UC San Diego

Muscle insulin resistance is a primary metabolic defect underlying the etiology of type 2 diabetes. Consumption of a high-fat/high-calorie diet (HFD) is associated with the development of insulin resistance and type 2 diabetes, while calorie restriction (CR) (60% of ad libitum [AL] food intake) robustly reverses muscle insulin resistance. Remarkably, the signaling mechanisms linking nutrient status to muscle insulin sensitivity are incompletely defined. Considering that the prevalence of diabetes continues to grow at an alarming rate, addressing this fundamental gap in knowledge has the potential to significantly impact human health. Thus, the objective of this dissertation was to define the mechanisms underlying muscle insulin action in the context of nutrient availability. Sirtuin 1 (SIRT1), a NAD+-dependent protein deacetylase, has been proposed to link perturbations in nutrient availability to muscle insulin action. In line with this, SIRT1 activity in skeletal muscle is increased by CR and decreased by HFD. Furthermore, mice with transgenic overexpression of SIRT1 exhibit a metabolic profile resembling CR, and small molecule activators of SIRT1 enhance insulin sensitivity in rodent models of insulin resistance. Nevertheless, little is known regarding the regulatory role of SIRT1 in muscle insulin action, particularly in vivo. We recently identified the SIRT1 target, signal transducer and activator of transcription 3 (STAT3), as an important regulator of muscle insulin sensitivity in response to CR. Furthermore, STAT3 is activated in insulin resistant states and inhibition of STAT3 in liver restores hepatic insulin sensitivity. Thus, we hypothesized that SIRT1 and STAT3 regulate muscle insulin sensitivity in response to nutrient availability. To address this hypothesis, we investigated muscle insulin signaling and sensitivity in response to HFD and CR using novel mouse models in which we modulated SIRT1 and STAT3 activity in skeletal muscle. Our findings demonstrate that muscle-specific overexpression of SIRT1 does not enhance muscle insulin action under AL or CR conditions or prevent HFD-induced obesity or insulin resistance. Finally, we showed that knockout of STAT3 in skeletal muscle does not enhance muscle insulin sensitivity on a control diet or HFD. Taken together, the studies from this dissertation broaden our understanding of the roles of SIRT1 and STAT3 in muscle insulin action in response to nutrient availability