| First Author | Gupte M | Year | 2020 |
| Journal | Cells | Volume | 9 |
| Issue | 5 | PubMed ID | 32365965 |
| Mgi Jnum | J:304175 | Mgi Id | MGI:6694383 |
| Doi | 10.3390/cells9051120 | Citation | Gupte M, et al. (2020) Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3beta) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity. Cells 9(5):1120 |
| abstractText | 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-3beta) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3beta prior to obesity). In the present study, we investigated the role of CM-GSK-3beta in a clinically more relevant model of established obesity (deletion of CM-GSK-3beta after established obesity). CM-GSK-3beta knockout (GSK-3beta(fl/flCre+/-)) and controls (GSK-3beta(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-3beta specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3beta 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-3beta in obese animals did not adversely affect the GSK-3alphaS21 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. |
