Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice
| Autor: | Patrice D. Cani, Marco Peters, Dominic J. Withers, Rachel L. Batterham, Alan Ashworth, Claude Knauf, Anne White, Rémy Burcelin, Philippe Valet, André Colom, Kaisa Piipari, Hind Al-Qassab, Angela Woods, K. Peter Giese, Ghazala Begum, Amanda Heslegrave, Michael L.J. Ashford, Mark A. Smith, Marc Claret, Keiko Mizuno, Phillip Mucket, David Carling, Julian J. Emmanuel |
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| Přispěvatelé: | Laboratory of Diabetes and Obesity, Endocrinology and Nutrition Unit, Hospital Clínic de Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Metabolic Signalling Group, Imperial College London-Clinical Sciences Centre-Medical Research Council (MRC), Biomedical Research Institute, University of Dundee-Ninewells Hospital and Medical School [Dundee], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellular Stress Group, Centre for Diabetes and Endocrinology, University College of London [London] (UCL)-Rayne Institute, Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Louvain Drug Research Institute, Manchester Academic Health Sciences Centre, University of Manchester [Manchester]-Faculties of Life Sciences and Medical and Human Sciences, Centre for the Cellular Basis of Behaviour, Institute of psychiatry-King‘s College London, The Breakthrough Breast Cancer Research Centre, Institute of cancer research, This work was supported by grants from the Biotechnology and Biological Sciences Research Council (to D.J.W.), the Medical Research Council (to D.J.W., R.L.B., K.P.G., and D.C.), the Wellcome Trust (to D.J.W., K.P.G., and M.L.A.), and the European Commission (contract no. LSHM-CT-2004-005272, to D.C.). M.C. is a recipient of a Miguel Servet contract (CP09/00233) from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (Spain)., UCL - SSS/LDRI - Louvain Drug Research Institute, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
MESH: Signal Transduction Pro-Opiomelanocortin Endocrinology Diabetes and Metabolism MESH: Neurons Cell Count AMP-Activated Protein Kinases MESH: Glucose Clamp Technique MESH: Eating Energy homeostasis Mice Eating 0302 clinical medicine MESH: Reverse Transcriptase Polymerase Chain Reaction Glucose homeostasis Homeostasis MESH: Pro-Opiomelanocortin MESH: Animals Neurons 0303 health sciences MESH: Statistics Nonparametric MESH: Electrophysiology Reverse Transcriptase Polymerase Chain Reaction digestive oral and skin physiology MESH: Energy Metabolism Glucose clamp technique Protein-Serine-Threonine Kinases Immunohistochemistry Electrophysiology MESH: Glucose MESH: Insulin Resistance MESH: Homeostasis Area Under Curve Female hormones hormone substitutes and hormone antagonists Signal Transduction medicine.medical_specialty endocrine system MESH: Mice Transgenic Hypothalamus Mice Transgenic Protein Serine-Threonine Kinases Carbohydrate metabolism Biology Statistics Nonparametric MESH: Protein-Serine-Threonine Kinases 03 medical and health sciences Insulin resistance Internal medicine MESH: Analysis of Variance Internal Medicine medicine Animals Protein kinase A MESH: Mice 030304 developmental biology Analysis of Variance MESH: Cell Count Body Weight AMPK MESH: Immunohistochemistry medicine.disease MESH: Hypothalamus MESH: Male MESH: Body Weight Metabolism Endocrinology Glucose nervous system Glucose Clamp Technique MESH: Area Under Curve Insulin Resistance Energy Metabolism MESH: Female 030217 neurology & neurosurgery |
| Zdroj: | Diabetes Diabetes, American Diabetes Association, 2011, 60 (3), pp.735-45. ⟨10.2337/db10-1055⟩ Diabetes, Vol. 60, no. 3, p. 735-745 (2011) Diabetes, 2011, 60 (3), pp.735-45. ⟨10.2337/db10-1055⟩ |
| ISSN: | 0012-1797 1939-327X |
| DOI: | 10.2337/db10-1055⟩ |
| Popis: | OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin–dependent protein kinase kinase β (CaMKKβ) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS Mice lacking either Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS Deletion of Camkkβ in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte–stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. |
| Databáze: | OpenAIRE |
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