title: O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat.
abstract: 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.
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 93042, Brazil.
authors.forename: Marcelo O
authors.initials: MO
authors.lastname: Dietrich
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Zhong-Wu
authors.initials: ZW
authors.lastname: Liu
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 93042, Brazil.
authors.forename: Marcelo R
authors.initials: MR
authors.lastname: Zimmer
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Min-Dian
authors.initials: MD
authors.lastname: Li
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Jay Prakash
authors.initials: JP
authors.lastname: Singh
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Kaisi
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Ruonan
authors.initials: R
authors.lastname: Yin
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: tamas.horvath@yale.edu.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: xiaoyong.yang@yale.edu.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yang
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D004032:Diet; D005215:Fasting; D005260:Female; D054439:Ghrelin / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000517:prevention & control
chemical_list: D054369:Agouti-Related Protein; D054439:Ghrelin; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase