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

• Published in: Diabetologia Vol. 54; no. 9; pp. 2392 - 2403
• Main Authors: Jamieson, P. M., Cleasby, M. E., Kuperman, Y., Morton, N. M., Kelly, P. A. T., Brownstein, D. G., Mustard, K. J., Vaughan, J. M., Carter, R. N., Hahn, C. N., Hardie, D. G., Seckl, J. R., Chen, A., Vale, W. W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-09-2011; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Body composition; Body Composition - drug effects; Body Composition - physiology; Carbohydrate metabolism; Corticotropin-releasing hormone; Diabetes. Impaired glucose tolerance; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy balance; Energy Metabolism - drug effects; Energy Metabolism - physiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting; Fundamental and applied biological sciences. Psychology; Genotype & phenotype; Glucose; Glucose - metabolism; High fat diet; Human Physiology; Hyperglycemia; Hyperglycemia - metabolism; Hyperglycemia - prevention & control; Hypertrophy; Insulin; Insulin - blood; Insulin resistance; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Internal Medicine; Kinases; Laboratories; Ligands; Lipids; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondrial uncoupling protein 2; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Musculoskeletal system; Myocytes; Neurosciences; Obesity; Obesity - metabolism; Obesity - prevention & control; Paracrine signalling; Phenotype; Phenotyping; Proteins; Receptors, Corticotropin-Releasing Hormone - deficiency; Receptors, Corticotropin-Releasing Hormone - genetics; Receptors, Corticotropin-Releasing Hormone - metabolism; Skeletal muscle; Striated muscle. Tendons; Transgenes; Transgenic animals; Transgenic mice; urocortin; Urocortins - genetics; Urocortins - metabolism; Vertebrates: osteoarticular system, musculoskeletal system; United Kingdom > UK; United States > US; CRFR2; Energy balance; Obesity; Glucose uptake; Transgenic mice; IGF-1; Urocortin 3; Skeletal muscle; Endocrinopathy; Transgenic animal; Glucose; Hyperglycemia; Nutritional status; Diabetes mellitus; Rodentia; Nutrition disorder; Insulin like growth factor 1; Striated muscle; Uptake; Feeding; Urocortin; Vertebrata; Phenotype; Mammalia; Diet; Mouse
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-011-2205-6

Aims/hypothesis
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/interpretation
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.