Endocrine Abstracts

Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type-2 which is highly expressed in skeletal muscle where it regulates glucose metabolism and muscle mass. Transgenic mice overexpressing Urocortin-3 (UCN3+) show accelerated peripheral glucose disposal and increased skeletal muscle mass with myocyte hypertrophy associated with decreased energy efficiency and improved glucose tolerance. We aimed to determine whether this phenotype would confer protection against the adverse metabolic consequences of an obesogenic high fat diet (HFD) challenge.

UCN3+ mice and control littermates were fed a low fat diet (LFD) or HFD (11 or 45% kcal as fat) from weaning. Caloric intake, glucose and insulin tolerance and glucose disposal to tissues in vivo were quantified at 16 weeks old. mRNA expression of metabolic genes, and expression and phosphorylation of insulin signalling molecules were examined in skeletal muscle and liver.

Despite consuming more calories, UCN3+ mice gained less weight and lost more body weight following fasting, suggesting they mobilise energy stores more efficiently. Fat depots were enlarged by HFD feeding in control but not UCN3+ mice, which were also protected from induction of glucose intolerance and insulin resistance. Glucose uptake and incorporation into glycogen was increased in UCN3+ muscle and liver, associated with a consistent decrease in muscle glycogen synthase phosphorylation in muscle indicative of increased enzyme activity. However, basal and insulin-stimulated phosphorylation of IRS-1 and Akt were not different between genotypes in liver or muscle, UCP2 mRNA was upregulated in UCN3+ muscle.

Elevated hepatic CPT1a and PEPCK mRNA levels and activity were consistent with increased gluconeogenesis and fatty acid oxidation. These data suggest the metabolically favourable phenotype of UCN3+ mice is the result of accelerated glucose uptake and utilisation in muscle by a non-PI-3 kinase-dependent mechanism with compensatory increases in hepatic lipid catabolism and gluconeogenesis.