title: Central insulin action regulates peripheral glucose and fat metabolism in mice.
abstract: Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, and Center of Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Koch
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Jost
authors.initials: J
authors.lastname: Seibler
authors.forename: A Christine
authors.initials: AC
authors.lastname: Könner
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hampel
authors.forename: Sigrid
authors.initials: S
authors.lastname: Irlenbusch
authors.forename: Georg
authors.initials: G
authors.lastname: Brabant
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Frieder
authors.initials: F
authors.lastname: Schwenk
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006720:Homozygote; D007328:Insulin / Q000378:metabolism*; D050155:Lipogenesis; D008071:Lipoprotein Lipase / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008957:Models, Genetic; D014018:Tissue Distribution
chemical_list: D007328:Insulin; D008071:Lipoprotein Lipase; D005947:Glucose