title: High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons.
abstract: Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K(ATP) channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(ΔIR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(ΔIR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(ΔIR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development.
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics University of Cologne, Köln, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Klöckener
authors.forename: Simon
authors.initials: S
authors.lastname: Hess
authors.forename: Bengt F
authors.initials: BF
authors.lastname: Belgardt
authors.forename: Lars
authors.initials: L
authors.lastname: Paeger
authors.forename: Linda A W
authors.initials: LA
authors.lastname: Verhagen
authors.forename: Andreas
authors.initials: A
authors.lastname: Husch
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hampel
authors.forename: Harveen
authors.initials: H
authors.lastname: Dhillon
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Zigman
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Williams
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Peter
authors.initials: P
authors.lastname: Kloppenburg
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002151:Calorimetry / Q000379:methods; D004041:Dietary Fats / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007276:Injections, Intraventricular / Q000379:methods; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced* / Q000473:pathology*; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014044:Tolbutamide / Q000494:pharmacology; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000473:pathology*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D020738:Leptin; D012333:RNA, Messenger; D054339:Steroidogenic Factor 1; C515058:steroidogenic factor 1, mouse; D049452:Green Fluorescent Proteins; D014044:Tolbutamide; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin