title: Defective Natriuretic Peptide Receptor Signaling in Skeletal Muscle Links Obesity to Type 2 Diabetes.
abstract: Circulating natriuretic peptide (NP) levels are reduced in obesity and predict the risk of type 2 diabetes (T2D). Since skeletal muscle was recently shown as a key target tissue of NP, we aimed to investigate muscle NP receptor (NPR) expression in the context of obesity and T2D. Muscle NPRA correlated positively with whole-body insulin sensitivity in humans and was strikingly downregulated in obese subjects and recovered in response to diet-induced weight loss. In addition, muscle NP clearance receptor (NPRC) increased in individuals with impaired glucose tolerance and T2D. Similar results were found in obese diabetic mice. Although no acute effect of brain NP (BNP) on insulin sensitivity was observed in lean mice, chronic BNP infusion improved blood glucose control and insulin sensitivity in skeletal muscle of obese and diabetic mice. This occurred in parallel with a reduced lipotoxic pressure in skeletal muscle due to an upregulation of lipid oxidative capacity. In addition, chronic NP treatment in human primary myotubes increased lipid oxidation in a PGC1α-dependent manner and reduced palmitate-induced lipotoxicity. Collectively, our data show that activation of NPRA signaling in skeletal muscle is important for the maintenance of long-term insulin sensitivity and has the potential to treat obesity-related metabolic disorders.
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Coué
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Badin
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Isabelle K
authors.initials: IK
authors.lastname: Vila
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Laurens
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Katie
authors.initials: K
authors.lastname: Louche
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Marie-Adeline
authors.initials: MA
authors.lastname: Marquès
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Bourlier
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Mouisel
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Tavernier
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors.forename: Arild C
authors.initials: AC
authors.lastname: Rustan
authors.affiliation: School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Galgani
authors.affiliation: Department of Kinesiology, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval, Canada.
authors.forename: Denis R
authors.initials: DR
authors.lastname: Joanisse
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Sanford-Burnham Medical Research Institute, Orlando, FL.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France Department of Clinical Biochemistry, Toulouse University Hospitals, Toulouse, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.affiliation: Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France cedric.moro@inserm.fr.
authors.forename: Cedric
authors.initials: C
authors.lastname: Moro
mesh_terms: D000328:Adult; D000818:Animals; D015992:Body Mass Index; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000517:prevention & control; D004038:Diet, Reducing; D018450:Disease Progression; D018149:Glucose Intolerance / Q000209:etiology* / Q000517:prevention & control; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011897:Random Allocation; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D015431:Weight Loss
chemical_list: D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; C073616:atrial natriuretic factor receptor C