34-OR: Maladaptive Increases in Skeletal Muscle Ketone Body Oxidation Contribute to Dysglycemia in Mice Subjected to Experimental Obesity

Type 2 diabetes (T2D) is a rapidly growing health epidemic, with intense investigation on whether perturbations in skeletal muscle carbohydrate and fatty acid metabolism contribute to obesity-induced insulin resistance and/or T2D. Conversely, whether perturbations in skeletal muscle ketone body oxidation take place in the pathology of obesity-induced insulin resistance/T2D remains unclear. Therefore, our goal was to investigate potential alterations in ketone body metabolism during the pathology of obesity-induced T2D, and to elucidate whether such changes are adaptive or maladaptive. C57BL/6J mice were subjected to low-fat (lean) or high-fat (obese) diet supplementation for 12 weeks. Obese mice exhibited glucose intolerance, which was associated with decreased circulating βOHB and elevated circulating glucose levels. In addition, obese mice demonstrated a marked increase in mRNA and protein expression of succinyl CoA:3-ketoacid CoA transferase (SCOT), the rate limiting enzyme of ketone body oxidation, within gastrocnemius muscles, which was associated with an increase in SCOT enzymatic activity. Of interest, SCOT activity requires succinyl-CoA as a substrate, which is also required for protein succinylation. Accordingly, siRNA knockdown of Oxct1 augmented lysine succinylation, whereas Oxct1 overexpression abolished lysine succinylation. Additionally, Oxct1 knockdown in C2C12 myotubes increased AMPK phosphorylation, which was recapitulated in mice with an Oxct1 skeletal muscle-specific deficiency (Oxct1SkM-/-). Intriguingly, Oxct1SkM-/- mice were protected against obesity-induced dysglycemia and insulin resistance. Our results suggest that ketone body metabolism is augmented in skeletal muscle during the pathology of obesity, which may contribute to dysglycemia and insulin resistance in T2D via potentially modifying protein succinylation and/or AMPK activity.