Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet

P. M. Jamieson, M. E. Cleasby, Y. Kuperman, N. M. Morton, P. A. T. Kelly, D. G. Brownstein, K. J. Mustard, J. M. Vaughan, R. N. Carter, C. N. Hahn, D. G. Hardie, J. R. Seckl, A. Chen, W. W. Vale

Research output: Contribution to journalArticlepeer-review



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.


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.


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 theUcn3 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.


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.

Original languageEnglish
Pages (from-to)2392-2403
Number of pages12
Issue number9
Publication statusPublished - Sep 2011


  • CRFR2
  • Energy balance
  • Glucose uptake
  • IGF-1
  • Obesity
  • Skeletal muscle
  • Transgenic mice
  • Urocortin 3


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