Control of brown and beige fat development

Abstract

Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight. Brown adipocytes develop in discrete and relatively homogenous depots of brown adipose tissue, whereas beige adipocytes are induced to develop in white adipose tissue in response to certain stimuli - notably, exposure to cold. Fate-mapping analyses have identified progenitor populations that give rise to brown and beige fat cells, and have revealed unanticipated cell-lineage relationships between vascular smooth muscle cells and beige adipocytes, and between skeletal muscle cells and brown fat. In addition, non-adipocyte cells in adipose tissue, including neurons, blood vessel-associated cells and immune cells, have crucial roles in regulating the differentiation and function of brown and beige fat.

Fig.1. Brown, white and beige adipocytes

There are three types of adipocyte: brown, white and beige. Mice have a major interscapular BAT depot, as indicated. Brown adipocytes in brown adipose tissue (BAT) are characterized by the presence of multilocular lipid droplets and densely packed mitochondria containing uncoupling protein 1 (UCP1). BAT is highly innervated and vascularized so that it can efficiently dissipate chemical energy as heat. White adipose tissue (WAT), dispersed in various subcutaneous and intra-abdominal depots, and contains mostly white adipocytes. White adipocytes are characterized by the presence of unilocular lipid droplets and few mitochondria that are devoid of UCP1. WAT is a major organ for the storage and release of energy. Beige adipocytes are found in various WAT depots and are especially prominent in the subcutaneous inguinal WAT. Beige fat cells develop in response to cold and certain other stimuli. Like brown adipocytes, beige cells have multilocular lipid droplets and densely packed UCP1+ mitochondria. Compared with brown adipocytes, beige adipocytes have more phenotypic flexibility, and can acquire a thermogenic or storage phenotype, depending on environmental cues.

Fig. 2. Development of brown adipocytes

Brown adipocytes are derived from a multipotent progenitor population in the dermomyotome that expresses En1, Pax7 and Myf5. During embryogenesis, these progenitors undergo commitment into brown fat preadipocytes and subsequently differentiate into mature brown adipocytes. Several transcription factors and signalling pathways have been implicated in regulating the development of brown adipose tissue (BAT): (1) EBF2 marks committed brown preadipocytes and might regulate brown adipose lineage specification; EWS interacts with YBX1 to regulate the transcription of BMP7, which promotes BAT development; (3) PRDM16 drives brown adipocyte differentiation through interactions with adipogenic transcription factors c/EBPβ and PPARγ; ZFP516 and EHMT1; (4) EBF2 cooperates with PPARγ to activate the brown fat-selective program.

Fig. 3. Development of beige adipocytes

(a) Possible mechanisms of beige adipocyte development in inguinal white adipose tissue (WAT). Different populations of precursors can be recruited by cold exposure or β-adrenergic signaling to differentiate into beige adipocytes. Pdgfrb⁺ mural cells, Myh11⁺ or SMA+ vascular smooth muscle cells, and Ebf2⁺; Pdgfrα⁺ adipogenic precursors have been reported to develop into beige adipocytes. EBF2, PRDM16, ZFP516 and PGC1α promote beige adipocyte differentiation. Myocardin-related transcription factor A (MRTFA) represses beige fat differentiation in smooth muscle-derived precursors. Cold-induced beige adipocytes lose the expression of UCP1 but can persist in the tissue after the cold stimulus is removed (for example, when the animals have warmed up). These de-activated beige cells have a white-like morphology but can be re-activated by an additional bout of cold or β-adrenergic signaling. (b) In epididymal WAT, a high-fat diet can induce bipotent Pdgfrα+ precursors to differentiate into white adipocytes, whereas cold exposure or β-adrenergic stimulation induces the differentiation of these cells into beige adipocytes.

Fig. 4. Crosstalk between brown/beige adipocytes and other adipose-resident cells

(a) Adipocytes and nerve cells. Parenchymal sympathetic nerve fibers secrete catecholamines to regulate the development and the thermogenic function of brown/beige adipocytes. Conversely, brown/beige adipocytes might also promote nerve remodeling by producing neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neuregulin 4 (NRG4). (b) Brown/beige adipocytes and vasculature. Adipocytes secrete vascular endothelial growth factor (VEGF) to stimulate angiogenesis. The enhanced vasculature provides increased nutrition and oxygen to sustain thermogenesis in brown/beige adipocytes, thereby promoting energy expenditure and insulin sensitivity. (c) Brown/beige adipocytes and immune cells. Interleukin (IL)-33 activates group 2 innate lymphoid cells (ILC2s), which secrete IL-13 and IL-5. IL-5 activates eosinophils, which produce IL-4. IL-4, in turn, induces the differentiation of M2 macrophages, which provide a critical source of catecholamines for beige fat activation. IL-4 (from eosinophils or ILC2s) also acts directly on Pdgfrα+ precursors to increase their proliferation and differentiation into beige adipocytes. Furthermore, ILC2s secrete met-enkephalin peptides to promote beige adipocyte differentiation. METRNL (Meteorin-like), secreted by muscle and adipose, activates eosinophils and type II cytokine signaling to drive beige adipocyte development.