Rnf20 deficiency in adipocyte impairs adipose tissue development and thermogenesis

Xiaojuan Liang,Sin Man Lam,Wei Li,Ying Zhao,Jianfei Pan,Yanfang Wang,Yiping Fan,Lilan Zhang,Jianguo Zhao,Guanghou Shui,Cong Tao,Lulu Liu,Wanzhu Jin,Chunwei Cao,Jin Zhang,Jiali Liu,Kui Li

doi:10.1007/s13238-020-00770-2

Abstract

RNF20, an E3 ligase critical for monoubiquitination of histone H2B at lysine 120 (H2Bub), has been implicated in the regulation of various cellar processes; however, its physiological roles in adipocytes remain poorly characterized. Here, we report that the adipocyte-specific knockout of Rnf20 (ASKO) in mice led to progressive fat loss, organomegaly and hyperinsulinemia. Despite signs of hyperinsulinemia, normal insulin sensitivity and improved glucose tolerance were observed in the young and aged CD-fed ASKO mice. In addition, high-fat diet-fed ASKO mice developed severe liver steatosis. Moreover, we observed that the ASKO mice were extremely sensitive to a cold environment due to decreased expression levels of brown adipose tissue (BAT) selective genes, including uncoupling protein 1 (Ucp1), and impaired mitochondrial functions. Significantly decreased levels of peroxisome proliferator-activated receptor gamma (Pparγ) were observed in the gonadal white adipose tissues (gWAT) from the ASKO mice, suggesting that Rnf20 regulates adipogenesis, at least in part, through Pparγ. Rosiglitazone-treated ASKO mice exhibited increased fat mass compared to that of the non-treated ASKO mice. Collectively, our results illustrate the critical role of RNF20 in control of white and brown adipose tissue development and physiological function.

Highlights

Obesity has become a major health concern and an important worldwide social problem
The mRNA levels of Rnf20 gene were dramatically reduced in adipose tissues, including sWAT, gonadal white adipose tissues (gWAT) and brown adipose tissue (BAT), in the 2-month-old adipocyte-specific knockout of Rnf20 (ASKO) mice (Fig. S1C)
Immunoblotting and quantitative analysis showed the significant loss of RNF20 protein in adipose tissues of the ASKO mice and a weak band in the ASKO mice suggested that RNF20 was not deleted in other cells, such as vascular cells and macrophages (Fig. S1D and S1E)

Summary

Introduction

Obesity has become a major health concern and an important worldwide social problem. Obesity occurs when energy intake increases or energy expenditure decreases (Tseng et al, 2010) and is a significant risk factor for a vast number of metabolic diseases, such as cardiovascular disease, type 2 diabetes, hypertension, fatty liver disease and atherosclerosis (Jin and Patti, 2009). BAT was found in the lower neck and supraclavicular areas in adult human by 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) scanning (Van Marken Lichtenbelt et al, 2009; Virtanen et al, 2009; Zingaretti et al, 2009). Another thermogenic adipocyte, named beige or “brite” (brown in white) adipocyte, was recently identified in WAT exposed to various environmental stimuli, such as cold exposure (Liang et al, 2019), exercise (Phillips, 2019), or treatment with β-adrenergic receptor agonist (Himms-Hagen et al, 2000). Accumulating evidence has shown that activating BAT and promoting the browning of WAT burns fat and is applicable for the treatment of obesity and related metabolic diseases

Methods

Results

Conclusion