Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet. / 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.
In: Diabetologia, Vol. 54, No. 9, 09.2011, p. 2392-2403.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet
A1 - Jamieson,P. M.
A1 - Cleasby,M. E.
A1 - Kuperman,Y.
A1 - Morton,N. M.
A1 - Kelly,P. A. T.
A1 - Brownstein,D. G.
A1 - Mustard,K. J.
A1 - Vaughan,J. M.
A1 - Carter,R. N.
A1 - Hahn,C. N.
A1 - Hardie,D. G.
A1 - Seckl,J. R.
A1 - Chen,A.
A1 - Vale,W. W.
AU - Jamieson,P. M.
AU - Cleasby,M. E.
AU - Kuperman,Y.
AU - Morton,N. M.
AU - Kelly,P. A. T.
AU - Brownstein,D. G.
AU - Mustard,K. J.
AU - Vaughan,J. M.
AU - Carter,R. N.
AU - Hahn,C. N.
AU - Hardie,D. G.
AU - Seckl,J. R.
AU - Chen,A.
AU - Vale,W. W.
PY - 2011/9
Y1 - 2011/9
N2 - <p>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.</p><p>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.</p><p>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.</p><p>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.</p>
AB - <p>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.</p><p>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.</p><p>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.</p><p>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.</p>
KW - CRFR2
KW - Energy balance
KW - Glucose uptake
KW - IGF-1
KW - Obesity
KW - Skeletal muscle
KW - Transgenic mice
KW - Urocortin 3
KW - GROWTH-FACTOR-I
KW - CORTICOTROPIN-RELEASING-FACTOR
KW - IMPROVES GLYCEMIC CONTROL
KW - SKELETAL-MUSCLE MASS
KW - INSULIN-RESISTANCE
KW - 11-BETA-HYDROXYSTEROID DEHYDROGENASE
KW - GLUCOSE-UTILIZATION
KW - ENERGY HOMEOSTASIS
KW - DIABETES-MELLITUS
KW - TUMOR-GROWTH
U2 - 10.1007/s00125-011-2205-6
DO - 10.1007/s00125-011-2205-6
M1 - Article
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 9
VL - 54
SP - 2392
EP - 2403
ER -