Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3.

Tizhong Shan,Gongshe Yang,Feng Yue,Xiaoqi Liu,Pengpeng Bi,Yan Xiong,Yizhen Wang,Shihuan Kuang,Qingyang Jiang,Zhiguo Li,Pengpeng Zhang

doi:10.1038/ncomms12205

Abstract

Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Here we show that Lkb1 controls BAT expansion and UCP1 expression in mice. We generate adipocyte-specific Lkb1 knockout mice and show that, compared with wild-type littermates, these mice exhibit elevated UCP1 expression in BAT and subcutaneous white adipose tissue, have increased BAT mass and higher energy expenditure. Consequently, KO mice have improved glucose tolerance and insulin sensitivity, and are more resistant to high-fat diet (HFD)-induced obesity. Deletion of Lkb1 results in a cytoplasm to nuclear translocation of CRTC3 in brown adipocytes, where it recruits C/EBPβ to enhance Ucp1 transcription. In parallel, the absence of Lkb1 also suppresses AMPK activity, leading to activation of the mTOR signalling pathway and subsequent BAT expansion. These data suggest that inhibition of Lkb1 or its downstream signalling in adipocytes could be a novel strategy to increase energy expenditure in the context of obesity, diabetes and other metabolic diseases.

Highlights

Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity
We found that Adipoq-Cre induces efficient deletion of Lkb[1] in various adipose tissues including BAT, and results in robust metabolic phenotypes
As brown and beige adipocytes improve glucose metabolism and insulin sensitivity[19,44], we examined whether expansion of BAT and browning of WAT in the Adipoq-Lkb[1] mice elicits beneficial metabolic effects

Summary

Introduction

Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. We generate adipocyte-specific Lkb[1] knockout mice and show that, compared with wild-type littermates, these mice exhibit elevated UCP1 expression in BAT and subcutaneous white adipose tissue, have increased BAT mass and higher energy expenditure. The absence of Lkb[1] suppresses AMPK activity, leading to activation of the mTOR signalling pathway and subsequent BAT expansion These data suggest that inhibition of Lkb[1] or its downstream signalling in adipocytes could be a novel strategy to increase energy expenditure in the context of obesity, diabetes and other metabolic diseases. The prevalence of beige or brown adipocytes in adult human is inversely correlated with body mass index, adiposity and fasting plasma glucose level[24], indicating these UCP1-expressing adipocytes play an important role in regulating metabolism. Our results demonstrate that Lkb[1] is a critical regulator of BAT growth and function, and suggest that Lkb[1] signalling may be therapeutically targeted to counteract obesity, diabetes and other metabolic diseases

Methods

Results

Conclusion