Insulin regulates POMC neuronal plasticity to control glucose metabolism

• Published in: eLife Vol. 7
• Main Authors: Dodd, Garron T, Michael, Natalie J, Lee-Young, Robert S, Mangiafico, Salvatore P, Pryor, Jack T, Munder, Astrid C, Simonds, Stephanie E, Brüning, Jens Claus, Zhang, Zhong-Yin, Cowley, Michael A, Andrikopoulos, Sofianos, Horvath, Tamas L, Spanswick, David, Tiganis, Tony
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 19.09.2018; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; Biochemistry; Brain; cellular signalling; Diabetes therapy; Excitability; Fasting; Feeding; Gene expression; Genes; Glucose; Glucose - metabolism; Human Biology and Medicine; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Hypothalamus; Hypothalamus - cytology; Insulin; Insulin - administration & dosage; Insulin - pharmacology; Insulin resistance; Kinases; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Neurons; Neurons - metabolism; Neuroscience; Nutrient deficiency; Obesity; Phosphatases; Physiological aspects; Plasticity (neural); POMC neurons; Pro-Opiomelanocortin - genetics; Pro-Opiomelanocortin - metabolism; Proopiomelanocortin; protein tyrosine phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Rodents; Victoria Australia; Cologne Germany; United Kingdom > UK; Australia; United States > US; human biology; cellular signalling; mouse; insulin; neuroscience; protein tyrosine phosphatase; medicine; POMC neurons; glucose metabolism; hypothalamus
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.38704

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.