Insulin and adipocyte IRF4 promote fat retention over muscle preservation during intermittent fasting in obesity

• High insulin drives fat retention and lower muscle preservation during 5:2 IF in obese mice • Adipocyte IRF4 mediates the balance of fat versus muscle preservation during IF • IRF4 controls murine fat and muscle preservation under equal or reduced caloric IF • Obesity and/or high insulin promote lean mass loss during an acute fast in men, not women High insulin drives fat retention and lower muscle preservation during 5:2 IF in obese mice Adipocyte IRF4 mediates the balance of fat versus muscle preservation during IF IRF4 controls murine fat and muscle preservation under equal or reduced caloric IF Obesity and/or high insulin promote lean mass loss during an acute fast in men, not women Intermittent fasting (IF) can lower body mass during obesity, but it is unknown why certain individuals lose less fat and more lean mass during IF. We hypothesized that hyperinsulinemia and an insulin-responsive adipocyte factor regulate the balance between fat and muscle loss. Chronic elevation of insulin led to higher adipose tissue mass, larger adipocytes, and lower muscle mass after 10 weeks of 5:2 IF in obese male mice. Chronic hyperinsulinemia lowered adipose tissue interferon regulatory factor 4 (IRF4). Whole-body or adipocyte-specific deletion of Irf4 resulted in higher adipose tissue mass and lower muscle mass after IF in obese male mice in two separate models of equal or reduced caloric intake during IF. Males living with obesity and higher blood insulin levels lost more lean mass after a 48-h fast. Therefore, hyperinsulinemia and lower adipocyte IRF4 alter nutrient partitioning to promote higher adipose retention and lower muscle preservation during IF during obesity.