Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3 beta) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3 beta prior to obesity). In the present study, we investigated the role of CM-GSK-3 beta in a clinically more relevant model of established obesity (deletion of CM-GSK-3 beta after established obesity). CM-GSK-3 beta knockout (GSK-3 beta (fl/flCre+/-)) and controls (GSK-3 beta (fl/flCre-/-)) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3 beta specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3 beta knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3 beta in obese animals did not adversely affect the GSK-3 alpha S21 phosphorylation (activity) and maintained canonical beta -catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.