Cuihua Wang
Xianju Wang1†
Wenxiang Hu- 1GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou, China
- 2Zhongshan School of Medicine, Sun Yat-Sen University, Guangdong, China
Thermogenic fat, consisting of brown and beige adipocytes, dissipates energy in the form of heat, in contrast to the characteristics of white adipocytes that store energy. Increasing energy expenditure by activating brown adipocytes or inducing beige adipocytes is a potential therapeutic strategy for treating obesity and type 2 diabetes. Thus, a better understanding of the underlying mechanisms of thermogenesis provides novel therapeutic interventions for metabolic diseases. In this review, we summarize the recent advances in the molecular regulation of thermogenesis, focusing on transcription factors, epigenetic regulators, metabolites, and non-coding RNAs. We further discuss the intercellular and inter-organ crosstalk that regulate thermogenesis, considering the heterogeneity and complex tissue microenvironment of thermogenic fat.
Introduction
Obesity is a chronic and complex condition resulting from an imbalance of excessive energy intake and insufficient energy expenditure, and it is tightly associated with type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), and other metabolic diseases (1). Adipose tissue is a metabolically active organ with significant roles in regulating whole-body energy homeostasis, whose dysfunction causes obesity and related metabolic disorders. Mammals have been shown to possess two classes of fat cells—white and thermogenic adipocytes. White adipocyte contains a large lipid droplet and a few mitochondria and plays an essential role in energy storage in triglycerides. In contrast, thermogenic adipocytes possess multilocular lipid droplets and higher amounts of mitochondria and dissipate energy in the form of heat.
Thermogenic adipocytes consist of brown adipocytes and beige adipocytes. Brown adipocytes are characterized by marker gene uncoupling protein 1 (Ucp1), which uncouples oxidative respiration from ATP synthesis, resulting in energy dissipation as heat (2). The brown adipose tissue (BAT) is predominantly located in the interscapular region of infants and rodents. UCP1-positive multilocular adipocytes were also found in cervical and supraclavicular regions in human adults using positron-emission tomography and computed tomography (PET/CT) imaging (3, 4). Importantly, BAT activity is inversely correlated with body mass index (BMI) and age in humans (5, 6). Moreover, Ucp1-deficient mice gain more weight than wild-type mice under thermoneutral conditions (7, 8), while transplantation of mouse BAT or CRISPR-enhanced human or mouse brown-like adipocytes improves glucose tolerance and insulin sensitivity in recipient mice (9, 10). These data suggest the importance of BAT in regulating energy metabolism and homeostasis both in mice and humans. In regard to beige adipocytes, they are predominantly spread in inguinal white adipose tissue (iWAT), and induced in response to cold environment, exercise training or activation of β-adrenergic receptors (β-AR) in mice (11). Intriguingly, the gene profile of mouse beige adipocyte is very similar to that of human BAT in the supraclavicular region during cold exposure (12). Induction of browning in iWAT by transgenic expression of PR domain-containing 16 (Prdm16) increases Ucp1 mRNA level and protects the mice from diet-induced obesity (13). Therefore, inducing the formation of beige adipocytes may serve as an alternative therapeutic strategy for combating obesity and metabolic diseases.
In this review, we summarize the cell autonomous and non-cell autonomous regulation of the biogenesis and function of thermogenic fat, which will facilitate the development of new therapies for metabolic diseases.
Molecular regulations of thermogenesis of brown and beige adipocytes
Brown adipocyte and beige adipocyte share similar functions in energy expenditure and thermogenesis, and various molecular events involve in the cell fate determination of thermogenic fat and thermogenesis, including transcriptional regulation, epigenetic modulation, non-coding RNA regulation and metabolic reprogramming (Figure 1).
Figure 1 Molecular regulation of thermogenesis of brown and beige adipocytes. (A). Beige pre-adipocyte and brown pre-adipocyte differentiate into beige adipocyte and brown adipocyte respectively. In specific conditions, white adipocytes convert into beige adipocytes, a process called “browning”. Under cold exposure or other signal induction, differentiated brown and beige adipocytes undergo thermogenesis, accompanied by higher glucose and fatty acid uptake, UCP1 expression, and uncoupled respiration. (B). Regulatory mechanisms behind thermogenesis of brown and beige adipocytes including the following 4 parts: 1. Transcriptional regulation; 2. Epigenetic modulation; 3. Non-coding RNA regulation; 4. Metabolic reprogramming. UCP1 is one of the most critical thermogenic genes, and its expression is critical for uncoupled cellular respiration. There are three core regulators in the thermogenesis program regulation: PPARγ, PRDM16, and PGC1α, and most other regulators regulate thermogenesis through them. Double-headed arrows indicate protein interaction and complex formation, while arrow-headed and bar-headed lines show inducing and inhibiting effects.
Transcriptional regulation of thermogenesis in brown and beige adipocytes
The cell fate determination of thermogenic fat is regulated by various adipocyte-specific lineage-determining transcription factors and co-factors as shown in Table 1. There are three core regulators in the regulation of thermogenesis of beige and brown adipocyte, proliferator-activated receptor γ(PPARγ), PRDM16 and peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α). PPARγ was indispensable for the function of both white and brown adipocytes. PPARγ ligands induce the browning of white adipocytes with the cooperation of PRDM16 (30). PRDM16 is highly expressed in brown adipocyte cells, and overexpression of PRDM16 leads to the browning of white adipocytes. Consistently, knock down of PRDM16 causes to the loss of brown fat cell identity (32). PGC1α also plays essential roles in energy metabolism and homeostasis. Although mice without PGC1α underwent normal brown fat differentiation, it accompanied with decreased thermogenic genes induction (25).
Table 1 Transcription regulators behind thermogenesis of brown and beige adipocytes.
As will discussed in more details below, there are more than 30 transcriptional regulators identified to positively or negatively regulate the formation and function of beige and brown adipocytes, and most of them function through the above three core regulators. CCAAT enhancer-binding protein beta (C/EBPβ) forms a transcriptional complex with PRDM16 to induce brown fat cell determination and differentiation (16). In contrast, CCAAT enhancer-binding protein alpha (C/EBPα) acts collaboratively with other corepressors C-terminal-binding protein 1/2 (CtBP1/2) to repress the expression of white fat genes (15). Early B-cell factor 2 (EBF2), a selective marker of brown and beige precursors (50), regulates the cell fate determination of brown fat precursor cells and the expression of thermogenic genes (17). Brown adipocytes isolated from mice with Ebf2 deficiency exhibit diminished mitochondrial density and larger lipid droplets (51). Interferon regulatory factor 4 (IRF4), which is induced by cold and cAMP, interacts with PGC1α to promote the expression of PRDM16 and then drive the expression of thermogenic genes (20). Claussnitzer et al. found that rs1421085 T-to-C single-nucleotide variant disrupts the function of AT-rich interative domain-containing protein 5B (ARID5B) that repress the expression of Iroquois homeobox protein 3 (IRX3) and Iroquois homeobox protein 5 (IRX5), which further result in a shift from beige adipocytes to white adipocytes (21). Loft et al. reported that kruepple-like factor 11 (KLF11), which is induced by PPARγ agonists, acts in cooperation with PPARγ to activate beige-selective gene program (23). Zinc finger transcription factors also play important roles in thermogenesis. Gupta et al. reported that zinc finger protein 423 (Zfp423) expression is enriched in white adipocytes compared to brown adipocytes and is repressed upon cold exposure (46). Zfp423 inhibits the activity of EBF2 and suppress PRDM16 activation to maintain white adipocyte identity, and loss of adipocyte Zfp423 induces an EBF2 NuRD-to-BAF coregulator switch and promotes thermogenic genes (47). Dempersmier et al. stated that zinc finger protein 516 (Zfp516) directly binds to the proximal region of the Ucp1 promoter and activates its expression to induce white fat cell browning and the development of brown fat cells (49). Taken together, the formation and function of thermogenic fat greatly rely on a complex transcriptional network coordinated by a set of core transcriptional factors.
Epigenetic modulation behind thermogenesis of brown and beige adipocytes
Adipogenesis is involved with complicated epigenetic remodeling that mainly include histone modification and DNA methylation, the two fundamental processes that play crucial roles in the regulation of gene expression and genome stability. In general, Histone modifications modulate chromatin structure, influencing gene accessibility and transcriptional activity, while DNA methylation directly modifies the DNA sequence, leading to gene silencing. A lot of studies have demonstrated the roles of epigenetic modulators in regulating the formation and function of thermogenic adipocytes (Table 2). In this review, we specifically focused on the role of histone modification, including histone acetylation, histone deacetylation, histone methylation, and histone demethylation.
Table 2 Epigenetic regulators behind thermogenesis of brown and beige adipocytes.
Epigenetic modulators catalyze the formation of active epigenetic markers in the regulatory regions of corresponding genes to positively regulate their expression. CREB binding protein (CBP) and histone acetyltransferase p300 (P300), which catalyze histone acetylation of H3K27, improve the expression of PPARγ and then promote adipocyte differentiation and white adipocyte browning (52). General control of amino acid synthesis 5-like 2 (GCN5) and P300/CBP-associated factor (PCAF), which acetylate histone H3K9, also facilitate brown adipogenesis through positively regulating the expression of Pparγand Prdm16 (53).
In regard to histone deacetylation, epigenetic modulators erase pre-settled active epigenetic marker at the regulatory regions of thermogenic genes to negatively regulate their expression. Histone deacetylases (HDAC1, HDAC2, HDAC3, HDAC9 and HDAC11) exert their influences on thermogenesis through deacetylation of H3K27ac (79). HDAC1 and HDAC2 negatively regulate brown adipocyte thermogenic program through decreasing acetylation of histone H3 lysine 27, an active epigenetic marker, on the promoter regions of Ucp1 and Pgc1α to inhibit their expression (54). Ferrari et al. showed HDAC3 deletion induce WAT browning through increased H3K27ac modification at the enhancer region of Pparγ and Ucp1 (55). However, other study revealed that HDAC3 primes Ucp1 and the thermogenic transcriptional program to maintain the brown adipose tissue identity through deacetylation of PGC1α by HDAC3 (80). Bagchi et al. reported that HDAC11 suppresses WAT browning through physical association with bromodomain-containing protein 2 (BRD2) (57). Other histone deacetylases, including NAD-dependent protein deacetylases-SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7, catalyze the deacetylation of H3K9ac, and/or H4K16ac (58, 81, 82). Shi et al. found that SIRT3 positively correlated with the expression of Pgc1α and Ucp1, and SIRT3 activates mitochondria functions and adaptive thermogenesis in brown adipose (61). Shuai et al. found SIRT5 promoted the browning of subcutaneous white adipose tissue through regulating H3K9me2 and H3K9me3 modification at the promoter regions of Pparγ and Prdm16 (62). Moreover, ten-eleven translocation (TET) proteins, oxidize 5-methylcytosines and promote specific DNA demethylation (83), were found to inhibit β3-AR dependent thermogenic genes’ expression and white fat browning through indirectly recruiting histone deacetylases to the promoter regions of concerning genes (63).
Histone methylation exerts essential roles in regulating chromatin functional states and usually includes two types of amino acids modification, lysine methyl-transferation and arginine methyl-transferation. Several studies have linked histone methylation with thermogenesis (79). Euchromatic histone methyltransferase 1 (EHMT1), which could catalyze methylation of histone 3 lysine 9 (H3K9me2 and me3), promotes adaptive thermogenesis through stabilizing PRDM16 protein (67). Lysine methyltransferase 5C (KMT5C), a H4K20 methyltransferase, positively regulates thermogenesis through regulating the expression of transformation related protein 53 (Trp53), a repressor of thermogenic program (69). DOT1-like (DOT1L), a lysine 79 of histone H3 (H3K79) methyltransferase, inhibits thermogenic adipocyte differentiation and function through repressing the expression of brown adipocyte tissue-selective genes (70).
Histone demethylases catalyze histone demethylation that usually correlates with enhanced adipogenesis and white adipocyte browning. LSD1, lysine-specific demethylase 1, increases the content of beige adipocytes in aging inguinal white adipose tissue through activating the expression of proliferator-activated receptor alpha (Pparα) (71). Similarly, lysine-specific demethylase 2 (LSD2) plays its vital roles primarily at the early stage of brown adipocyte differentiation, and its deletion in vivo was accompanied with compromised expression of thermogenic genes (72). Tateishi et al. demonstrated lysine-specific demethylase 3A (KDM3A) positively regulates Pparα and Ucp1 expression, and KDM3A-deficient mice developed obesity and hyperlipidemia (74). Pan et al. revealed that JmjC domain-containing protein 3 (JMJD3) demethylases repressive mark H3K27me3 at the promoter regions of Ucp1 and Cell death-inducing DFFA-like effector a (Cidea) in order to activate thermogenic program and induce white adipocyte browning (77). Moreover, UTX, ubiquitously transcribed tetratricopeptide repeat on chromosome X, catalyzes demethylation of H3K27me2/3 at the promoter region of Ucp1 and Pgc1α to positively regulate their expression and promote brown adipocyte thermogenic genes expression (78). Altogether, various epigenetic remodelers act through altering histone acetylation and methylation dynamics to regulate the thermogenic program in response to the external stimuli.
Non-coding RNAs regulation of thermogenesis of brown and beige adipocytes
Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play important roles in the development and physiology of white, brown and beige adipocytes, and non-coding RNAs themselves can serve as markers of different adipocyte tissue depots (Table 3).
Table 3 Non-coding RNAs behind thermogenesis of brown and beige adipocytes.
miRNAs usually exert their functions on regulating thermogenesis through complementary reaction with the UTR regions of mRNA transcripts of effector genes. MiR-26 is upregulated during human adipogenesis and induces brown adipocyte differentiation through directly targeting ADAM metallopeptidase domain 17 (ADAM17) (84). MiR-30b/c target 3’UTR of receptor-interacting protein 140 (RIP140), a negative regulator of thermogenic genes, to promote brown adipose tissue function and the development of beige fat (91). MiR-32 is highly expressed during cold exposure, and increases fibroblast growth factor 21 (Fgf21) expression through repressing the expression of transducer of ErbB-2.1 (Tob1), which further promotes white fat cell browning and BAT thermogenesis (92). Ge et al. showed miR-34a inhibits white adipocytes browning through targeting fibronectin type III domain-containing protein 5 (Fndc5) expression (93), while Fu et al. demonstrated miR-34a promotes the deacetylation of PGC1α and its activation by targeting fibroblast growth factor receptor 1 (FGFR1), klotho beta-like protein (βKL) and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) (94). MiR-106b-93 cluster negatively regulate the expression of Ucp1 and promote the lipid content in differentiated brown adipocytes (95). Giroud et al. reported miR-125b prevents beige adipocyte formation through decreasing mitochondrial biogenesis (96). miR-133 targets 3’ UTR of Prdm16 to repress its expression that lead to impaired brown fat differentiation and WAT browning (97, 98). MicroRNA 155 is down-regulated during brown preadipocyte differentiation and inhibition of miR-155 enhances brown adipocyte differentiation and white adipocytes browning. Mechanistically, miR-155 forms a bistable feedback loop with CEBP-β (99). MiR-193b–365, referred to as miR-193b and miR-365, showed two contradictory results, that Sun et al. found that blocking of miR-193b–365 impair brown adipocyte adipogenesis by upregulating the expression of runt-related transcriptional factor 1 translocation partner 1 (Runx1t1) (102), while Feuermann et al. reported that miR-193b–365 are not required for the differentiation and development of BAT (103). The detailed roles of miR-193b–365 in vivo and in vitro need to be further clarified.
The regulation of lncRNAs in the thermogenesis of brown and beige adipocytes are mainly through interacting with other important transcription factors such as PGC1α, EBF2, and PPARγ (113). Recent study identified Blnc1 as a vital lncRNA in promoting the function of brown and beige adipocytes, and then further experiments demonstrated Blnc1 acts synergistically with EBF2 to drive thermogenic gene program (108). Similarly, lncRNA-AK079912 was also reported to play a positive role in brown preadipocyte differentiation and white adipocytes browning, which is mediated by PPARγ (109). A brown adipose tissue-enriched lncRNA, lncBATE10, was found to be differently regulated in cold or exercise conditions, and it regulates brown adipose tissue gene program through decoying the repressor factor-CUGBP Elav-like family member 1 (CELF1) from Pgc1α’s mRNA elements (110). In together, the influences of lncRNAs on the regulatory network of brown and beige adipocytes differentiation remain elusive, and especially their direct roles in affecting core transcriptional factors of thermogenic program need to be further elucidated. In summary, miRNAs and lncRNAs, the tight regulators of gene expression, play an indispensable role in regulating brown and beige adipogenesis, which further complicates the regulatory network of thermogenesis.
Metabolic reprogramming behind thermogenesis of brown and beige adipocytes
The development and function of thermogenic fat involves intensive metabolic reprogramming (114). Table 4 summarized the nutrients and metabolites that regulates thermogenesis. Notably, most of the studies were conducted in rodent models and their implications in human need to be further explored.
Table 4 Metabolic reprogramming behind thermogenesis of brown and beige adipocytes.
Wu et al. reported that NAFLD patients treated with Berberine (BBR) for 1 month exhibited increased brown adipocyte mass and activity in mice, since BBR promotes the DNA demethylation of Prdm16 promoter to activate its expression (117). Dietary capsaicin induces white adipocyte browning through facilitating the interaction and activation of PPARγ and PRDM16, depending on transient receptor potential vanilloid 1 (TRPV1) channels (119). Chlorogenic acid (CGA), a Chinese traditional medicine, induces brown adipocyte thermogenesis through promoting mitochondria function and glucose uptake (121). Lone et al. and Wang et al. demonstrated that curcumin promotes browning of white adipocytes through upregulating Ucp1 expression (125, 126). Ellagic Acid (EA), located mainly in fruits and plant extracts, also increases iWAT browning through decreasing the expression of Zfp423 and aldehyde dehydrogenase family 1 member a1 (Aldh1a1) and increasing thermogenic genes expression (128). Epicatechin (Epi), a cacao flavanol, can induce white adipose tissue browning through improving mitochondrial function and upregulating the expression of key thermogenic genes (131).
Apart from the aforementioned nutrients and small molecules that regulate thermogenesis of brown and beige adipocytes, there are other metabolites performing the similar functions, including flavan-3-Alcohol, fucoxanthin, irisin, leptin, luteolin, Menthol Neuregulin 4 (Nrg4), Prostaglandin (PG), Purple Sweet Potato (PSP), Quercetin, Resveratrol, Rice Bran, Sesamol, Taurine, Telmisartan, and 3-Hydroxydaidzein (134, 135, 137–140, 142–153, 155), which will be discussed in details in the below sections.
Intercellular communications within thermogenic fat
As extensively discussed in a recent review (156), thermogenic fat consists of various cell types or cell states in stromal vascular fractions (SVFs) and mature adipocytes, identified by state-of-art single-cell RNA-sequencing (scRNA-seq) or single nuclei RNA-sequencing (snRNA-seq) in mice (157–165) and humans (157, 162, 165–168). These subpopulations of thermogenic fat, including immune cells, endothelial cells, neurons, smooth muscle cells, Schwann cells, and a few other cell types, create a unique adipose niche and regulate adipose tissue function, such as thermogenic fat turnover, expansion, and remodeling (156). Here we focus on the intercellular crosstalk between thermogenic fat cells and endothelial cells, immune cells, and neurons (Figure 2).
Figure 2 Cellular interaction between thermogenic adipocytes and resident cells. (A). Interaction between sympathetic nerve and thermogenic adipocyte. Sympathetic nerve secretes norepinephrine (NE) that promotes white adipocyte browning and brown adipocyte activation; in turn, beige adipocytes and brown adipocytes promote nerve remodeling through secreting neurotrophic factor, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neuregulin-4 (NRG4) as well as Zinc. (B). Interaction between vascular endothelial cells and thermogenic adipocyte. Vascular endothelial cells secrete endothelin 1 (EDN1) and nitric oxide (NO) to promote the thermogenic function of brown and beige adipocytes. Besides, the secreted EDN1 and platelet-derived growth factor C (PDGF-C) also regulate the adipogenesis of preadipocytes. Reciprocally, thermogenic adipocytes and their progenitors secrete several factors that promote angiogenesis in adipose tissue. ANGPT2, angiopoietin 2; VEGF, vascular endothelial growth factor. (C). Interaction between resident immune cells and thermogenic adipocytes. Various cytokines and signals mediate the bi-directional communication between thermogenic fat and different kinds of immune cells.
Endothelial cells in the thermogenic adipose tissue
Adipose tissue, especially BAT, is one of the most vascularized tissues in the body (169). A lot of stimuli, including cold, diet, exercise, and nutrition state, modulate angiogenesis and vascular remodeling in adipose tissue. Vascular Endothelial Growth Factor A (VEGFA) and Vascular Endothelial Growth Factor B (VEGFB) are two important angiogenic factors in adipose tissue in response to cold or β3-AR activation. BAT-specific overexpression of VEGFA increases vascularization and improves thermogenesis in mice after cold exposure, and protects mice against diet-induced obesity (170). Similarly, VEGFB promotes the proliferation of endothelial cells and fatty lipid oxidation in thermogenic fat in mice, providing a novel cure strategy for obesity and diabetes diseases (171). Besides, Seki et al. revealed that endothelial-specific Vegfr2-/- mice showed impaired angiogenesis as well as reduced browning of iWAT, which is modulated through the endothelial cells-derived platelet-derived growth factor-CC (PDGF-CC)-induced signaling pathway, since administration of PDGF-CC upregulated the expression level of Ucp1 and promoted browning of iWAT both in mice and humans (172). Endothelial cells-secreted endothelin 1 (EDN1) and nitric oxide inhibit biogenesis and the function of brown and beige adipocytes in vitro (173, 174). In contrast, endothelial deficiency of lysosomal acid lipase (LAL) impairs vascularization and thermogenesis in BAT and WAT (175). The decreased production of vasodilatory factors and increased vasoconstricting factors production, due to dysfunction of endothelial cells, lead to insulin resistance and diabetes (176). The diverse functions of endothelial cells suggest the existence of different subpopulations. Indeed, Sun et al. observed two distinct types of endothelial cells in human deep-neck BAT using scRNA-seq (162). Vijay et al. also identified three types of endothelial cells in human WAT, with the largest population of endothelial cells defined as fatty-acid-handling microvascular endothelial cells and another subpopulation was lymphatic-derived (167). However, delineating the exact role of each subpopulation of endothelial cells in thermogenic fat needs further investigation. Taken together, these bidirectional communications between thermogenic fat and endothelial cells maintain the adipose homeostasis, and dysfunction of them cause metabolic disorders.
Immune cells in the thermogenic adipose tissue
Several types of immune cells reside in adipose tissue, including macrophages, natural killer (NK) cells, lymphocytes, dendritic cells, neutrophils, eosinophils, T cells, and mast cells, which play an important role in regulating metabolic homeostasis (177, 178). The adipose immune cells composition is highly variable in response to the nutritional status, as well as environmental stimuli (179).
Among the immune cells that infiltrate into obese adipose tissue, macrophages are functionally and numerically dominant. Activated macrophages are divided into two main categories, M1 macrophages and M2 macrophages. M1 macrophages produce pro-inflammatory cytokines and chemokines, while M2 macrophages secrete anti-inflammatory cytokines that alleviate inflammation. Several studies show that activated M1-like macrophages facilitate the infiltration of other immune cells into obese adipose tissues and impairs insulin sensitivity (180). In detail, studies identified TNFα as a pro-inflammatory cytokine produced from M1 macrophages that suppresses the emergence of thermogenic adipocytes in mice (181). It was also reported that the direct contact between M1 macrophage and white adipocyte could inhibit the browning process as well as Ucp1 expression in iWAT of mice, mainly though the direct adhesion between α4-integrin in activated M1 macrophage and vascular cell adhesion molecule 1 (Vcam-1) in adipocytes (182). In contrast to M1 macrophages, M2 macrophages exert positive effects on brown adipocyte activity and WAT browning (183). Signal transducer and activator of transcription 6 (Stat6)-deficient or macrophage-specific interleukin-4 receptor α (Ilr4α) knockout mice exhibited impaired BAT thermogenic response, suggesting the positive role of M2 macrophages in BAT thermogenesis, which is further supported by the specific depletion of Ilr4α in myeloid cells of mice (184, 185). M2 macrophages could produce catecholamine to sustain adaptive thermogenesis, which may also reflect the situations in WAT browning, as similar recruitment of M2 macrophages were also found in iWAT of cold-induced mice (185, 186). Another study demonstrated that a fraction of M1 macrophages were concentrated around the sympathetic nerve endings in the adipose tissue of obese people (187). Such macrophages are called sympathetic neuron-associated macrophages (SAM), which can transport catecholamine released from sympathetic nerve endings into the cell body and degrade it through monoamine oxidase A, thereby inhibiting the browning of iWAT induced by sympathetic nerve in obese mice (187, 188). Mutually, thermogenic fat could also secrete batokines to regulate the activation and function of macrophages. CXC Motif Chemokine Ligand 14 (CXCL14), one of the batokines secreted by brown adipocytes, promotes the M2 macrophage phenotype in adipose tissue and leads to WAT browning, and Cxcl14-deficient mice show impaired BAT activity and altered glucose homeostasis in response to cold exposure (189). Adiponectin is another adipokine that promotes the activation of M2 macrophages and then results in cold-induced browning of WAT in mice (190). Adipose-secreted bone morphogenetic protein 4 (BMP4) also increase the accumulation of M2 macrophages and induce beige fat biogenesis in iWAT of mice (191). Moreover, adipocytes deficient in fatty acid synthase (iAdFASNKO) show increased macrophage polarization, and ablation of macrophage from iWAT in iAdFASNKO mice inhibit beige adipogenesis (161).
Innate lymphoid type 2 cells (ILC2s), another group of adipose resident immune cells, also activate M2 macrophage and regulate thermogenesis in brown and beige adipocytes (192). Activation of ILC2s in the iWAT of mice strongly stimulates the biogenesis of beige fat (193). Mechanistically, ILC2 activation leads to the proliferation of adipocyte precursors and their commitment to the beige fat lineage in mice (193). ILC2 cells also secrete peptide methionine-enkephalin (Met-Enk), which directly targets subcutaneous white adipocytes to induce their browning (194). Moreover, ILC2s respond to the stimulation of interleukin (IL)-33 and produce IL-13 and IL-4 to promote the browning of iWAT in mice, although the cellular origin and signal pathways involved in the endogenous IL-33 production in adipose tissue remain unidentified (193). Consistent with this, Il-33 deficient mice in iWAT have fewer beige adipocyte formations and larger white adipocyte compared to control mice (194). In a recent study, the unique ILC populations were profiled in human WAT (168), which suggests ILC3s may play a similar role as ILC2 in adipose homeostasis, but function as a more important mediator of adipose tissue inflammation and obesity (168, 194).
Eosinophils are the main IL-4-producing cells in iWAT of mice, and play a key role in the thermogenesis and metabolic homeostasis (195). METRNL, a circulating factor meteorin-like hormone, is induced after exercise and cold exposure in the skeletal muscle and adipose tissue of mice, respectively (196). METRNL promotes alternative activation of adipose tissue macrophages and thermogenic and anti-inflammatory gene programs in iWAT through an eosinophil-dependent increased Il-4 expression, and blocking IL4/IL13 signaling abrogates METRNL-induced browning of iWAT in mice (196). Moreover, eosinophils-derived IL-4 directly work on PDGFRα+ adipocyte precursors to induce beige adipogenesis both in vitro and in vivo (193). In response to chemokine ligand 11 (CCL11) stimulation, eosinophils are recruited to iWAT and promote type 2 immune responses and beige adipogenesis in mice (197).
Neurons in the thermogenic adipose tissue
BAT is highly innervated by the complex sympathetic nervous system, which can transmit signals from the central nervous system to BAT (198). BAT thermogenesis is triggered by the release of norepinephrine from its sympathetic nerve terminals, which binds to β3-AR that result in the activation of UCP1 (198). Sympathetic innervation increases after cold exposure in BAT and subcutaneous WAT both in mice and human adults (199). More detailed analysis revealed that sympathetic arborizations in iWAT cover 90% of individual adipocytes, and the sympathetic arborizations are important for the cold-induced browning of iWAT in mice (200). Mutually, the thermogenic fat also regulates the sympathetic innervation and neuron activity. Overexpression of PRDM16 in mice significantly increase the number of sympathetic parenchymal nerve fibers infiltrating the iWAT compared with that in wild-type mice, although the exact mechanism of the recruitment of sympathetic nerves in iWAT remain elusive (200). A recent study revealed that mice lack of fatty acid synthase in fat (iAdFASNKO) activated the sympathetic nerve fiber to result in browning in iWAT of mice (161). Zeng et al. reported that thermogenic adipocytes express mammal-specific endoplasmic reticulum membrane protein (Calsyntenin-3β), which promotes the secretion of S100b from brown adipocytes and stimulates neurite outgrowth in mice (201). Luan group further demonstrated that thermogenic adipocytes secrete zinc that promotes sympathetic innervation, and administration of zinc ameliorates obesity by promoting sympathetic neuron-induced thermogenesis in mice (202). These studies revealed the beneficial and critical role of sympathetic innervation in maintenance of thermogenic fat in response to cold exposure and other environmental challenge.
Inter-organ communications around thermogenic fat
The coordination of multiple tissues and organs is very important for maintaining systemic homeostasis and responding to nutritional and environmental challenges, and its dysregulation leads to various metabolic disorders (203–205). The thermogenic fat function as an endocrine organ by secreting specific factors (brown adipokines or batokines) and interact with distant organs that express the corresponding receptors, and vice versa (Figure 3).
Figure 3 Inter-organ communications between thermogenic fat depots and different organs. Multiple organs, such as the brain, liver, muscle, and gut, can have crosstalk with thermogenic fat depots. The communications between these organs and the thermogenic fat depot mainly involve the secretion of different kinds of molecules, including peptide hormones, lipokines, glucocorticoids, and bile acids. Dashed arrows mean the secretion of factors; solid arrows mean positive effects; blunt-end lines mean inhibitory effects.
Brain-thermogenic fat communication
Besides the local effects of nerve on the thermogenic fat, the brain-thermogenic fat communication axis plays an important role in regulating systemic energy balance. Adipose tissue transmits the message to the brain via secreted factors and sensory innervation (206, 207). Leptin, an adipokine, is mainly produced by the obese (ob) gene in adipocytes, and regulates the balance of energy via decreasing food intake and inducing energy expenditure (208, 209). Although the role of leptin in regulating energy balance is well known, the underlying mechanism is still elusive. Recent work has shown that leptin target the melanocortin receptor 4 (MC4R) and melanocortin receptor 3 (MC3R) in the brain of mice (210, 211). Mc4r-deficient mice exhibit reduced upregulation of Ucp1 in BAT exposed to cold condition or high-fat food (212). In contrast, central administration of MC3/4-R agonists MTII promote Ucp1 mRNA expression in mice (213), suggesting the role of MC4R-expressing neuronal populations in regulating BAT thermogenesis. It was also shown that leptin and insulin act synergically on hypothalamic neurons to promote iWAT browning in mice (214). Bone morphogenetic protein 8b (BMP8b), a factor induced by nutritional and thermogenic stimuli in mature BAT and hypothalamus, is also involved in central control of BAT thermogenesis, and central BMP8B treatment increases sympathetic activation of BAT in mice, depending on the hypothalamic AMP-activated protein kinase (AMPK) activation (215).
Central control could also inhibit the browning process, as fasting and chemical-genetic activation of orexigenic agouti-related protein (AgRP) neurons in the hypothalamus suppress iWAT browning in mice (216). Mechanistically, the levels of O-linked β-N-acetylglucosamine (O-GlcNAc) transferase and O-GlcNAc modification in AgRP neurons are increased after fasting in mice, thus promoting neuronal excitability and inhibiting iWAT browning (216). It was also reported that glucocorticoids, a class of steroid hormones synthesized in the adrenal cortex, also suppress Ucp1 expression and BAT thermogenesis in mice (217). In contrast, the glucocorticoids promote UCP1 expression in human brown adipocytes and increase glucose uptake and energy expenditure in response to mild cold condition (218). Understanding the species-specific action of glucocorticoid on BAT thermogenesis will provide not only the understanding for BAT-brain axis, but also new therapeutic strategy for maintaining energy homeostasis. Overall, these studies show the differential effects of central control of function of thermogenic fat, mainly depending on the different types of neurons.
Liver-thermogenic fat communication
The liver is a metabolic organ important for glucose and lipid metabolism, whose dysfunction leads to many kinds of metabolic diseases. The interaction between the liver and thermogenic fat are mainly mediated by peptide hormones, lipokines as well as bile acids. Fibroblast growth factor 21 (FGF21) is a circulating peptide hormone, which is mainly expressed in the liver in response to starvation or exercise and induced in BAT and WAT when fasted or exposed to cold environment both in mice and humans (219). FGF21 not only acts locally in an endocrine and autocrine manner, but also travels to distant organs to exert its role by secreting into the bloodstream (220). Studies showed that administration of FGF21 increases energy expenditure and improves insulin sensitivity in mice (221). Owen et al. further revealed that FGF21 improves energy expenditure through enhanced sympathetic nerve activity in BAT of mice (222). Moreover, the administration of recombinant FGF21 for 6 weeks in diabetic rhesus monkeys lead to a significant decline in glucose level, body weight, and circulating lipids levels (223). Similarly, Activin-E, a member of transforming growth factor beta (TGFβ) superfamily, is primarily produced by the liver and functions as a hepatokine to activate thermogenesis both in iWAT and BAT of mice (224, 225). Follistatin (Fst), which binds and neutralizes the activity of TGFβ superfamily, is secreted by the liver and promotes brown preadipocyte differentiation and cold-induced brown thermogenesis in mice, although the autocrine effect could not be excluded, since Fst is also induced in brown adipocytes in response to cold (226–228).
On the other hand, brown adipocytes secrete batokines to regulate the functions of the liver. As discussed above, FGF21 mediate the bi-directional crosstalk between BAT and the liver in mice (204, 221, 222). Besides, brown adipocyte-derived Neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of ligands, attenuates hepatic lipogenic signaling and protects mice against diet-induced insulin resistance and hepatic steatosis (142). In mice, acute psychological stress induces IL6 secretion from brown adipocytes and then promotes hyperglycemia through hepatic enhanced gluconeogenesis (229). Other reports revealed that some adipokines, such as adiponectin, suppress hepatic injury induced by alcohol intake in mice model (230).
Another class of molecules that mediate the communication between the liver and thermogenic fat are lipokines, which can be secreted both by the adipose tissue and the liver (231, 232). Through quantitative and systemic lipidomic analyses, Cao et al. identified C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that functions as an important regulator of metabolic homeostasis, such as suppression of hepatosteatosis in mice (231). Similarly, using non-targeted liquid chromatography-mass spectrometry-based lipidomics, Simcox et al. identified that acylcarnitine,produced by the mouse liver in response to cold exposure, transports to BAT to induce UCP1-dependent uncoupling respiration and heat production (232). Bile acids also participate in the communication between the liver and thermogenic fat. TGR5, a G-protein-coupled receptor, could bind to the bile acids transported to brown or beige adipocytes from the liver and induce cold-induced thermogenesis in mice (233–235). BAT also regulate liver inflammation, although the exact pathway governing this crosstalk remains unclear. Previous studies showed that Ucp1-/- mice exhibits decreased capacity to clear succinate from both the liver and the circulation, thus driving liver inflammation through the interaction with stellate cells and macrophages (236, 237). Collectively, these studies show that the intensive crosstalk between the liver and thermogenic fat mediated by various circulating factors, including peptide hormones, lipokines as well as bile acids.
Skeletal muscle-thermogenic fat communication
Upon muscle contraction, skeletal muscles produce and release circulating cytokines and other peptides, known as myokines, which exert endocrine effects and mediate the communication between muscle and other organs (238–240). In reciprocal, cold- or exercise-induced batokines from thermogenic fat also regulate the function of skeletal muscle.
The earliest identified and most studied myokine is IL-6, which can increase up to 100 folds in circulation during physical exercise (241). Daily injection of IL-6 for 1 week significantly increases Ucp1 mRNA levels in iWAT of mice (242). Moreover, administration of recombinant human IL-6 enhances lipolysis as well as fatty acid oxidation both in healthy young and elderly humans (243, 244). Consistent with this, elevated IL-6 secretion is also observed in differentiating human beige adipocytes, and blockage of IL-6 receptor by specific antibody inhibits human brown adipocyte differentiation (245). Irisin is another myokine that mediates the communication between skeletal muscle and thermogenic fat, which is secreted from skeletal muscle in a PGC1α-dependent manner and stimulates Ucp1 expression and thermogenesis both in vitro and in vivo (246). Irisin is also induced by cold exposure in human and promotes brown fat thermogenesis in collaboration with FGF21, representing a cold-activated endocrine axis regulating both shivering and non-shivering thermogenesis (247). METRNL is released by skeletal muscle and adipose tissue after exercise or upon cold exposure respectively, and significantly promotes browning of WAT depots (183), stimulates energy expenditure and improves glucose tolerance, which is mediated by the recruitment of resident eosinophil in WAT depots of mice (196). Roberts et al. identified β-aminoisobutyric acid (BAIBA), a myokine secreted after exercise, increases the expression of brown adipocyte marker genes and induces a brown adipocyte-like phenotype both in human iPSC-derived white adipocytes and in white adipose depot of mice (248).
Meanwhile, batokines from thermogenic fat also regulate the function of skeletal muscle. 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), a lipokine secreted from BAT when exposed to cold or exercise in mice and human, increases skeletal muscle fatty acid oxidation and uptake (249, 250). 12-hydroxyeicosapentaenoic acid (12-HEPE), a 12-lipoxygenase-derived lipokine that is secreted in response to cold exposure and β-AR signaling, also promotes glucose uptake in muscle as well as BAT in mice (251). These studies clearly show the mutually regulatory network between skeletal muscle and thermogenic fat to maintain thermogenic fat homeostasis.
GI tract-thermogenic fat communication
The gastrointestinal tract (GI tract) plays a very important role in thermogenesis through gut microbiota or directly secreting factors from intestinal cells (252). In a study that compared the metabolic profiling between germ-free mice and conventional mice, Mestdagh et al. revealed increased lipolysis while reduced lipogenesis in BAT of germ-free mice (253). Suarez et al. also showed that depletion of microbiota, either by antibiotic treatment or in germ-free mice, promote the browning of iWAT and perigonadal visceral adipose tissue in lean mice, obese mice and high-fat diet-fed mice (254). However, Zietak et al. found cold exposure markedly alter the microbiome composition, and cold-adapted microbiota improved energy metabolism (255). Transplantation of the gut microbiota from cold-induced mice to germ-free mice increase insulin sensitivity, cold tolerance, and browning of WAT (256). Other study revealed that acetate and lactate from the gut microbiota promote the browning of iWAT of mice after intermittent fasting, although the underlying mechanism remains unclear (257). Of note, administration of the bacterial metabolite butyrate also increases the thermogenic capacity of the germ-free mice (258).
Besides gut microbiota, the GI tract also secrete various factors to regulate thermogenesis. Secretin, secreted by the gut and upregulated during fasting, increases lipolysis and inhibits glucose uptake in mice (259). Li et al. revealed that secretin mediates a gut-BAT-brain axis, which stimulates brown fat thermogenesis and satiation in mice (260). The similar role of secretin is also observed in human (261). Glucagon-like peptide 1 (GLP-1), a peptide released from enteroendocrine cells in the gut, increases insulin secretion in beta cells and activates BAT thermogenesis in mice (262). GLP-1 has also been proved to increase satiety and reduce energy intake in human (263). GLP-1 agonists significantly induce BAT thermogenesis and promote browning of iWAT in mice (264). Numerous evidences support that GLP-1 agonists decrease the risk of developing cardiovascular disease in diabetes and obesity both in mice and humans (265). Ghrelin, another growth-hormone-releasing acylated peptide from stomach, also modulates thermogenesis in BAT as well as lipid utilization in WAT, possibly through the gut-brain-BAT axis, as this occurs when ghrelin was centrally administered in mice (266–269). Further studies need to investigate whether and how thermogenic fat could influence the gut homeostasis, as this has not been explored in depth so far.
Conclusion
Understanding of the development route of thermogenic fat will provides novel therapeutic interventions for metabolic diseases. In this review, we discussed the regulatory network of thermogenic fat at the molecular and cellular levels, respectively. The molecular regulation of thermogenic fat mainly involves transcriptional regulation, epigenetic regulation, non-coding RNA regulation and metabolic reprogramming. Among these regulators, PPARγ, PRDM16 and PGC1α represent the core regulators, as most of the other regulators regulate the thermogenesis depending on them. Besides, thermogenic fat is also educated by other cell types within adipose depots or other organs. These complex and comprehensive regulatory networks help to maintain the functionality of thermogenic fat in response to kinds of changes of the environment. This holds a promising strategy for inducing artificial thermogenesis to counteract obesity in vivo. For example, recent study has shown that thermogenesis could be induced through local hyperthermia therapy, mainly through the HSF1-A2B1 transcriptional axis (270). However, whether this kind of induced thermogenesis represents a new specific regulatory network or converges on the core regulators still needs to be identified. In future, more advanced technology, such as spatial transcriptomics and epigenomics methodologies, should be applied to this field to better delineate the development route of thermogenic fat.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
WH was supported by the Natural Science Foundation of China (82270868).
Acknowledgments
The authors thank the members of the laboratory of WH for valuable discussions and proofreading. The authors also acknowledge the many investigators who have contributed to this area of research and whose work, in many cases, could not be cited owing to the limitation of references allowed in this Review. The figures were created by Biorender.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: thermogenic fat, energy expenditure, transcription factor, epigenetic modification, intercellular regulation, inter-organ crosstalk
Citation: Wang C, Wang X and Hu W (2023) Molecular and cellular regulation of thermogenic fat. Front. Endocrinol. 14:1215772. doi: 10.3389/fendo.2023.1215772
Received: 02 May 2023; Accepted: 14 June 2023;
Published: 03 July 2023.
Edited by:
Endre Károly Kristóf, University of Debrecen, HungaryReviewed by:
Monica Colitti, University of Udine, ItalyRosemari Otton, Universidade Cruzeiro do Sul, Brazil
Copyright © 2023 Wang, Wang and Hu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wenxiang Hu, hu_wenxiang@gzlab.ac.cn
†These authors have contributed equally to this work