The relationship between mitochondrial metabolism and insulin action in skeletal muscle

The prevalence of obesity and insulin resistance has increased at an alarming rate in recent years. Many studies published in the last decade have implicated defective mitochondrial metabolism as a possible factor driving the development of lipid-induced insulin resistance. The studies described in this thesis have investigated the effect of manipulating mitochondrial function on skeletal muscle insulin action.In the first study, the effect of broadly increasing mitochondrial metabolism via Peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β), a master regulator of mitochondrial biogenesis and function, was investigated. Acute, PGC-1β-mediated increases in mitochondrial function and antioxidant defences partially ameliorated lipid-induced insulin resistance, in association with reductions in the reactive lipid species long-chain acyl-CoA (LCACoA) and reduced oxidative stress. The subsequent study investigated the possibility of achieving a similar result by specifically upregulating lipid metabolism pathways via upregulation of a known regulator of lipid metabolism and a downstream effector of PGC-1β, estrogen-related receptor α (ERRα). Overexpression of ERRα increased markers of lipid metabolism; however this had no effect on high-fat-diet induced insulin resistance, LCACoA accumulation or oxidative stress within the muscle. In an attempt to further increase the beneficial effects of PGC-1β, PGC-1β and ERRα were simultaneously overexpressed. Unexpectedly, dual PGC-1β/ERRα upregulation did not induce any of the metabolic pathways induced by overexpression of PGC-1β or ERRα alone and thus did not prevent lipid-induced insulin resistance. Lastly, the effect of post-translational protein modifications (PTMs) on mitochondrial function was investigated in the genetically obese ob/ob mouse, identifying an association between protein hyperacetylation and reduced mitochondrial oxidative capacity. This was further correlated with the expression of mitochondrial deacetylases SIRT3 and SIRT5, indicating that sirtuin-mediated protein acetylation may be an additional level of regulation of mitochondrial function, and potentially insulin action.These studies suggest that changing mitochondrial capacity can influence insulin action in skeletal muscle, and that protein acetylation is associated with mitochondrial function and muscle insulin action. While it remains unknown whether defective mitochondrial metabolism may be a causative factor in the development of insulin resistance, these studies suggest that targeting manipulation of mitochondrial metabolism may be beneficial for the treatment of insulin resistance