Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle
- 31 October 2006
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 103 (44), 16580-16585
- https://doi.org/10.1073/pnas.0607337103
Abstract
Skeletal muscle is the principal tissue responsible for insulin-stimulated glucose disposal and is a major site of peripheral insulin resistance. Urocortin 2 (Ucn 2), a member of the corticotropin-releasing factor (CRF) family, and its cognate type 2 CRF receptor (CRFR2) are highly expressed in skeletal muscle. To determine the physiological role of Ucn 2, we generated mice that are deficient in this peptide. Using glucose-tolerance tests (GTTs), insulin-tolerance tests (ITTs), and hyperinsulinemic euglycemic glucose clamp studies, we demonstrated that mice lacking Ucn 2 exhibited increased insulin sensitivity and were protected against fat-induced insulin resistance. Administration of synthetic Ucn 2 to mutant mice before the GTTs and ITTs restored blood glucose to WT levels. Administration of a CRFR2 selective antagonist to WT mice resulted in a GTT profile that mirrored that of Ucn 2-null mice. Body composition measurements of Ucn 2-null mice on a high-fat diet demonstrated decreases in fat and increases in lean tissue compared with WT mice. We propose that null mutant mice display increased glucose uptake in skeletal muscle through the removal of Ucn 2-mediated inhibition of insulin signaling. In keeping with these data, Ucn 2 inhibited insulin-induced Akt and ERK1/2 phosphorylation in cultured skeletal muscle cells and C2C12 myotubes. These data are consistent with the hypothesis that Ucn 2 functions as a local negative regulator of glucose uptake in skeletal muscle and encourage exploration of the possibility that suppression of the Ucn 2/CRFR2 pathway may provide benefits in insulin-resistant states such as type 2 diabetes.Keywords
This publication has 35 references indexed in Scilit:
- Advances in Male ContraceptionEndocrine Reviews, 2008
- ENDOCRINOLOGY OF THE STRESS RESPONSEAnnual Review of Physiology, 2005
- Unraveling the Cellular Mechanism of Insulin Resistance in Humans: New Insights from Magnetic Resonance SpectroscopyPhysiology, 2004
- Hormones and the Stressed BrainAnnals of the New York Academy of Sciences, 2004
- CRF and CRF Receptors: Role in Stress Responsivity and Other BehaviorsAnnual Review of Pharmacology and Toxicology, 2004
- Cellular mechanisms of insulin resistanceJCI Insight, 2000
- The Neural Network that Regulates Energy Balance Is Responsive to Glucocorticoids and Insulin and Also Regulates HPA Axis Responsivity at a Site Proximal to CRF NeuronsaAnnals of the New York Academy of Sciences, 1995
- Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus.JCI Insight, 1992
- Quantitation of Muscle Glycogen Synthesis in Normal Subjects and Subjects with Non-Insulin-Dependent Diabetes by13C Nuclear Magnetic Resonance SpectroscopyNew England Journal of Medicine, 1990
- Corticotropin releasing factor produces behavioural activation in ratsNature, 1982