Dynamic transcriptome changes during adipose tissue energy expenditure reveal critical roles for long noncoding RNA regulators.

Zhiqiang Bai,Arcinas Camille Esther Walet,Lei Sun,Zhi-Chun Zhang,Myeong Jin Yoon,Hye-Jin Kim,Peng Chen,Hongyuan Yang,Sook-Yoong Chia,Dan Xu,Kinyui Alice Lo,Shao-Hai Xu,Diana Teh Chee Siang,Xiao-Ran Chai,Sujoy Ghosh

doi:10.1371/journal.pbio.2002176

Abstract

Enhancing brown fat activity and promoting white fat browning are attractive therapeutic strategies for treating obesity and associated metabolic disorders. To provide a comprehensive picture of the gene regulatory network in these processes, we conducted a series of transcriptome studies by RNA sequencing (RNA-seq) and quantified the mRNA and long noncoding RNA (lncRNA) changes during white fat browning (chronic cold exposure, beta-adrenergic agonist treatment, and intense exercise) and brown fat activation or inactivation (acute cold exposure or thermoneutrality, respectively). mRNA–lncRNA coexpression networks revealed dynamically regulated lncRNAs to be largely embedded in nutrient and energy metabolism pathways. We identified a brown adipose tissue–enriched lncRNA, lncBATE10, that was governed by the cAMP-cAMP response element-binding protein (Creb) axis and required for a full brown fat differentiation and white fat browning program. Mechanistically, lncBATE10 can decoy Celf1 from Pgc1α, thereby protecting Pgc1α mRNA from repression by Celf1. Together, these studies provide a comprehensive data framework to interrogate the transcriptomic changes accompanying energy homeostasis transition in adipose tissue.

Highlights

Obesity has reached an epidemic proportion in both developed and developing nations, resulting in a steep rise in healthcare expenses and a growing population with associated comorbidities and chronic illnesses [1]
Fat accumulation is a major health problem in many countries, but unlike white fat— which stores calories—brown fat is packed with mitochondria to burn energy
Promoting “browning” of white fat and enhancing brown fat activity are seen as promising therapeutic strategies to fight obesity

Summary

Introduction

Obesity has reached an epidemic proportion in both developed and developing nations, resulting in a steep rise in healthcare expenses and a growing population with associated comorbidities and chronic illnesses [1]. An attractive approach for obesity therapy is to augment the mass and activities of thermogenic brown adipose tissue (BAT) or promote white adipose tissue (WAT) to take on BAT-like features [2,3,4,5,6,7,8]. Beige adipocytes exhibit WAT phenotypes basally but can be induced to take on BAT features and exert BAT-like function, a process referred to as browning, by stimuli such as cold exposure, beta-adregenic agonist stimulation, or extensive physical exercise [2,5,6]. Lin’s group identified Blnc, a BATenriched, Ebf-2–regulated lncRNA, which was important for the thermogenic differentiation of brown and beige adipocytes [17]. Lnc-BATE1, was subsequently demonstrated to be necessary for the proper development and maintenance of mature brown adipocytes [18]

Methods

Results

Conclusion