Affiliation:
1. Department of Molecular and Integrative Physiology University of Michigan Medical School Ann Arbor MI 48109 USA
2. Elizabeth Weiser Caswell Diabetes Institute University of Michigan Ann Arbor MI 48109 USA
3. Department of Endocrinology Beijing Tongren Hospital Capital Medical University Beijing Diabetes Institute Beijing 100730 China
4. Department of Medicine University of Chicago Chicago IL 60637 USA
5. Department of Surgery University of Michigan Medical School Ann Arbor MI 48109 USA
6. Department of Internal Medicine University of Michigan Medical School Ann Arbor MI 48109 USA
7. Department of Surgery Veterans Affairs Ann Arbor Healthcare System An Arbor MI 48105 USA
Abstract
AbstractWhite adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi‐58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte β adrenergic receptors (Adrb1‐3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N6‐methyladenosine (m6A)‐based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi‐58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts’ m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte‐specific deletion of Mettl14 are resistant to HFD‐induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A‐based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.
Funder
National Institutes of Health
University of Michigan Center for Gastrointestinal Research
U.S. Department of Veterans Affairs
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)