TET2 facilitates PPARγ agonist–mediated gene regulation and insulin sensitization in adipocytes

Bian, Fuyun; Ma, Xiang; Villivalam, Sneha Damal; You, Dongjoo; Choy, Lauren Raquel; Paladugu, Anushka; Fung, Sarah; Kang, Sona

doi:10.1016/j.metabol.2018.08.006

Cited by 33 publications

(32 citation statements)

References 59 publications

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“…This results in demethylation and H3K4me1/H3K27ac around PPARγ binding sites in 3T3-L1 adipocytes [31][32][33]. Interestingly, in mature adipocytes, TET2 facilitates the transcriptional activity of PPARγ and the insulin-sensitizing efficacy of PPARγ agonist by sustaining PPARγ DNA binding at certain target loci [34]. These studies employed non-brown/beige adipocyte cell lines, yet it is likely that the TETs play additional roles in thermogenic adipocytesoutside of their effect on Prdm16.…”

Section: Brown Adipocyte Differentiationmentioning

confidence: 99%

The role of DNA methylation in thermogenic adipose biology

Han

Kang

2019

Epigenetics

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The two types of thermogenic fat cells, beige and brown adipocytes, play a significant role in regulating energy homeostasis. Their development and thermogenesis are tightly regulated by dynamic epigenetic mechanisms, which could potentially be targeted to treat metabolic disorders such as obesity. However, we are just beginning to catalog and understand these dynamic changes. In this review, we will discuss the current understanding of the role of DNA (de) methylation events in beige and brown adipose biology in order to highlight the holes in our knowledge and to point the way forward for future studies. ARTICLE HISTORY

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Section: Brown Adipocyte Differentiationmentioning

confidence: 99%

The role of DNA methylation in thermogenic adipose biology

Han

Kang

2019

Epigenetics

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“…We found that AKG is a rate‐limiting factor controlling DNA demethylation in the Prdm16 promoter, and its deficiency in progenitor cells profoundly attenuates brown adipogenesis (Yang et al, ). Recent studies showed that TET‐mediated DNA demethylation regulates the expression of proxisome‐proliferator‐activated receptor (PPAR)γ, which initiates adipocyte differentiation (Bian et al, ; Yoo et al, ). During aging, however, the cellular metabolic flux declines, which is expected to reduce the AKG concentration in nuclei and thus impede DNA demethylation and brown adipogenesis.…”

Section: Introductionmentioning

confidence: 99%

Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice

et al. 2019

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Aging usually involves the progressive development of certain illnesses, including diabetes and obesity. Due to incapacity to form new white adipocytes, adipose expansion in aged mice primarily depends on adipocyte hypertrophy, which induces metabolic dysfunction. On the other hand, brown adipose tissue burns fatty acids, preventing ectopic lipid accumulation and metabolic diseases. However, the capacity of brown/beige adipogenesis declines inevitably during the aging process.Previously, we reported that DNA demethylation in the Prdm16 promoter is required for beige adipogenesis. DNA methylation is mediated by ten-eleven family proteins (TET) using alpha-ketoglutarate (AKG) as a cofactor. Here, we demonstrated that the circulatory AKG concentration was reduced in middle-aged mice (10-month-old) compared with young mice (2-month-old). Through AKG administration replenishing the AKG pool, aged mice were associated with the lower body weight gain and fat mass, and improved glucose tolerance after challenged with high-fat diet (HFD).These metabolic changes are accompanied by increased expression of brown adipose genes and proteins in inguinal adipose tissue. Cold-induced brown/beige adipogenesis was impeded in HFD mice, whereas AKG rescued the impairment of beige adipocyte functionality in middle-aged mice. Besides, AKG administration up-regulated Prdm16 expression, which was correlated with an increase of DNA demethylation in the Prdm16 promoter. In summary, AKG supplementation promotes beige adipogenesis and alleviates HFD-induced obesity in middle-aged mice, which is associated with enhanced DNA demethylation of the Prdm16 gene. K E Y W O R D S adipose tissue browning, aging, alpha-ketoglutarate, DNA demethylation, glucose tolerance, high-fat diet S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Tian Q, Zhao J, Yang Q, et al. Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice. Aging Cell.

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“…Several key factors in regulating BAT function have been identified such as peroxisome proliferator-activated receptor γ (PPARγ), PPARγ cofactor-1α (PGC-1α), and PR domain containing 16 (PRDM16) [7][8][9]. PPARγ, forming a heterodimer with retinoid X receptor (RXR), activates Ucp1 gene expression by binding to the peroxisome proliferator response element (PPRE) in the Ucp1 promoter [10].…”

Section: Introductionmentioning

confidence: 99%

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

Fang

et al. 2019

Metabolism

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The thermogenic brown adipose tissue (BAT) has been proposed as a potential target to prevent or treat obesity and related metabolic diseases. BAT secretes adipokines to regulate the thermogenic program in an autocrine or paracrine manner. Follistatin-like 1 (FSTL1), a glycoprotein involved in adipogenesis and obesity, however, the function of FSTL1 in BAT thermogenesis and in the regulation of systemic energy homeostasis are not fully understood. Methods: Whole-body ablation Fstl1 heterozygous mice (Fstl1 +/−) and its littermates control were injected with CL316,243 to assess energy balance. A series of FSTL1 overexpression and knockdown experiments were carried out to evaluate its function in regulating thermogenic gene expression in brown adipocytes. Results: FSTL1 expression was induced upon BAT activation during cold challenge or β3-adrenergic activation. FSTL1 haploinsufficiency in mice led to reduced thermogenic gene expression, impaired BAT recruitment, and decreased heat production. FSTL1 cell-autonomously promoted the β3-adrenergic signaling, which was required to upregulate PPARγ and UCP1 in brown adipocytes. Furthermore, only glycosylated FSTL1 could be secreted from brown adipocytes to induce the β3-adrenergic activation. Conclusions: Our results suggest FSTL1 as a novel stimulator of the β-adrenergic signaling and BAT thermogenesis.

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TET2 facilitates PPARγ agonist–mediated gene regulation and insulin sensitization in adipocytes

Abstract: Our data demonstrate that TET2 works as an epigenetic regulator of Rosi-mediated insulin sensitization and transcriptional regulation in adipocytes.

Cited by 33 publications

References 59 publications

The role of DNA methylation in thermogenic adipose biology

The role of DNA methylation in thermogenic adipose biology

Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

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