Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Department of Physiology, Monash University, Victoria, Australia
Robert S Lee-Young
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia; Monash Metabolic Phenotyping Facility, Monash University, Victoria, Australia
Salvatore P Mangiafico
Department of Medicine (Austin Hospital), The University of Melbourne, Melbourne, Australia
Jack T Pryor
Department of Physiology, Monash University, Victoria, Australia; Warwick Medical School, University of Warwick, Coventry, United Kingdom
Astrid C Munder
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Department of Physiology, Monash University, Victoria, Australia
Stephanie E Simonds
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Department of Physiology, Monash University, Victoria, Australia
Jens Claus Brüning
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Center for Endocrinology, Diabetes, and Preventive Medicine, University Hospital Cologne, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; National Center for Diabetes Research, Neuherberg, Germany
Zhong-Yin Zhang
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States
Michael A Cowley
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Department of Physiology, Monash University, Victoria, Australia
Sofianos Andrikopoulos
Department of Medicine (Austin Hospital), The University of Melbourne, Melbourne, Australia
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, United States; Department of Anatomy and Histology, University of Veterinary Medicine, Hungary, Europe
David Spanswick
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; Department of Physiology, Monash University, Victoria, Australia; Warwick Medical School, University of Warwick, Coventry, United Kingdom
Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.
