Integrated analysis of insulin resistance reveals metabolic remodeling following diet switch-triggered calorie reduction

Insulin resistance (IR) links obesity to metabolic disorders. While weight loss reverses IR, we show that calorie reduction (CR) can do so in obese mice within a day before significant weight loss. In contrast to whole-body IR, individual tissues do not revert to their original chow diet-fed states after CR. In the liver, improved insulin sensitivity correlates with reduced triacylglycerol and diacylglycerol and protein kinase C epsilon activity, alongside substantially decreased de novo lipogenesis and increased ketones. In muscle, insulin-sensitive glucose disposal was restored, whereas obesity-associated adipose tissue changes largely persisted following CR, specifically the reduction in fasting lipolytic activity mediated at least, in part, by lower β-adrenergic receptor 3 expression. This, combined with enhanced oxidative pathways in muscle and liver, resulted in lowered plasma free fatty acid levels and muscle and liver lipids, facilitating insulin-stimulated glucose disposal and thus restored insulin sensitivity.