In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Automated summary

Metabolic regulation in skeletal muscle plays a crucial role in maintaining blood glucose levels. Obesity leads to insulin resistance in skeletal muscle, resulting in elevated blood glucose and the development of type 2 diabetes. Through multiomic analysis of skeletal muscle in wild-type and leptin-deficient obese mice, this study constructed regulatory transomic networks to understand the metabolic regulation after oral glucose administration. The findings indicate that glucose-responsive metabolites have a significant impact on metabolic regulation, particularly in carbohydrate metabolic pathways, in wild-type mice. In contrast, the metabolic regulation by glucose-responsive metabolites is largely disrupted in obese mice, with increased reliance on glucose-responsive genes, especially in carbohydrate and lipid metabolic pathways. The study also identified characteristic metabolic regulatory pathways in central carbon, branched amino acids, and ketone body metabolism. These findings provide valuable insights into how skeletal muscle responds to changes in blood glucose and the dysregulation observed in obesity.