title: Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet.
abstract: OBJECTIVE
  Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3.
  
  
  METHODS
  Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (Ucn3(+)) under control conditions and following an obesogenic high-fat diet (HFD) challenge.
  
  
  RESULTS
  Ucn3(+) mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin-stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in Crfr2 (also known as Crhr2)-null mice negated key aspects of the Ucn3(+) phenotype. Ucn3(+) mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in Ucn3(+) muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in Ucn3(+) muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed.
  
  
  CONCLUSIONS
  Urocortin 3 acting on CRFR2 in skeletal muscle of Ucn3(+) mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity.
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Pauline.Jamieson@ed.ac.uk
authors.forename: P M
authors.initials: PM
authors.lastname: Jamieson
authors.forename: M E
authors.initials: ME
authors.lastname: Cleasby
authors.forename: Y
authors.initials: Y
authors.lastname: Kuperman
authors.forename: N M
authors.initials: NM
authors.lastname: Morton
authors.forename: P A T
authors.initials: PA
authors.lastname: Kelly
authors.forename: D G
authors.initials: DG
authors.lastname: Brownstein
authors.forename: K J
authors.initials: KJ
authors.lastname: Mustard
authors.forename: J M
authors.initials: JM
authors.lastname: Vaughan
authors.forename: R N
authors.initials: RN
authors.lastname: Carter
authors.forename: C N
authors.initials: CN
authors.lastname: Hahn
authors.forename: D G
authors.initials: DG
authors.lastname: Hardie
authors.forename: J R
authors.initials: JR
authors.lastname: Seckl
authors.forename: A
authors.initials: A
authors.lastname: Chen
authors.forename: W W
authors.initials: WW
authors.lastname: Vale
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000502:physiology; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism* / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000378:metabolism* / Q000517:prevention & control*; D010641:Phenotype; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054832:Urocortins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C101531:CRF receptor type 2; D004041:Dietary Fats; D007328:Insulin; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C549823:urocortin 3 protein, mouse; D007334:Insulin-Like Growth Factor I; D005947:Glucose