In this proposal we will use mouse models that have mutations in the Cdk4 locus. Cdk4-/- mice are diabetic and lean, and in contrast, Cdk4R24C mice are non-diabetic and heavier. These observations are consistent with the documented, albeit not very well characterized, role of the RB/E2F pathway in adipogenesis amd muscle differentiation. Since Cdk4 is an upstream regulator of the E2F-RB pathway, we hypothesize that Cdk4 activity may regulate adipogenesis and muscle development and function. Further, the effect of Cdk4 on production of insulin, sex hormones and glucose regulation may impact the energy balance in the Cdk4R24C model. We are studying mechanisms of glucose tolerance and energy homeostasis by evaluating CDk4-dependent functions in different metabolic organs in the Cdk4 mice. The findings are revealing important role of Cdk4 in process that modulate energy balance.