title: Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action.
abstract: Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (AgRP IR KO) exhibited impaired hepatic insulin action because the ability of insulin to suppress hepatic glucose production (hGP) was reduced, but the ability of insulin to suppress lipolysis was unaltered. To the contrary, in POMC IR KO mice, insulin lowered hGP but failed to suppress adipose tissue lipolysis. High-fat diet equally worsened glucose tolerance in AgRP and POMC IR KO mice and their respective controls but increased hepatic triglyceride levels only in POMC IR KO mice, consistent with impaired lipolytic regulation resulting in fatty liver. These data suggest that although insulin signaling in AgRP neurons is important in regulating glucose metabolism, insulin signaling in POMC neurons controls adipose tissue lipolysis and prevents high-fat diet-induced hepatic steatosis.
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Shin
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Nika
authors.initials: N
authors.lastname: Filatova
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lindtner
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Chi
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Seta
authors.initials: S
authors.lastname: Degann
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Douglas
authors.initials: D
authors.lastname: Oberlin
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY christoph.buettner@mssm.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D002153:Calorimetry, Indirect; D003080:Cold Temperature; D059305:Diet, High-Fat; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; D007004:Hypoglycemic Agents; D007328:Insulin; D014280:Triglycerides; D011333:Pro-Opiomelanocortin; D011972:Receptor, Insulin; D005947:Glucose