title: Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance.
abstract: Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne 50931, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne 50937, Germany; Max Planck Institute for Metabolism Research, Cologne 50931, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Tsaousidou
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Institute for Zoology, University of Cologne, Cologne 50674, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Paeger
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne 50674, Germany.
authors.forename: Bengt F
authors.initials: BF
authors.lastname: Belgardt
authors.affiliation: Baker IDI Heart and Diabetes Institute, Cellular and Molecular Metabolism Laboratory, Melbourne, VIC 3004, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Pal
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne 50931, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne 50937, Germany; Max Planck Institute for Metabolism Research, Cologne 50931, Germany.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Wunderlich
authors.affiliation: Mouse Phenotyping Core Facility, Cologne Excellence Cluster on Cellular Stress Responses, Cologne 50931, Germany.
authors.forename: Hella
authors.initials: H
authors.lastname: Brönneke
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Institute for Zoology, University of Cologne, Cologne 50674, Germany.
authors.forename: Ursel
authors.initials: U
authors.lastname: Collienne
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne 50931, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne 50937, Germany; Max Planck Institute for Metabolism Research, Cologne 50931, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hampel
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne 50931, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne 50937, Germany; Max Planck Institute for Metabolism Research, Cologne 50931, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich 81675, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Institute for Zoology, University of Cologne, Cologne 50674, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kloppenburg
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne 50931, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne 50931, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne 50937, Germany; Max Planck Institute for Metabolism Research, Cologne 50931, Germany. Electronic address: bruening@sf.mpg.de.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D050154:Adiposity / Q000187:drug effects; D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D051550:I-kappa B Kinase / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology*
chemical_list: D054369:Agouti-Related Protein; D007328:Insulin; D020738:Leptin; D050505:Mutant Proteins; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose