Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity

Author:

Wang Qi1ORCID,Zhang Bichen1ORCID,Stutz Bernardo2ORCID,Liu Zhong-Wu2ORCID,Horvath Tamas L.23ORCID,Yang Xiaoyong123ORCID

Affiliation:

1. Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.

2. Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

3. Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA.

Abstract

The ventromedial hypothalamus (VMH) is known to regulate body weight and counterregulatory response. However, how VMH neurons regulate lipid metabolism and energy balance remains unknown. O-linked β- d - N -acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), catalyzed by O-GlcNAc transferase (OGT), is considered a cellular sensor of nutrients and hormones. Here, we report that genetic ablation of OGT in VMH neurons inhibits neuronal excitability. Mice with VMH neuron-specific OGT deletion show rapid weight gain, increased adiposity, and reduced energy expenditure, without significant changes in food intake or physical activity. The obesity phenotype is associated with adipocyte hypertrophy and reduced lipolysis of white adipose tissues. In addition, OGT deletion in VMH neurons down-regulates the sympathetic activity and impairs the sympathetic innervation of white adipose tissues. These findings identify OGT in the VMH as a homeostatic set point that controls body weight and underscore the importance of the VMH in regulating lipid metabolism through white adipose tissue–specific innervation.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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