title: Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity.
abstract: Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-C(POMC) mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP(3) (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-C(POMC) mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-C(POMC) mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance.
authors.affiliation: Institute for Genetics, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center of Molecular Medicine Cologne, D-50674 Cologne, Germany.
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Ernst
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Wunderlich
authors.forename: Simon
authors.initials: S
authors.lastname: Hess
authors.forename: Moritz
authors.initials: M
authors.lastname: Paehler
authors.forename: Andrea
authors.initials: A
authors.lastname: Mesaros
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
authors.forename: André
authors.initials: A
authors.lastname: Kleinridders
authors.forename: Andreas
authors.initials: A
authors.lastname: Husch
authors.forename: Heike
authors.initials: H
authors.lastname: Münzberg
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hampel
authors.forename: Jens
authors.initials: J
authors.lastname: Alber
authors.forename: Peter
authors.initials: P
authors.lastname: Kloppenburg
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D004195:Disease Models, Animal; D004435:Eating / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005246:Feedback / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins / Q000235:genetics; D007031:Hypothalamus / Q000473:pathology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D007328:Insulin; D020738:Leptin; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008565:Membrane Proteins; D009478:Neuropeptide Y; C502741:STT3-A protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011333:Pro-Opiomelanocortin; D019869:Phosphatidylinositol 3-Kinases