Epigenetic dynamics of the thermogenic gene program of adipocytes

Yi, Danielle; Nguyen, Hai P.; Sul, Hei Sook

doi:10.1042/bcj20190599

Cited by 19 publications

(13 citation statements)

References 106 publications

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“…As in most biological processes, BAT as well as beige fat, rely heavily on environmental cues for its full activation of the thermogenic gene program. Integrating epigenetic effectors into the thermogenic network may provide a comprehensive understanding in the regulation of thermogenic gene program (Yi et al, 2020). Here, we identify Dot1l (disruptor of telemetric silencing 1-like) as an interacting partner of Zc3h10 and a critical coactivator of thermogenic genes.…”

Section: Introductionmentioning

confidence: 99%

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Nguyen

Dinh

et al. 2020

eLife

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Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.

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Section: Introductionmentioning

confidence: 99%

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Nguyen

Dinh

et al. 2020

eLife

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“…p38, a MAP kinase, phosphorylates multiple transcription factors, including ATF2 and IRF4, both of which can bind to the enhancer or promoter regions to activate UCP1 transcription ( 22 ). In addition, we recently found that ZC3H10, previously known to bind RNA, is phosphorylated by p38 upon cold, activating the thermogenic gene program in adipocytes ( 17 ).…”

Section: β 3 -Adrenergic Signalingmentioning

confidence: 99%

“…For example, cold temperature stimulates the sympathetic nervous system to release norepinephrine, which then binds β 3 -adrenergic receptor ( 15 ). β 3 -adrenergic signaling has a wide range of downstream targets including numerous transcription factors and co-activators that can induce thermogenic genes ( 22 ). In addition to the transcriptional regulation, β 3 -adrenergic signaling also increases lipolysis and glucose uptake to support thermogenesis ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Signaling Pathways Regulating Thermogenesis

Tabuchi

Sul

2021

Front. Endocrinol.

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Obesity, an excess accumulation of white adipose tissue (WAT), has become a global epidemic and is associated with complex diseases, such as type 2 diabetes and cardiovascular diseases. Presently, there are no safe and effective therapeutic agents to treat obesity. In contrast to white adipocytes that store energy as triglycerides in unilocular lipid droplet, brown and brown-like or beige adipocytes utilize fatty acids (FAs) and glucose at a high rate mainly by uncoupling protein 1 (UCP1) action to uncouple mitochondrial proton gradient from ATP synthesis, dissipating energy as heat. Recent studies on the presence of brown or brown-like adipocytes in adult humans have revealed their potential as therapeutic targets in combating obesity. Classically, the main signaling pathway known to activate thermogenesis in adipocytes is β3-adrenergic signaling, which is activated by norepinephrine in response to cold, leading to activation of the thermogenic program and browning. In addition to the β3-adrenergic signaling, numerous other hormones and secreted factors have been reported to affect thermogenesis. In this review, we discuss several major pathways, β3-adrenergic, insulin/IGF1, thyroid hormone and TGFβ family, which regulate thermogenesis and browning of WAT.

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“…Peroxisome proliferator-activated receptor gamma (PPARγ), encoded by PPARG , is the target of thiazolidinediones antidiabetic treatment, as discussed above. PPARγ participates in the differentiation of adipocytes and activation of thermogenic gene expression in brown adipocytes [ 116 ]. PPARγ is a major regulator of adipocyte differentiation and function [ 117 ].…”

Section: Main Textmentioning

confidence: 99%

Mammalian tumor-like organs. 2. Mammalian adipose has many tumor features and obesity is a tumor-like process

Kozlov

2022

Infect Agents Cancer

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Background In previous publications, the author developed the theory of carcino-evo-devo, which predicts that evolutionarily novel organs should recapitulate some features of tumors in their development. Main text Mammalian adipose is currently recognized as a multi-depot metabolic and endocrine organ consisting of several adipose tissues. Although lipid-storing cells and proteins are ancient, the adipose organ as a whole is evolutionarily novel to mammals. The adipose expansion has remarkable similarities with the growth of solid tumors. These similarities are the following: (1) The capability to unlimited expansion; (2) Reversible plasticity; (3) Induction of angiogenesis; (4) Chronic inflammation; (5) Remodeling and disfunction; (6) Systemic influence on the organism; (7) Hormone production; (8) Production of miRNAs that influence other tissues; (9) Immunosuppression; (10) DNA damage and resistance to apoptosis; (11) Destructive infiltration in other organs and tissues. These similarities include the majority of “hallmarks of cancer”. In addition, lipomas are the most frequent soft tissue tumors, and similar drugs may be used for the treatment of obesity and cancer by preventing infiltration. This raises the possibility that obesity, at least in part, may represent an oncological problem. The existing similarities between adipose and tumors suggest the possible evolutionary origin of mammalian adipose from some ancestral benign mesenchymal hereditary tumors. Indeed, using a transgenic inducible zebrafish tumor model, we described many genes, which originated in fish and were expressed in fish tumors. Their human orthologs LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA acquired functions connected with the adipose organ. They are also involved in tumor development in humans. Conclusion If the hypothesis of the evolutionary origin of the adipose organ from the ancestral hereditary tumor is correct, it may open new opportunities to resolve the oncological problem and the problem of the obesity epidemic. New interventions targeting LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA gene network, in addition to what already is going on, can be designed for treatment and prevention of both obesity and tumors.

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Epigenetic dynamics of the thermogenic gene program of adipocytes

Cited by 19 publications

References 106 publications

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Signaling Pathways Regulating Thermogenesis

Mammalian tumor-like organs. 2. Mammalian adipose has many tumor features and obesity is a tumor-like process

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