Adipocyte Utx Deficiency Promotes High-Fat Diet-Induced Metabolic Dysfunction in Mice.

Fenfen Li,Jia Jing,Xin Cui,Hang Shi,Shirong Wang,Liqing Yu,Bingzhong Xue

doi:10.3390/cells11020181

Fenfen Li, Jia Jing + Show 5 more

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https://doi.org/10.3390/cells11020181

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Abstract

While the main function of white adipose tissue (WAT) is to store surplus of energy as triacylglycerol, that of brown adipose tissue (BAT) is to burn energy as heat. Epigenetic mechanisms participate prominently in both WAT and BAT energy metabolism. We previously reported that the histone demethylase ubiquitously transcribed tetratricopeptide (Utx) is a positive regulator of brown adipocyte thermogenesis. Here, we aimed to investigate whether Utx also regulates WAT metabolism in vivo. We generated a mouse model with Utx deficiency in adipocytes (AUTXKO). AUTXKO animals fed a chow diet had higher body weight, more fat mass and impaired glucose tolerance. AUTXKO mice also exhibited cold intolerance with an impaired brown fat thermogenic program. When challenged with high-fat diet (HFD), AUTXKO mice displayed adipose dysfunction featured by suppressed lipogenic pathways, exacerbated inflammation and fibrosis with less fat storage in adipose tissues and more lipid storage in the liver; as a result, AUTXKO mice showed a disturbance in whole body glucose homeostasis and hepatic steatosis. Our data demonstrate that Utx deficiency in adipocytes limits adipose tissue expansion under HFD challenge and induces metabolic dysfunction via adipose tissue remodeling. We conclude that adipocyte Utx is a key regulator of systemic metabolic homeostasis.

Highlights

Obesity is associated with various metabolic disorders, including insulin resistance/type 2 diabetes and fatty liver disease [1]
We discovered an unexpected role of adipocyte Utx in the development of white adipose tissue remodeling and dysfunction and hepatic steatosis under high-fat diet (HFD)-induced metabolic stress
Utx in overall adipose tissue biology, we created a mouse with Utx deletion in adipocytes (AUTXKO) by breeding the Utx-floxed mouse with the Adiponectin-Cre line

Summary

Introduction

Obesity is associated with various metabolic disorders, including insulin resistance/type 2 diabetes and fatty liver disease [1]. Adipose tissue is a key organ in the regulation of energy homeostasis, as it hosts three kinds of adipocytes with distinct features: white adipocytes, brown adipocytes and beige adipocytes. White adipose tissue (WAT), which is equipped with metabolic pathways that can efficiently convert excess energy into triglyceride, is the main organ for energy storage in the body and is the determinant of the overall adiposity [2]. WAT mass can expand via hypertrophy or hyperplasia or a combination of both. While adipocyte hypertrophy results from the uptake of extracellular lipids by lipoproteins or production of intracellular lipids by de novo lipogenesis, hyperplasia involves an adipogenic process in which adipose progenitor cells (APCs) undergo proliferation and differentiation to form mature adipocytes [3]

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