Reactome | Transcriptional regulation of brown and beige adipocyte differentiation

Transcriptional regulation of brown and beige adipocyte differentiation

Stable Identifier

R-HSA-9843743

DOI

10.3180/R-HSA-9843743.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Transcriptional regulation of brown and beige adipocyte differentiation

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Brown and beige adipocytes convert chemical energy produced by the oxidation of fatty acids and glucose into heat, which is important for thermoregulation and control of body weight. Brown and beige adipocytes largely share the transcription program involved in adaptive non-shivering thermogenesis but develop from different lineages (reviewed in Wang and Seale 2016, Ghaben and Scherer 2019). Brown adipocytes share their precursor cells with skeletal muscle cells and develop in discrete, homogeneous brown adipose tissue depots. Beige adipocytes share their precursor cells with white adipocytes and develop in white adipose tissue in response to environmental stimuli, mainly exposure to cold, with an ability to revert to a white adipocyte-like phenotype. Development of beige adipocytes in white adipose tissue is known as white adipose tissue browning (reviewed in Wang and Seale 2016).

Brown and beige adipocytes have been characterized in most detail in rodents. In humans, brown adipose tissue was thought to regress after infancy, but was shown by multiple studies published after 2007 to persist in substantial deposits into adulthood adulthood (reviewed in Bartlet and Heeren 2014, Wang and Seale 2016, Ghaben and Scherer 2019, and Cannon et al. 2020). Molecular profiles that correspond to both brown and beige rodent adipocytes have been identified in human brown-designated adipose tissue, and therefore both brown and beige adipocytes are now thought to be conserved in humans (Nedergaard et al. 2007; Virtanen et al. 2009; Cypess et al. 2009; Sharp et al. 2012; Wu et al. 2012; Nedergaard and Cannon 2013; de Jong et al. 2019; reviewed in Bartlet and Heereb 2014, Wang and Seale 2016, and Cannon et al. 2020).

The major protein marker of brown and beige adipocytes is Uncoupling protein 1 (UCP1). UCP1 resides at the inner mitochondrial membrane where it translocates protons (H+) from the intermembrane space into the mitochondrial matrix. UCP1 thus dissipates the proton-motive force to be used by ATP synthase, converting the energy released by the respiratory chain into heat (reviewed in Bartlet and Heereb 2014, Wang and Seale 2016). Brown adipose tissue is innervated by the sympathetic nervous system. Noradrenaline is secreted by sympathetic neurons when the central nervous system senses cold. Brown adipocytes possess adrenergic receptors on their surface that are activated by noradrenaline. Activated adrenergic receptors trigger a signaling cascade that induces lipolysis and activates UCP1 (reviewed in Wang and Seale 2016).

Multiple transcription factors that regulate the thermogenic molecular signature are shared between brown and beige adipocytes, such as EBF2, PRDM16, ZNF516, and PPARGC1A. Master regulators of adipogenesis, such as PPARG and CEBPB, are shared between white, brown, and beige adipocytes (reviewed in Wang and Seale 2016).

Besides its role in thermoregulation, white adipose tissue browning is implicated in cancer-associated cachexia, a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia (reviewed in Weber et al. 2022).

For review, please refer to Bartelt and Heeren 2014, Wang and Seale 2016, Ghaben and Scherer 2019, Cannon et al. 2020, Weber et al. 2022.

Literature References

PubMed ID	Title	Journal	Year
32378255	Human brown adipose tissue: Classical brown rather than brite/beige? Nedergaard, J, Cannon, B, Petrovic, N, de Jong, JMA, Fischer, AW	Exp Physiol	2020
27552974	Control of brown and beige fat development Wang, W, Seale, P	Nat Rev Mol Cell Biol	2016
17473055	Unexpected evidence for active brown adipose tissue in adult humans Nedergaard, J, Bengtsson, T, Cannon, B	Am J Physiol Endocrinol Metab	2007
24146030	Adipose tissue browning and metabolic health Heeren, J, Bartelt, A	Nat Rev Endocrinol	2014
35646636	Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia Weber, BZC, Kir, S, Arabaci, DH	Front Oncol	2022
19357407	Functional brown adipose tissue in healthy adults Enerbäck, S, Taittonen, M, Laine, J, Orava, J, Heglind, M, Nuutila, P, Virtanen, KA, Westergren, R, Niemi, T, Savisto, NJ, Lidell, ME	N Engl J Med	2009
30610207	Adipogenesis and metabolic health Ghaben, AL, Scherer, PE	Nat Rev Mol Cell Biol	2019
22796012	Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human Enerbäck, S, Schrauwen, P, Spiegelman, BM, Hoeks, J, Nuutila, P, Sparks, LM, Giang, AH, Tu, H, van Marken Lichtenbelt, WD, Choi, JH, Ye, L, Huang, K, Khandekar, M, Wu, J, Boström, P, Virtanen, KA, Schaart, G	Cell	2012
23652104	How brown is brown fat? It depends where you look Nedergaard, J, Cannon, B	Nat Med	2013
19357406	Identification and importance of brown adipose tissue in adult humans Lehman, S, Kahn, CR, Goldfine, AB, Kolodny, GM, Palmer, EL, Tseng, YH, Williams, G, Kuo, FC, Tal, I, Doria, A, Rodman, D, Cypess, AM	N Engl J Med	2009
23166672	Human BAT possesses molecular signatures that resemble beige/brite cells Hu, H, Tomoda, E, Gilsanz, V, Pavlova, Z, Wang, L, Ruiz, L, Shinoda, K, Ohno, H, Scheel, DW, Kajimura, S, Sharp, LZ	PLoS One	2012
32694768	Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice Virtanen, K, Frontini, A, Cinti, S, Jespersen, NZ, Pires, ND, Balaz, M, Sun, W, Nuutila, P, Feizi, A, Scheele, C, Niemi, T, Wolfrum, C, Nedergaard, J, Cannon, B, Petrovic, N, Petrovic, K, Nielsen, S, Bokhari, MH, de Jong, JMA, Fischer, AW	Nat Metab	2019