Induction of beige cells causes the browning of white fat and improves energy metabolism. However, the central mechanism that controls adipose tissue browning and its physiological relevance are largely unknown. Here, we demonstrate that fasting and chemical-genetic activation of orexigenic AgRP neurons in the hypothalamus suppress the browning of white fat. O-linked β-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins regulates fundamental cellular processes. The levels of O-GlcNAc transferase (OGT) and O-GlcNAc modification are enriched in AgRP neurons and are elevated by fasting. Genetic ablation of OGT in AgRP neurons inhibits neuronal excitability through the voltage-dependent potassium channel, promotes white adipose tissue browning, and protects mice against diet-induced obesity and insulin resistance. These data reveal adipose tissue browning as a highly dynamic physiological process under central control, in which O-GlcNAc signaling in AgRP neurons is essential for suppressing thermogenesis to conserve energy in response to fasting. PaperClip
Bibliographical noteFunding Information:
We thank Dr. Steven Jones from University of Louisville for providing Ogt -flox mice and Dr. Alison Xu from University of California at San Francisco for donating AgRP -Cre mice. This work was supported by NIH R01 DK089098, American Diabetes Association, and Ellison Medical Foundation to X.Y., American Heart Association Scientist Development Grant to H.-B.R., NIH DP1 DK098058 and ADA Mentor-Based Fellowship to T.L.H., and CNPq/Brazil to M.O.D. and M.R.Z.