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

ABSTRACT: 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?) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3? prior to obesity). In the present study, we investigated the role of CM-GSK-3? in a clinically more relevant model of established obesity (deletion of CM-GSK-3? after established obesity). CM-GSK-3? knockout (GSK-3?fl/flCre+/-) and controls (GSK-3?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? specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3? 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? in obese animals did not adversely affect the GSK-3?S21 phosphorylation (activity) and maintained canonical ?-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.

SUBMITTER: Gupte M 

PROVIDER: S-EPMC7291092 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature