) is a hormone that was found to induce the thermogenic programme in ingWAT through a mechanism that involves eosinophil-derived IL-4 and alternative activation of macrophages. Blocking IL4–IL13 signalling in mice impaired METRNL-induced thermogenesis and β-oxidation gene programmes¹⁰⁶. Future investigations are required to identify the physiologically relevant METRNL-producing cell type(s) inside or outside adipose tissue.

The second mechanism by which eosinophils and IL-4 signalling regulate adipose thermogenesis is through the induction of proliferation and commitment of adipocyte precursors into beige adipocytes^92,94. Genetic mouse models lacking eosinophils, IL-4 and IL-13, or IL-4Rα show a considerable reduction in both number and proliferation rate of PDGFRA⁺ adipocyte progenitors in ingWAT. Intriguingly, IL4Rα-mediated signalling in PDGFRA⁺ adipocyte progenitors, and not in myeloid cells, is responsible for the effects of IL-4 on the expansion of adipocyte progenitor pool and beige adipogenesis⁹². Consistent with these findings, adipocyte-derived FGF21 was shown to induce WAT browning through CCL11-mediated recruitment of eosinophils, which in turn secrete IL-4 and promote proliferation and adipogenic commitment of PDGFRA⁺ adipocyte progenitors⁹⁴.

Innate lymphoid type 2 cells (ILC2s) are another group of adipose-resident immune cells that are the major source of IL-5 and IL-13, which promote the recruitment and accumulation of eosinophils and alternatively activated M2 macrophages¹⁰⁷. Upon activation with cytokines IL-33, IL-25 and thymic stromal lymphopoietin, ILC2s produce IL-5, IL-13 and IL-9, and initiate a type 2 immune response¹⁰⁸. Studies have revealed that ILC2s also directly regulate beige adipocyte formation by regulating adipocyte precursor numbers and fate^92,95. In a study in which IL-33 was administered to activate ILC2s in mice housed under thermoneutral conditions, ILC2-derived IL-13 and eosinophil-derived IL-4 were observed to stimulate the proliferation of adipocyte progenitors in ingWAT and increased the expression of beige markers CD137 and TMEM26 (REF.³⁸). The effects of IL-4 and IL-13 on the expansion of beige adipocyte progenitors required IL-4Ra expression on PDGFRA⁺ progenitors, indicating that these cytokines act directly on adipocyte progenitors to increase WAT browning⁹². Future studies should address the cellular source and pathways involved in endogenous IL-33 production in adipose tissue, which could potentially be targeted as a therapeutic strategy to induce beige adipose tissue expansion to counteract obesity. ILC2s also produce methionine–enkephalin peptides that enhance UCP1 expression by acting directly on adipocytes and inducing browning of ingWAT in vivo⁹⁵.

Another population of lymphocytes implicated in a 2020 study of the regulation of BAT thermogenesis in mice are γδ T cells¹⁰⁹. The pro-thermogenic function of γδ T cells is mediated by IL-17F release from γδ T cells and interaction with the receptor IL-17RC on brown adipocytes. Perturbing this signalling axis causes defects in BAT innervation and impaired adaptive thermogenesis. TGFβ1 has been identified as the secreted factor downstream of the IL-17F–IL-17RC pathway that communicates with sympathetic nerves to promote neurite growth and expand BAT innervation¹⁰⁹ (FIG. 1). Finally, B220⁺ B cells, CD4⁺ αβ T cells and M2 macrophages in ingWAT in mice have been shown to produce acetylcholine, which acts through the CHRNA2 (cholinergic receptor nicotinic α2-subunit) on beige adipocytes to induce the thermogenic response¹¹⁰.

Autocrine and paracrine factors

In addition to the interactions between adipocytes and other cell types within adipose tissue, adipocytes release multiple factors (proteins^111–122, lipids^123,124 and metabolites¹²⁵) into their niche that act in an autocrine and/or paracrine manner to regulate the thermogenic function of brown and/or beige adipocytes (FIG. 4). The thermogenic adipocyte-derived secreted factors include members of the BMP–TGFβ superfamily¹²², FGF families of growth factors^113,120, the secreted SLIT2 fragments¹¹⁸, bradykinin¹²¹, the secreted enzyme peptidase M20 domain containing 1 (PM20D1)¹¹⁷, ependymin-related protein 1 (EPDR1)¹¹⁹, adenosine¹²⁶, and lipokines 12,13-diHOME^123,127 and 12-HEPE¹²⁴, as well as others. Some of them also mediate inter-organ communications. Using single-nucleus RNA sequencing and functional studies, a population of adipocytes were identified that express CYP2E1 and ALDH1A1 that can secrete acetate to repress the thermogenic activity of neighbouring adipose cells¹²⁵. The role of these autocrine and/or paracrine factors in adipose tissue has been extensively reviewed elsewhere^128,129. Thus, we only highlight the key factors regulating adipocyte thermogenesis in FIG. 4.

Fig. 4 | — Several factors released by brown and beige adipocytes function in an autocrine and/or paracrine manner to regulate nutrient utilization and thermogenic gene expression in adipocytes. The secreted factors (pale blue circles and boxes) include members of bone morphogenetic protein (BMP) and transforming growth factor-β (TGFβ), such as BMP8b, myostatin (MSTN), fibroblast growth factor (FGF) families of growth factors (for example, FGF6, FGF9 and FGF21), bradykinin, SLIT2, PM20D1, adenosine and others. Additionally, thermogenic adipocyte-derived lipokines, such as 12,13-diHOME and 12-HEPE, promote fatty acid and glucose uptake to adipocytes, thereby controlling key aspects of fuel utilization and energy metabolism in brown adipose tissue and white adipose tissue. CREB, cAMP responsive element binding protein; FATP1, fatty acid transport protein 1; GPCR, G protein-coupled receptor; HSL, hormone-sensitive lipase; PKA, protein kinase A; PM20D1, the secreted enzyme peptidase M20 domain containing 1. UCP1, uncoupling protein 1.

Inter-organ communication

Although the beneficial anti-obesity effects of BAT have been traditionally attributed to its high metabolic rate and fuel utilization capacity, in the past 10 years studies have highlighted the secretory role of BAT. Some of these adipocyte-released factors act locally and others can target distant organs that express the corresponding receptors for the ligands. Notably, certain factors can target both BAT and other organs. Some of these interactions could trigger positive or negative feedback loops that further modulate BAT-mediated thermogenesis. Here we review the current understanding of the endocrine BAT and/or beige adipose tissue-derived factors (batokines) and their roles in systemic metabolism. We also discuss factors secreted from other organs that modulate functions of thermogenic adipocytes (FIG. 5).

Fig. 5 | — Thermogenic adipose tissue (shown here as beige and brown adipocytes) is recognized as an endocrine organ, which can secrete several factors (pale yellow) to regulate the gene expression or functions in distant organs, such as the heart, liver, muscle and white adipose tissue. These organs, as well as the brain and gut, can also communicate to thermogenic adipose tissue through the secretion of endocrine factors (pale blue) in response to different stimulations. This inter-organ communication highlights the importance of thermogenic adipose tissue in whole-body metabolism. ACTH, adrenocorticotropic hormone; BAIBA, β-aminoisobutyric acid; EPDR1, ependymin-related protein 1; EVs, extracellular vesicles; FGF, fibroblast growth factor; GCs, glucocorticoids; GLP1, glucagon-like peptide 1; METRNL, meteorin-like glial cell differentiation regulator; NE, noradrenaline; NPs, natriuretic peptides; NRG4, neuregulin 4; PM20D1, peptidase M20 domain containing 1; SLIT2, slit guidance ligand 2; TGFβ2, transforming growth factor-β2; TSH, thyroid-stimulating hormone.

BAT–WAT communication

Fatty acids are key contributors to the thermogenesis process in BAT and beige adipose tissue by serving both as fuel for thermogenesis and stimulators of UCP1 function. Studies have demonstrated that in the absence of food or BAT lipolysis, fatty acids released from WAT are indispensable for BAT thermogenesis. Blocking lipolysis in BAT and beige adipose tissue in mice by genetic ablation of Atgl (that encodes an enzyme that catalyses the initial step in triglyceride hydrolysis)¹³⁰ or CGI-58 (that encodes an activator of ATGL)¹³¹ in UCP1-expressing cells did not impair cold-induced thermogenesis. A 2019 study showed that TGFβ2 protein is upregulated and secreted from subcutaneous WAT of mice after exercise training. Transplantation of WAT from trained mice to untrained mice promotes glucose uptake in many tissues, including endogenous BAT, through secretion of TGFβ2 (REF.¹³²).

BAT–brain communication

Within adipose tissue, BAT-secreted factors can target sympathetic and sensory nerves¹³³ to promote neurite projection and activity. In addition to these local effects, the BAT–brain communication axis regulates systemic energy balance and food intake by informing the CNS of the energetic status of the body.

Besides the well-known sympathetic signalling pathway, several central actions mediated by hormones also contribute to BAT thermogenesis. For example, cold exposure stimulates the hypothalamus to release TSH-releasing hormone, which stimulates the pituitary to release TSH that acts on the thyroid to induce thyroid hormone secretion; thyroid hormone, T₃ and/or T₄, then directly drives BAT thermogenesis by induction of UCP1 (REF.¹³⁴). T₃ can also act on the hypothalamus to regulate WAT browning, lipid oxidation in BAT and hepatic lipogenesis¹³⁵. Mechanistically, T₃ suppress AMPK signalling in the ventromedial nucleus of the hypothalamus to modulate peripheral metabolism via activation of the parasympathetic nervous system and sympathetic nervous system (SNS).

BMP8b¹²² and oestrogens also contribute to energy expenditure via this hypothalamus–SNS–BAT axis. The central action of oestradiol decreases ceramide-induced lipotoxicity and oestrogen receptor stress in mice¹³⁶. Moreover, the neurons in the arcuate nucleus of the hypothalamus contribute to WAT browning. Coordination of leptin and insulin signalling in pro-opiomelanocortin (POMC)-expressing neurons, the anorexigenic (appetite-suppressing) neurons, promote WAT browning in mice¹³⁷; however, activation of O-GlcNAc signalling in AgRP orexigenic (appetite-inducing) neurons upon fasting in mice suppresses WAT browning to conserve energy¹³⁸.

Glucocorticoids are a type of corticosteroid that are synthesized in the adrenal cortex. In rodents, glucocorticoids have been demonstrated to suppress the expression of UCP1 in brown adipocytes^139,140; however, a 2019 study demonstrated that glucocorticoid-induced obesity is independent of the decrease in UCP1-mediated thermogenesis in mice¹⁴¹. Interestingly, glucocorticoids seem to exert opposite effects in humans. For example, acute administration of the synthetic glucocorticoid predniso-lone promoted glucose uptake and increases skin temperatures in the supraclavicular BAT region of human volunteers during mild cold exposure (16–17 °C)¹⁴². Similarly, in human brown adipocytes, glucocorticoids increased isoprenaline-induced UCP1 expression and mitochondrial respiration¹⁴². Further studies are needed to investigate the mechanisms underlying the observed differences between humans and mouse models.

BAT–heart communication

Increasing evidence indicates an association between reduced BAT activity and cardiovascular abnormalities in humans and mice^143–145. For example, a mouse model with loss of Ucp1-expressing cells is prone to developing obesity on a normal chow diet but also displays deleterious cardiovascular phenotypes such as cardiomyopathy, fibrosis and hypertension¹⁴³. Genetic ablation of Ucp1 in mice also results in cardiac hypertrophy and adverse echocardiographic function in response to stimulation. Consistently, transplantation of normal BAT into Ucp1^−/− mice provides cardioprotective effects¹⁴⁴. In 2021, a large retrospective study demonstrated that the presence of BAT is associated with a low prevalence of cardiometabolic diseases and improved blood glucose and lipid content in humans, including individuals with obesity¹⁴⁵. The authors of this study proposed that BAT mediates cardiovascular health, at least partially, through the release of some potential cardiovascular regulators.

The direct causal relationship between BAT-secreted FGF21 and cardiovascular function was established in a study in hypertensive mice¹⁴⁶. Activation of adenosine receptor A2aR signalling in hypertensive rats ameliorated hypertension-related cardiac hypertrophy¹²⁶. Notably, in a chemical-induced hypertension mouse model, A2aR activation in BAT promoted FGF21 release and improved heart performance. Specific blockage of FGF21 secretion from BAT attenuates the recovery from heart injury in the mice, indicating crosstalk between BAT and the heart through FGF21 (REF.¹⁴⁶).

Factors produced by the heart could regulate BAT activity. Cold exposure increases secretion of B-type natriuretic peptides from the heart into the circulation¹⁴⁷. Natriuretic peptide treatment in mouse and human adipocytes promotes mitochondrial biogenesis, thermogenic gene expression and induces lipolysis in brown and beige adipocytes via the cGMP–PKG–p38 signalling pathway¹⁴⁷.

BAT–liver communication

Enhanced fatty acid utilization by activated BAT results in fatty acid clearance from the circulation, which potentially improves the ectopic deposition of lipids in the liver^148,149. Emerging evidence also indicates the presence of direct crosstalk between brown and/or beige adipocytes and hepatocytes through batokines (such as NRG4 (REF.¹⁴⁸), adiponectin¹⁴⁹ and FGF21 (REF.¹⁵⁰)). MicroRNAs (miRNAs) are packaged into extracellular vesicles (EVs), thereby providing a potent and targeted way for miRNA shuttling between organs, as EVs can maintain miRNA stability and enable specific delivery to certain tissues via surface ligands or receptors¹⁵¹. One study in rodents¹⁵² demonstrated that BAT serves as a major source of circulating miRNA in EVs. Furthermore, miRNAs in BAT-derived EVs regulate FGF21 gene expression and secretion in the liver. Of note, the levels of circulating EVs are considerably reduced in mice with severe lipodystrophy, and BAT transplantation from wild-type mice rescues the levels of most miRNAs in EVs¹⁵².

FGF21 mediates a bidirectional communication axis between BAT and the liver. Liver-derived FGF21 has a role in the activation of thermogenesis in mouse neonatal BAT¹⁵³. Moreover, cold exposure in mice was found to stimulate the liver to produce acylcarnitines, which can be delivered to BAT to act as substrates to facilitate UCP1-dependent uncoupling respiration and heat production¹⁵⁴. The action of CPT1B in generating acylcarnitines from free fatty acids is usually inhibited by elevated levels of malonyl-CoA in brown adipocytes upon cold exposure¹⁵⁴. Thus, the rate-limiting step of fatty acid oxidation is bypassed by using liver-derived acylcarnitines as fuel, which is more efficient for thermogenesis.

Beyond their role in lipid absorption of the intestine, bile acids also serve as signalling molecules to regulate lipid metabolism and energy expenditure in BAT. Bile acids bind to the G protein-coupled receptor (GPCR) TGR5 in brown adipocytes, and induce cAMP-dependent activation of type 2 iodothyronine deiodinase and thermogenesis¹⁵⁵. Genetic deletion of hepatic Na⁺ taurocholate co-transporting polypeptide in mice inhibits the clearance of bile acids from plasma, which increases the circulating levels of bile acids and protects the mice against diet-induced obesity by promoting BAT function¹⁵⁶. Similarly, the bile acid–TGR5 axis is also involved in subcutaneous WAT browning in mice after cold exposure or high-fat diet feeding¹⁵⁷. In humans, oral administration of the bile acid chenodeoxycholic acid elevates whole-body energy expenditure and glucose uptake in BAT¹⁵⁸.

BAT–skeletal muscle communication

Increasing evidence shows that exercise triggers major adaptations in BAT and WAT, including BAT activation, remodelling of WAT depots and subcutaneous WAT browning¹⁵⁹. Other than changes in energetic demands, these adaptations are thought to result from altered secretion of muscle-derived factors (myokines) that affect adipose tissue function. Additionally, in 2018, two studies identified the cold or exercise-induced batokines that can influence skeletal muscle function^127,160.

12,13-diHOME is a cold-induced and exercise-induced batokine in mice and humans^123,127. In addition to enhancing fatty acid utilization in BAT¹²³, 12,13-diHOME can also promote fatty acid uptake and oxidation in myocytes¹²⁷. Moreover, a BAT–muscle crosstalk axis was identified that is mediated by myostatin secretion from BAT¹⁶⁰. Loss of the transcription factor IRF4 in BAT of mice induces myostatin expression and secretion in BAT, resulting in reduced exercise capacity, impaired mitochondrial function and several other abnormalities in skeletal muscles. Furthermore, the authors of this study observed a similar increase in myostatin expression in BAT and circulating levels of myostatin when housing mice at thermoneutrality as compared with room temperature, which also led to decreased exercise capacity¹⁶⁰.

Accumulating evidence suggests that the exercise-induced myokine IL-6 is required for exercise-induced BAT activity and WAT browning, based on studies using an IL-6-deficient mouse model^161,162. Moreover, daily injection of IL-6 in mice for a week stimulated UCP1 induction in BAT and beige adipose tissue¹⁶². Of note, IL-6 is also a batokine^161,163. For example, acute psychological stress in rodents was demonstrated to induce IL-6 secretion from BAT via β₃-adrenergic signalling. This effect anticipates adaptation of fight or flight responses by promoting hepatic gluconeogenesis, but also reducing tolerance to inflammation¹⁶³. In addition, exercise-induced increases in circulating METRNL were found to improve glucose tolerance and energy expenditure in mice via the promotion of BAT and/or beige adipose tissue activity and the induction of anti-inflammatory cytokines¹⁰⁶. Conversely, blocking METRNL actions through neutralizing antibodies attenuates the exercise-induced thermogenesis response and M2 macrophage activation upon exercising in mice¹⁰⁶. Other exercise-induced myokines (including irisin¹⁶⁴, lactate¹³² and β-aminoisobutyric acid¹⁶⁵) have also been found to promote the activity of BAT and beige adipose tissue. These findings indicate that mutual communication between BAT and skeletal muscle maintains the balance between energy utilization and storage depending on the physiological demands.

BAT–gut communication

The gastrointestinal tract (gut) has been recognized for its role in diet-induced thermogenesis through secreted factors from intestinal cells that trigger the gut–brain–BAT axis or directly activate the gut–BAT axis. Moreover, an increasing number of studies have demonstrated the roles of gut microbiota in whole-body metabolism of the host via the pleiotropic effects of microbial metabolites.

Glucagon-like peptide 1 (GLP1) is a peptide hormone that is secreted from intestinal enteroendocrine L cells. GLP1 not only enhances glucose-stimulated insulin secretion in β-cells but also activates BAT thermogenesis. Meal-induced thermogenesis is generally believed to be induced through GLP1-mediated regulation of efferent sympathetic innervation in BAT by modulating AMPK activation in the hypothalamus in rodent models¹⁶⁶. A 2018 study showed a novel gut–BAT–brain axis involving secretin, which is secreted by the duodenum. Prandial increases in the release of secretin result in its direct binding to the secretin receptor in BAT, which leads to the activation of lipolysis and thermogenesis. BAT, in turn, relays unknown signals to the brain to suppress food intake¹⁶⁷. In humans, the level of circulating secretin after a meal is correlated with energy expenditure and fatty acid uptake¹⁶⁷. Administration of secretin substantially promotes glucose uptake in human neck BAT^167,168.

The gut microbiota produces metabolites, nutrients and vitamins in a dynamic manner¹⁶⁹ and has been linked with the activities of BAT and WAT. Germ-free mice or mice with microbiota depletion display increased lipolysis in BAT¹⁷⁰ and browning of subcutaneous and visceral WAT depots¹⁷¹. By contrast, antibiotic-induced microbiota depletion in mice impaired the thermogenic function of BAT and reduced WAT browning¹⁷². These conflicting observations might result from the differences in the compositions of the antibiotic cocktail and the duration of treatment used in these studies. Of note, the composition of gut microbiota substantially changes upon cold exposure. Transplantation of the microbiome from cold-induced mice improved BAT function¹⁷³ and WAT browning¹⁷⁴ in recipient mice, leading to improvements in insulin sensitivity and cold tolerance. Furthermore, intermittent fasting in mice alters the composition of the microbiota, which activates the function of BAT, thereby contributing in part to the anti-obesity effects of intermittent fasting¹⁷⁵.

Therapeutic applications

Given the role of BAT and beige adipose tissue in energy expenditure and modulation of glucose and lipid metabolism, and its crosstalk to other tissues, targeting thermogenic adipose tissue provides a promising therapeutic approach to combatting obesity and metabolic dis orders. Several studies have demonstrated that increasing the amount and activity of BAT improves metabolism in mouse models of obesity or diabetes mellitus¹⁷⁶. However, rodent and human thermogenic adipose tissue depots are different in their anatomical locations and amounts relative to total body weight, as well as the molecular basis and developmental origin of the tissue. It is generally believed that merely increasing the level of UCP1 expression or the amount of thermogenic adipose tissue might not be sufficient to drive thermogenesis; constant activation signals are also required. From the translational point of view, we focus here on the therapeutic potential of activating thermogenic adipose tissue in humans and/or converting human white adipocytes into thermogenic adipocytes through pharmacological, gene-based or cell-based therapies (FIG. 6).

Fig. 6 | — In pharmacological therapies, several compounds, proteins, lipids or metabolites have been applied for treating obesity in human clinical trials through the regulation of thermogenic adipose tissue activity and energy expenditure. In gene therapy, the delivery of DNA (transgene), mRNA, microRNA or Cas9–guideRNA systems is used for increasing the expression of genes involved in the thermogenic pathway. Targeted delivery into thermogenic adipose tissue or white adipose tissue increases efficiency and specificity and minimizes the adverse effects on other cell types. Cell-based therapies include autologous and allogeneic cell therapy according to the source of the transplanted cells. In autologous cell therapy, precursor cells isolated from an individual with obesity can be engineered and differentiated to thermogenic adipose tissue, followed by transplanting back to the same individual. Allogeneic cell therapy uses precursor cells from healthy donors. Although this strategy overcomes the burden of cell source, preventing transplanted cells from immune rejection needs to be considered using hydrogel encapsulation or reducing immunogenicity before allogeneic cell transplantation into the recipients. Although gene-based and cell-based therapy have not yet been applied for treating obesity in humans, these might be potential strategies.

Pharmacological approaches

Exposure to cold is a potent stimulus activating BAT function and inducing the conversion of WAT to beige adipose tissue through stimulating β-adrenergic signalling in both humans and mice. However, cold exposure is inconvenient, uncomfortable and ultimately an unrealistic intervention in many cases. Besides, cold exposure might induce other unwanted effects such as an increase in blood pressure¹⁷⁷. Therefore, much effort has been invested in identifying more specific, potent pharmacological products with minimized adverse consequences (TABLE 1).

Table 1 |.

Pharmacological therapies targeting activation of thermogenic adipose tissue in humans

Type of therapy	Compound	Manipulation	Study participants	Effects	Refs
β₃-Adrenergic agonist	Mirabegron	Oral administration: 200 mg, one dose	Healthy lean men	Higher BAT activity than in placebo- treated individuals; increased energy expenditure	(NCT01950520)^178,179
		Oral administration: 50 mg or 200 mg, one dose	Healthy lean men	Compared with pretreatment: no change in BAT activity with 50 mg dose; higher BAT activity with 200 mg dose	(NCT02811289)¹⁸⁰
		Oral administration: 100 mg per day for 4 weeks	Healthy lean women	Higher BAT activity than pretreatment; increased energy expenditure	(NCT03049462)¹⁸¹
		Oral administration: 50 mg per day for 12 weeks	People with obesity	Activation of WAT beiging; improved insulin sensitivity; improved β-cell function	(NCT02919176)¹⁸²
Capsaicinoids	Capsinoids	Oral administration: 10 mg/kg per day for 4 weeks	People with obesity	Increased energy expenditure	¹⁸⁴
		Oral administration: 6 mg per day for 12 weeks	People with obesity	Increased fat oxidation; no change in energy expenditure	¹⁸⁵
		Oral administration: 9 mg, one dose	Healthy lean men	Higher BAT activity than in placebo- treated individuals; increased energy expenditure	¹⁸⁶
Thyroid hormones	Levothyroxine	Oral administration: 137.75 μg per day for 24 weeks	Patients with thyroidectomy	Higher BAT activity than pretreatment; increased energy expenditure	(NCT02499471)¹⁹⁰
Thyroid hormones	Liothyronine	Oral administration: 570 ng/kg per day for 2 weeks	Patients with insulin receptor mutation	Increased glucose disposal	(NCT02457897)¹⁹¹
GLP1	GLP1	Intravenous infusion: 50 pmol/kg per h for 4 h	Healthy lean men	Decreased energy expenditure	¹⁹⁵
GLP1	Exenatide	Subcutaneous injection: 10 μg twice per day for 24 weeks	People with obesity but without diabetes mellitus	Decreased body weight and food intake; no change in energy expenditure	(NCT00856609)¹⁹⁶

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BAT, brown adipose tissue; GLP1, glucagon-like peptide 1; WAT, white adipose tissue.

Mirabegron.

Mirabegron is a β₃-adrenergic receptor agonist approved by the FDA for treating overactive bladder by relaxing the bladder muscles and ameliorating the symptoms. Acute, single-dose mirabegron treatment (200 mg) increased BAT glucose uptake and energy expenditure in healthy humans^178,179. Unfortunately, this dosage was associated with the adverse effect of elevated blood pressure, which explains why dosages higher than 50 mg per day are prohibited for clinical use. A 2020 study in humans found that 200 mg of mirabegron activates BAT, yet 50 mg cannot, although both doses increase energy expenditure in humans¹⁸⁰. In two 2020 studies, healthy human volunteers and individuals with obesity were treated with lower doses of mirabegron, 100 mg for 4 weeks¹⁸¹ and 50 mg for 12 weeks¹⁸², respectively. This dosage leads to activation of thermogenic adipose tissue, reduced inflammation in adipose tissues and skeletal muscle, improvements in glucose tolerance, insulin sensitivity and pancreatic β-cell function, with few adverse effects on cardiovascular function^181,182.

Capsaicinoids.

Capsaicinoids are a group of phenolic alkaloids and the active components in chili peppers¹⁸³. Interest in using capsaicinoids is growing due to their potential anti-obesity effects. Compared with control individuals who received placebo, oral supplementation of capsaicinoids in individuals with overweight or obesity induced adipose tissue loss by increasing fatty acid oxidation and elevating resting energy expenditure^184,185 that was correlated with enhanced glucose uptake in human BAT¹⁸⁶. Capsaicin acts on TRPV1, which is primarily expressed in afferent sensory neurons and arterial smooth muscle within skeletal muscle, heart and adipose tissues¹⁸⁷ and its activation leads to elevation of intracellular calcium levels and downstream signalling. In mice, TRPV1 deletion completely blocks the anti-obesity effects mediated by capsaicin¹⁸⁸. In addition, in a 2016 study, the combination of capsaicinoid treatment and mild cold exposure (17 °C) synergistically promoted beige adipocyte development and weight loss in mice¹⁸⁹. This finding provides a potential therapeutic regimen combining dietary and environmental modifications in mammals.

Thyroid hormone analogues.

As discussed above, thyroid hormones, T₃ and/or T₄, activate thermogenic functioning in the BAT of mice. In a longitudinal study in patients with thyroid carcinoma after thyroidectomy, substitutional treatment with levothyroxine (a T₄ analogue) was associated with increased basal metabolic rate and increased glucose uptake by BAT (NCT02499471)¹⁹⁰. In addition, patients with severe insulin resistance caused by mutations of the insulin receptor showed improved glucose uptake in WAT and muscle after administration of liothyronine (a T₃ analogue) for 6 months. However, glucose uptake by BAT was not quantified in that study (NCT02457897)¹⁹¹. Notably, two independent studies reported in 2019 found that BAT thermogenesis is dispensable for thyroid hormone-induced energy expenditure^192,193, to which the main contributor might be skeletal muscle¹⁹⁴.

GLP1 agonists.

As discussed above, GLP1 activates BAT thermogenesis via the brain in mice¹⁶⁶, whereas it seems to have an opposite effect in humans. GLP1 infusion in healthy men has been reported to decrease diet-induced thermogenesis due to a reduction in food absorption and by limiting the nutrients supplied by food¹⁹⁵. Another study demonstrated that subcutaneous injection of exenatide, a GLP1 agonist, considerably decreased energy intake with no change in the resting energy expenditure in people with obesity (NCT00856609)¹⁹⁶. Considering the profound effects on the gut, and other systemic effects of GLP1, an ongoing clinical trial aims to investigate the specific effects of SAR425899, a novel GLP1 agonist, through direct injection into subcutaneous WAT of people with obesity (NCT03376802).

Gene-based therapy

Gene-based therapy is a technique in which genetic material is introduced into the target cells or tissues to permanently or transiently manipulate gene expression for the correction of mutations or treatment of diseases. Selective genes have been targeted in vitro and in animal models to activate BAT function and promote WAT browning. For example, the activation of UCP1-mediated thermogenesis provides an efficient way to dissipate excess energy and consume fuels to provide metabolic health benefits¹⁹⁷.

Mice that ectopically express UCP1 in adipose tissue¹⁹⁸ display increased energy expenditure and are protected from diet-induced obesity. Several studies have demonstrated that overexpression of UCP1 in non-thermogenic human cells enables uncoupling respiration from mitochondrial biogenesis^199,200. However, the potential leakage of the mitochondrial membrane that results from unsuitable incorporation of extremely high levels of UCP1 should be taken into consideration. Introduction of upstream transcriptional regulators such as PRDM16 or PPARGC1A induces UCP1 transcription and drives the conversion of white adipocytes to beige adipocytes in mice¹⁷⁶ and in human cells in vitro²⁰¹. Furthermore, introducing CEBPB and PRDM16 transgenes into human inducible pluripotent stem cells (iPSCs) or CEBPB and MYC into human dermal fibroblasts, induces the formation of lipid-laden brown adipocytes²⁰². Of note, engineering fibroblasts to become human brown adipocytes seems to provide a more convenient and potent system than using iPSCs, the use of which also raises a safety issue due to the use of an oncogene such as MYC. A 2020 study showed that a long intergenic non-coding RNA that is induced in adipocytes by adrenergic signalling stimulates transcription of mitochondrial oxidative metabolism genes, lipolysis and respiration in human adipocytes²⁰³. This regulatory process might provide another strategy for gene-based BAT activation.

Several new tools have been developed based on CRISPR–Cas9 that enable targeted inhibition or activation of gene expression, or the insertion of a transgene into genomic DNA. One study takes advantage of the CRISPR–Cas9 method to replace a truncated UCP1 gene with a UCP1 transgene driven using an adiponectin promoter into endogenous loci in pigs. Pigs with the reconstituted UCP1 gene became leaner and displayed improved cold tolerance²⁰⁴. Of note, the expression and activity of UCP1 must be physiologically regulated, and not constitutively activated, which would exhaust energy. A 2018 study showed the development of CRISPR delivery particles (CriPs), which are Cas9–single guide RNA ribonucleoprotein (RNP) complexes coated with amphipathic peptides, enabling more efficient gene editing in primary mouse white pre-adipocytes²⁰⁵. CriP-mediated deletion of nuclear receptor-interacting protein 1 (NRIP1) successfully promoted browning of white adipocytes in vitro. NRIP1 is a co-repressor known to negatively regulate UCP1 expression. However, further in vivo investigation is required to reveal the therapeutic potential of targeting NRIP1. In summary, gene therapy performed in human adipocytes or stem cells is a potential therapeutic approach in humans, after appropriate safety evaluations.

Cell-based therapy

In clinical applications, the unlimited resource provided by cells renders stem cell therapy a more feasible strategy than tissue transplantation. Considering the limited amount of BAT and brown adipocyte progenitor cells that are present in adult humans, the approaches of using white adipocyte progenitors or even fewer committed stem cells seem more applicable (BOX 2).

Box 2 |. Cell-based therapies.

Cell-based therapies offer treatment strategies for patients and diseases that existing pharmaceuticals cannot adequately address. One potential benefit of a cell-based approach, compared to strategies based around single molecules, is that the cells serve as a ‘living factory’ to provide a more comprehensive and persistent therapeutic effect.

Autologous cell therapy

Cells are taken from an individual and administered back into the same individual to minimize the possibility of immune rejection. Autologous cell-based therapy is a preferred therapeutic intervention and has been an active area of research. This approach is moving towards successful commercial development and patient access partially due to the advances in the delivery systems and genome engineering methods^220,221 in the past 10 years.

Allogeneic cell therapy

In older people (aged ≥65 years) or patients with lipodystrophy, the limited number of adipocytes does not allow autologous cell therapy. In these cases, progenitors derived from healthy individuals provide an alternative for allogeneic cell therapy. Strategies to minimize immune rejection should be considered in individuals undergoing allogeneic transplantation. Hydrogel-mediated encapsulation has been applied to minimize the immune response and maintain the transplant–host communication for transplanted cells²²². Moreover, engineering iPSCs in order to generate hypoimmunogenic iPSCs, followed by differentiation, can enable immune escape in immunocompetent allogeneic recipients²²³.

Overexpression of PRDM16 and CEBPB, two important factors involved in thermogenic differentiation, stimulated fibroblasts to differentiate into adipocytes and form an ectopic adipose pad with BAT-like characteristics after transplantation into mice. These differentiated brown-like adipocytes have been shown to be functional and able to take up glucose²⁰⁶. Alternatively, other groups have used pharmacological treatments to induce thermogenic differentiation in stem cells. For example, one method was established to differentiate human PSCs to brown adipocytes using a haemopoietin cocktail, which was composed of KIT ligand, Fms-related tyrosine kinase 3 ligand, IL-6, VEGF and BMP7 (REF.²⁰⁷). Upon subcutaneous transplantation into mice, these brown-like adipocytes were stimulated with β-adrenergic receptor agonists and behaved similarly to endogenous classic brown adipocytes. Alongside the contribution to energy expenditure by transplants themselves, batokines secreted from transplants might add to the regulation of whole-body metabolism^161,208,209.

Another group isolated adipocyte progenitors residing in the capillary network of human WAT and defined an in vitro protocol using forskolin to differentiate them into beige adipocytes. After implanting them into the subcutaneous dorsal region of immuno-deficient NOD-SCID IL2rg-null (NSG) mice, human beige adipocytes can enhance glucose utilization and improve glucose tolerance when the mice are fed a high-fat diet²⁰⁸. More recently, in 2020, a CRISPR synergistic activator was used to establish human brown-like (HUMBLE) adipocytes via overexpressing UCP1 in human white adipocytes. HUMBLE cells acquired brown adipocyte-like features and provided long-term metabolic benefits in nude mice fed a high-fat diet after subcutaneous transplantation^209,210.

Of note, different transplantation studies have identified distinct secreted factors mediating the activation of endogenous thermogenic adipose and/or other tissues and the modulation of systemic metabolism. The differences can be attributed to the use of different species (mice or humans), different transplants (whole tissues, beige cells or brown-like cells), and different transplantation sites (visceral cavity or subcutaneous). Each study examined a unique condition that generates certain signals contributing to the wide range of effects and phenotypes reported. Collectively, these investigations enabled us to gain a comprehensive understanding of the potential of cell-based therapy approaches to tackle obesity and metabolic diseases.

Conclusions

Brown and beige adipocytes arise from distinct origins during embryonic development; however, they share similar effects in thermoregulation and nutrient utilization. The thermogenic adipose niche has an essential role in shaping adipose tissue function and homeostasis. Secreted factors from brown and/or beige adipocytes regulate adipocytes and other cell types within the adipose niche and control systemic metabolism through long-range communications with other organs. Scientific advances have shed light on both intercellular interactions within adipose tissue and inter-organ communications at the systemic level. The knowledge learned, when combined with genetic, pharmacological and cell-based tools, as well as biocompatible delivery systems, promises to lead to effective therapeutics to meet the ever-growing demand for preventing and treating obesity, type 2 diabetes mellitus and related metabolic disorders.

Although multiple therapeutic strategies targeting BAT and beige adipose tissue have been shown to work well in rodent models, most of these tools are not applicable to humans. A notable knowledge gap exists in the translational application from mice to humans, especially considering the differences in BAT between the two species. For example, a 2020 study showed that thermogenesis in human BAT is driven by the β₂-adrenergic receptor, not by the β₃-adrenergic receptor, which is the dominant isoform in adipose tissue of mice¹⁸⁰; however, β₃-adrenergic receptor agonists can activate BAT in humans as noted above. One group also claimed that the β₁-adrenergic receptor is the predominant adrenergic receptor and contributes to the function of human BAT²¹¹. In addition, to avoid unwanted adverse effects of pharmacological therapy on other tissues, targeted delivery of drugs to adipose tissues would offer a promising solution (BOX 3).

Box 3 |. Targeted delivery.

In development of therapeutics using either genetic or pharmacological approaches, tissue-specific and cell type-specific targeting strategies are greatly desired. Improving targeting specificity would enable reductions in effective dosages and off-target effects and would improve cost effectiveness and safety of treatment. Customization of gene expression with the cell-specific or inducible promoters would allow selective genetic manipulation in a spatiotemporal manner. Another strategy would be to engineer the designated surface receptors or ligands on nanoparticles, carriers or Cas9 protein to be selectively delivered to certain cells via specific binding. To achieve targeted delivery of white adipose tissue, two adipose vasculature targeting peptides, iRGD and P3, have been conjugated to the membrane of lipid nanoparticles and have delivered either a PPARγ activator or a prostaglandin E2 analogue to induce WAT browning²²⁴.

To mimic human conditions in mice, studies were performed in middle-aged mice housed under thermoneutral conditions (30 °C) and fed with a diet containing 45% fat. These studies concluded that classic BAT obtained from mice subjected to this humanized physiological condition is similar to human BAT in terms of cellular, molecular and morphological characteristics²¹². The concept of using environmental and dietary cues in mouse models, instead of inserting human genes to establish humanized mice, provides a system mimicking the current obesogenic human lifestyle for metabolic studies, especially for BAT metabolism, which is highly regulated by temperature and diet. Although this manipulation aimed to create a ‘humanized’ condition in mice, issues related to the heterogeneity of human BAT, and the origin and identity of thermogenic adipose tissue, distinguish humanized mouse models and humans^213,214. In addition, considering the complexity and crosstalk of different cell types within BAT and beige adipose tissue, using human adipose organ-oids as platforms to develop a therapeutic strategy might shorten the gaps of translational medicine.

Regarding therapeutic approaches that aim to increase the amount or activity of thermogenic adipose tissue, besides conventional pharmacological interventions, cell-based and gene therapies also offer feasible therapeutic options. Autologous cell therapy is considered a safer and minimally invasive approach compared with conventional treatments because it reduces the risk of rejection and provides longer lasting effects after a single administration. Gene therapy using the viral delivery system has been applied in many non-metabolic diseases due to its high efficacy. However, unintended genome integration, high immunogenicity and safety issues associated with gene delivery need to be addressed. Other non-insertional genetic approaches, such as microRNA-based or mRNA-based medicine, which are associated with a low risk of permanent genomic alteration, might be more applicable in humans. Nevertheless, future research on the compatibility of such approaches to target adipose tissue is warranted. In conclusion, the current advances in fundamental knowledge and new technologies hold promise for beginning to fully harness the therapeutic potential of thermogenic adipose tissue to combat metabolic diseases.

Key points.

Brown adipocytes and white adipocytes in different depots originate from distinct progenitor pools in the embryonic mesoderm.
Beige adipocytes are formed in white adipose tissue in response to cold acclimation, exercise training or pharmacological activation of β-adrenergic receptors through reprogramming of white adipocytes or de novo differentiation from adipocyte progenitors.
Adipose tissue plasticity enables the rapid adaptation of the organism to fluctuations in nutritional load and metabolic demand and is a hallmark of metabolic health.
Adipose-resident cell types establish an extensive network of cellular crosstalk to coordinate depot-specific functions and remodelling.
Communication between thermogenic adipose tissue and distant organs enables the regulation of systemic metabolism beyond thermogenesis.
Targeting thermogenic adipose tissue offers a potential therapeutic strategy to combat obesity and metabolic disorders, such as type 2 diabetes mellitus and cardiovascular diseases.

Acknowledgements

The authors acknowledge the support of NIH grants R01DK077097, R01DK102898 and R01DK122808 (to Y.-H.T.), and P30DK036836 (to Joslin Diabetes Center’s Diabetes Research Center, DRC) from the National Institute of Diabetes and Digestive and Kidney Diseases, and of US Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.). F.S. acknowledges the support of an American Diabetes Association Postdoctoral Fellowship #1-18-PDF-169 and NIH K01DK125608. C.-H.W. acknowledges the support of a Postdoctoral Research Abroad Program (106-2917-I-564-069) and a grant (MOST 110-2320-B-039-063-MY3) from the Ministry of Science and Technology, Taiwan.

Footnotes

Competing interests

Y.-H.T. is an inventor on US Patent 7,576,052 related to BMP7 and US patent applications related to 12,13-diHOME and FGF6/9. The other authors declare no competing interests.

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PERMALINK

The evolving view of thermogenic adipocytes — ontogeny, niche and function

Farnaz Shamsi

Chih-Hao Wang

Yu-Hua Tseng

Abstract

Origin of thermogenic adipocytes

Origin of brown adipocytes

Somites.

Origin of beige adipocytes

WAT browning.

Two possible models of beige adipocyte recruitment.

A role for mural progenitors.

Heterogeneity in adipocyte progenitors.

Intercellular crosstalk in the adipose niche

Box 1 |. Different mechanisms for intercellular communication in the adipose tissue microenvironment.

Neurons

Fig. 1 |. Cellular crosstalk between neurons and other adipose-resident cells.

Crosstalk between sympathetic nerves and adipocytes.

Crosstalk between sympathetic nerves and adipose vasculature.

Crosstalk between sympathetic nerves and immune cells.

Vascular cells

Fig. 2 |. Cellular crosstalk between vasculature and other adipose-resident cells.

Cellular crosstalk between adipocytes and vascular cells.

Cellular crosstalk between adipocyte progenitors and vascular cells.

Cellular crosstalk between adipose immune cells and vasculature.

Adipose immune cells

M1 macrophages.

Type 2 immune response.

Fig. 3 |. Cellular crosstalk between immune cells and other adipose-resident cells.

Crosstalk between immune cells, adipocytes and adipocyte progenitors.

Autocrine and paracrine factors

Fig. 4 |. Autocrine and paracrine factors regulating brown and beige adipocytes.

Inter-organ communication

Fig. 5 |. Inter-organ communication of thermogenic adipose tissue and other tissues.

BAT–WAT communication

BAT–brain communication

BAT–heart communication

BAT–liver communication

BAT–skeletal muscle communication

BAT–gut communication

Therapeutic applications

Fig. 6 |. Cell-based, gene-based and pharmacological therapies for activation and conversion of thermogenic adipose tissue.

Pharmacological approaches

Table 1 |.

Mirabegron.

Capsaicinoids.

Thyroid hormone analogues.

GLP1 agonists.

Gene-based therapy

Cell-based therapy

Box 2 |. Cell-based therapies.

Autologous cell therapy

Allogeneic cell therapy

Conclusions

Box 3 |. Targeted delivery.

Key points.

Acknowledgements

Footnotes

References

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