Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) 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-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/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-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β 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-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-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.

Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases

“… 116 However, deleting CM‐GSK3β after established obesity (a clinically more relevant model) did not adversely affect cardiac function, but improved glucose tolerance. 117 Consistently, chronic treatment of GSK3 inhibitor in established HFD induced obese rats improved insulin resistance without exacerbating obesity‐induced cardiac hypertrophy. 118 …”

“…The CM‐specific deletion of GSK3β led to cardiac dysfunction and heart failure in obese animals fed an HFD without affecting body weight, fat mass, and other metabolic parameters such as cholesterol, insulin, and blood glucose 116 . However, deleting CM‐GSK3β after established obesity (a clinically more relevant model) did not adversely affect cardiac function, but improved glucose tolerance 117 . Consistently, chronic treatment of GSK3 inhibitor in established HFD induced obese rats improved insulin resistance without exacerbating obesity‐induced cardiac hypertrophy 118 …”

Isoform-Specific Role of GSK-3 in High Fat Diet Induced Obesity and Glucose Intolerance

“…130860, Envigo, Madison, WI, USA) followed by four weeks of washout to eliminate any residual tamoxifen or tamoxifen-induced toxicity. The tamoxifen diet protocol has been well-established in our laboratory and consistently reported [21,36]. Baseline parameters such as body weight, fat mass, lean mass, glucose tolerance, and insulin tolerance were assessed in all of the animals.…”