Employing our defined Cdk6 mouse models and in vitro differentiation assay, we have observed that the loss of either CDK6 (Cdk−/−) or its kinase domain (K43M) results in white fat browning, enhanced energy expenditure, improved glucose tolerance and insulin sensitivity, and resistance to high-fat diet (HFD)-induced obesity (DIO). The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.