Dnmt3b Deficiency in Myf5+-Brown Fat Precursor Cells Promotes Obesity in Female Mice.

Shirong Wang,Huidong Shi,Xin Cui,Jia Jing,Fenfen Li,Bingzhong Xue,Qiang Cao,Hang Shi

doi:10.3390/biom11081087

Abstract

Increasing energy expenditure through activation of brown fat thermogenesis is a promising therapeutic strategy for the treatment of obesity. Epigenetic regulation has emerged as a key player in regulating brown fat development and thermogenic program. Here, we aimed to study the role of DNA methyltransferase 3b (Dnmt3b), a DNA methyltransferase involved in de novo DNA methylation, in the regulation of brown fat function and energy homeostasis. We generated a genetic model with Dnmt3b deletion in brown fat-skeletal lineage precursor cells (3bKO mice) by crossing Dnmt3b-floxed (fl/fl) mice with Myf5-Cre mice. Female 3bKO mice are prone to diet-induced obesity, which is associated with decreased energy expenditure. Dnmt3b deficiency also impairs cold-induced thermogenic program in brown fat. Surprisingly, further RNA-seq analysis reveals a profound up-regulation of myogenic markers in brown fat of 3bKO mice, suggesting a myocyte-like remodeling in brown fat. Further motif enrichment and pyrosequencing analysis suggests myocyte enhancer factor 2C (Mef2c) as a mediator for the myogenic alteration in Dnmt3b-deficient brown fat, as indicated by decreased methylation at its promoter. Our data demonstrate that brown fat Dnmt3b is a key regulator of brown fat development, energy metabolism and obesity in female mice.

Highlights

Obesity poses a serious health threat to the current society due to its ability to increase mortality and morbidities including various metabolic disorders, such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular diseases [1]
Rodents possess two distinct types of thermogenic adipocytes: the classic brown adipose tissue (BAT) that mainly resides in the confined areas such as interscapular region and inducible beige adipocytes that are dispersed in white adipose tissue (WAT) and can be induced by β-adrenergic activation in response to cold challenge or β adrenergic agonists [2,9,10,11,12,13]
To determine the role of brown fat DNA methyltransferase 3b (Dnmt3b) in the regulation of diet-induced obesity, we generated a genetic model with deletion of Dnmt3b in brown fat-skeletal muscle lineage precursor cells (3bKO) by crossing Dnmt3b-floxed mice with Myf5-cre mice

Summary

Introduction

Obesity poses a serious health threat to the current society due to its ability to increase mortality and morbidities including various metabolic disorders, such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular diseases [1]. Brown fat is a key contributor to whole body energy expenditure due to its ability to generate adaptive thermogenesis [2,3]. Brown fat is capable of producing heat due to its unique expression of UCP1, a mitochondrial inner membrane protein that uncouples oxidative phosphorylation from ATP synthesis, thereby profoundly increasing energy expenditure [1,4,5,6]. Brown and beige adipocyte thermogenesis has been shown as a promising therapeutic target for the treatment of obesity [14,15,16].

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Conclusion