Brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function is coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators.
Histone modification, DNA methylation and chromatin conformational changes have crucial roles in the determination and maintenance of brown and beige adipocyte fate.
Currently, more than 50 transcriptional regulators are known to control brown or beige adipocyte differentiation. A large proportion of the regulators, if not all of them, function through master regulators such as peroxisome proliferator-activated receptor-γ (PPARγ) and their partners CCAAT/enhancer-binding protein-ß (C/EBPβ), PR domain zinc-finger protein 16 (PRDM16) and PPARγ co-activator-1α (PGC1α).
Various external stimuli, such as chronic cold exposure and synthetic PPARγ ligands, promote beige adipocyte biogenesis in adipocyte precursors. These cues are sensed by cell surface receptors (such as the β-adrenergic receptor) and nuclear receptors (such as PPARγ), leading to dynamic changes in chromatin structures, as well as changes in expression and activity of the key transcriptional regulators.
White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes.
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The authors apologize for their inability to cite many papers that contributed to the advancement of this field, owing to a space limit. S.K. is supported by the US National Institutes of Health (NIH; DK97441 and DK108822), the Pew Charitable Trust and the Japan Science and Technology Agency. T.I. and J.S. are supported by grants-in-aid for scientific research (B, 25291002 and S, 22229009) and the translational systems biology and medicine initiative (TSBMI) from the Ministry of Education, Science, Sports and Culture (MEXT), Japan. The authors thank Yoshihiro Matsumura for critical reading of the manuscript.
The authors declare no competing financial interests.
- Interscapular BAT
Brown adipose tissue (BAT) is a specialized organ that produces heat. BAT is localized in the interscapular and perirenal regions of rodents and infants.
Myogenic progenitor cells that differentiate into myocytes (muscle cells).
- Transcriptional co-regulator
Transcriptional regulator that acts through forming a complex with DNA-binding transcriptional factors.
- Pioneer factors
Transcription factors that can access their target genomic sites in closed chromatin. Pioneer factors trigger enhancer competency and control cell fate determination.
- Retinoid X receptor
(RXR). A nuclear receptor that heterodimerizes with other nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). Endogenous ligands remain unknown.
- Epididymal WAT and inguinal WAT
Inguinal white adipose tissue (WAT) is a major subcutaneous WAT depot in rodents. Epididymal WAT is a visceral WAT.
- Human multipotent adipose-derived stem (hMADS) cells
Cells derived from the prepubic fat pad of a 4-month-old male donor. hMADS cells differentiate to white adipocytes using an adipogenic cocktail, and also to beige adipocytes as a result of chronic treatment with synthetic peroxisome proliferator-activated receptor (PPAR) agonists such as rosiglitazone.
Enhancer domains that are densely occupied with transcriptional regulators and mediator complexes. Superenhancers have key roles in regulating expression of genes essential for cell fate.
- Somitic mesoderm
Mesodermal tissue, which in vertebrate embryos forms in concert with the neural tube during neurulation. This area develops into somites that give rise to skeletal muscle, bone, connective tissues and skin.
- Cancer cachexia
A wasting syndrome that leads to body weight loss and atrophy of WAT and skeletal muscle in response to a malignant growth.
A Cys-rich secreted peptide from adipocytes that is associated with obesity and diabetes.
- Mediator complex subunit 1
(MED1). A core component of the Mediator complex that functions as a transcriptional co-activator. MED1 associates with general transcription factors and RNA polymerase II and has an essential role in activator-dependent transcription in all eukaryotes.
A secreted peptide from skeletal muscle (that is, a myokine) that regulates browning of WAT and thermogenesis.
- Nuclear receptor co-repressor
(NCoR). A transcriptional repressor that recruits histone deacetylases to the regulatory elements of its target genes and represses their transcription.
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Cite this article
Inagaki, T., Sakai, J. & Kajimura, S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol 17, 480–495 (2016). https://doi.org/10.1038/nrm.2016.62
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