The role of integrin alpha 7 in diet-induced obesity and signalling

Integrins are heterodimeric transmembrane proteins and have been shown to play a key role in insulin signalling and glucose metabolism. Integrin α7β1 is the predominant integrin in adult skeletal muscle, a tissue responsible for approximately 80% of insulin-stimulated glucose uptake. Previous studies have demonstrated the role of integrin α7β1 in the maintenance of skeletal muscle, but no studies have investigated it with a metabolic focus. In this thesis, we used an integrin α7 whole-body deletion mouse model (α7KO) to elucidate the role of integrin α7 in metabolism. In this study we showed that the deletion of integrin α7 resulted in leaner mice when fed either a chow or a high fat diet (HFD), as well as containing significantly less adipose tissue than controls when fed a HFD. Histological analysis showed that integrin α7KO mice suffered from significantly worse liver steatosis when fed a HFD compared to controls and had higher serum levels of indicative enzymes of liver damage. However, liver damage observed in integrin α7KO mice had no effect on bile acid production. Integrin α7KO mice were significantly more insulin sensitive and glucose tolerant than control mice. Protein quantification of skeletal muscle showed increased levels of pAkt(Ser473) and pAkt(Thr308) in integrin α7KO mice compared to controls when fed a HFD and were exacerbated when challenged with insulin. We demonstrated that the muscle-specific transgenic overexpression of the adult integrin α7 splice variants X2A and X2B rescued the insulin sensitive, glucose tolerant, and steatotic liver phenotype. However, splice variants X1A and X1B could not rescue the insulin sensitive or glucose tolerance phenotype, but partially rescued the steatotic liver phenotype. In this thesis, we have demonstrated that integrin α7 plays a fundamental role in diet-induced obesity and metabolism