title: Urocortin 3 activates AMPK and AKT pathways and enhances glucose disposal in rat skeletal muscle.
abstract: Insulin resistance (IR) in skeletal muscle is an important component of both type 2 diabetes and the syndrome of sarcopaenic obesity, for which there are no effective therapies. Urocortins (UCNs) are not only well established as neuropeptides but also have their roles in metabolism in peripheral tissues. We have shown recently that global overexpression of UCN3 resulted in muscular hypertrophy and resistance to the adverse metabolic effects of a high-fat diet. Herein, we aimed to establish whether short-term local UCN3 expression could enhance glucose disposal and insulin signalling in skeletal muscle. UCN3 was found to be expressed in right tibialis cranialis and extensor digitorum longus muscles of rats by in vivo electrotransfer and the effects studied vs the contralateral muscles after 1 week. No increase in muscle mass was detected, but test muscles showed 19% larger muscle fibre diameter (P=0.030), associated with increased IGF1 and IGF1 receptor mRNA and increased SER256 phosphorylation of forkhead transcription factor. Glucose clearance into the test muscles after an intraperitoneal glucose load was increased by 23% (P=0.018) per unit mass, associated with increased GLUT1 (34% increase; P=0.026) and GLUT4 (48% increase; P=0.0009) proteins, and significantly increased phosphorylation of insulin receptor substrate-1, AKT, AKT substrate of 160 kDa, glycogen synthase kinase-3β, AMP-activated protein kinase and its substrate acetyl coA carboxylase. Thus, UCN3 expression enhances glucose disposal and signalling in muscle by an autocrine/paracrine mechanism that is separate from its pro-hypertrophic effects, implying that such a manipulation may have promised for the treatment of IR syndromes including sarcopaenic obesity.
authors.affiliation: Department of Comparative Biomedical SciencesRoyal Veterinary College, University of London, Royal College Street, London NW1 0TU, UKLaboratory of Neuronal Structure and FunctionSalk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USAQueen's Medical Research InstituteCentre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Manon M
authors.initials: MM
authors.lastname: Roustit
authors.affiliation: Department of Comparative Biomedical SciencesRoyal Veterinary College, University of London, Royal College Street, London NW1 0TU, UKLaboratory of Neuronal Structure and FunctionSalk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USAQueen's Medical Research InstituteCentre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Vaughan
authors.affiliation: Department of Comparative Biomedical SciencesRoyal Veterinary College, University of London, Royal College Street, London NW1 0TU, UKLaboratory of Neuronal Structure and FunctionSalk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USAQueen's Medical Research InstituteCentre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Jamieson
authors.affiliation: Department of Comparative Biomedical SciencesRoyal Veterinary College, University of London, Royal College Street, London NW1 0TU, UKLaboratory of Neuronal Structure and FunctionSalk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USAQueen's Medical Research InstituteCentre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK mcleasby@rvc.ac.uk.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cleasby
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019899:Paracrine Communication / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D054832:Urocortins / Q000502:physiology*
chemical_list: D054832:Urocortins; D051058:Oncogene Protein v-akt; D000263:Adenylate Kinase; D005947:Glucose
keywords: AMPK; GLUT4; PI3K signalling; glucose disposal; skeletal muscle; urocortin 3