title: Insulin-Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity.
abstract: Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IRΔMCH) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IRΔMCHmice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
authors.forename: A Christine
authors.initials: AC
authors.lastname: Hausen
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
authors.forename: Johan
authors.initials: J
authors.lastname: Ruud
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Biocenter, Institute for Zoology, University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Hess
authors.affiliation: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Biocenter, Institute for Zoology, University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany.
authors.forename: Hristo
authors.initials: H
authors.lastname: Varbanov
authors.affiliation: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Biocenter, Institute for Zoology, University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kloppenburg
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; National Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: bruening@sf.mpg.de.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007028:Hypothalamic Hormones / Q000235:genetics*; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D008124:Locomotion / Q000187:drug effects; D008543:Melanins / Q000235:genetics*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010907:Pituitary Hormones / Q000235:genetics*
chemical_list: D007028:Hypothalamic Hormones; D007328:Insulin; D008543:Melanins; D010907:Pituitary Hormones; C019463:melanin-concentrating hormone; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose
keywords: MCH; PI3K; energy homeostasis; glucose homeostasis; insulin receptor; insulin signaling; lateral hypothalamus; locomotor activity; selective insulin resistance