KMT5c modulates adipocyte thermogenesis by regulating Trp53 expression

Abstract

Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a β3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.

p53 Regulates a miRNA-Fructose Transporter Axis in Brown Adipose Tissue Under Fasting

“…Our data showing p53 activation with concomitantly decreased BAT activity after 24 h of fasting is consistent with a recent study that demonstrated p53 as a negative regulator of the thermogenic program in brown adipocytes in mice ( Zhao et al, 2020 ). Therefore, we further investigated the potential underlying regulatory mechanisms.…”

Survivin is essential for thermogenic program and metabolic homeostasis in mice

“…SKO mice were generated by crossing survivin flox/flox mice with Adiponectin-Cre +/- mice, which were a kind gift from Dr. Junli Liu from our institute. The adiponectin-Cre +/- mice were also used and validated by another recent study [ 23 ]. After the Cre/loxp excision, the exon1–4 of Birc5 gene was deleted.…”

Asparagine reinforces mTORC1 signaling to boost thermogenesis and glycolysis in adipose tissues

“…The immortalized brown preadipocytes, primary brown or beige adipocytes are cultured and induced differentiation following the standard protocol as described previously (Pan et al, 2015;Zhao et al, 2020). Briefly, confluent brown preadipocytes (day 0) were induced by DMEM (Thermo Fisher, 11965092) containing 10% FBS, 20 nM insulin, 1 nM T3, 0.5 lM dexamethasone, 0.5 mM isobutylmethylxanthine, and 0.125 mM indomethacin for 48 h (day 0-2).…”