Integrated Analysis of Insulin Resistance Reveals Metabolic Remodelling 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 CD-fed states after CR. In the liver, improved insulin sensitivity correlates with reduced tri-(TAG) and diacylglycerol (DAG) and protein kinase C epsilon (PKCε) activity, alongside substantially decreased de novo lipogenesis (DNL) 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 (ADRB3) expression. This, combined with enhanced oxidative pathways in muscle and liver resulted in lowered plasma free fatty acid (FA) levels and muscle/liver lipids, facilitating insulin-stimulated glucose disposal and thus restored insulin sensitivity.