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.
David Savage (Thu,) studied this question.