| First Author | Gupte M | Year | 2024 |
| Journal | Am J Physiol Cell Physiol | Volume | 327 |
| Issue | 6 | Pages | C1349-C1358 |
| PubMed ID | 39344416 | Mgi Jnum | J:389044 |
| Mgi Id | MGI:7786766 | Doi | 10.1152/ajpcell.00552.2024 |
| Citation | Gupte M, et al. (2024) Animal models of haploinsufficiency revealed the isoform-specific role of GSK-3 in HFD-induced obesity and glucose intolerance. Am J Physiol Cell Physiol 327(6):C1349-C1358 |
| abstractText | Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase with two isoforms (alpha and beta) is implicated in the pathogenesis of type 2 diabetes mellitus (T2D). Recently, we reported the isoform-specific role of GSK-3 in T2D using homozygous GSK-3alpha/beta knockout mice. Although the homozygous inhibition models are idealistic in a preclinical setting, they do not mimic the inhibition seen with pharmacological agents. Hence, in this study, we sought to investigate the dose-response effect of GSK-3alpha/beta inhibition in the pathogenesis of obesity-induced T2D. Specifically, to gain insight into the dose-response effect of GSK-3 isoforms in T2D, we generated tamoxifen-inducible global GSK-3alpha/beta heterozygous mice. GSK-3alpha/beta heterozygous and control mice were fed a high-fat diet (HFD) for 16 wk. At baseline, the body weight and glucose tolerance of GSK-3alpha heterozygous and controls were comparable. In contrast, at baseline, a modest but significantly higher body weight (higher lean mass) was seen in GSK-3beta heterozygous compared with controls. Post-HFD, GSK-3alpha heterozygous and controls displayed a comparable phenotype. However, GSK-3beta heterozygous were significantly protected against obesity-induced glucose intolerance. Interestingly, the improved glucose tolerance in GSK-3beta heterozygous animals was dampened with chronic HFD-feeding, likely due to significantly higher fat mass and lower lean mass in the GSK-3beta animals. These findings suggest that GSK-3beta is the dominant isoform in glucose metabolism. However, to avail the metabolic benefits of GSK-3beta inhibition, it is critical to maintain a healthy weight.NEW & NOTEWORTHY The precise isoform-specific role of GSK-3 in obesity-induced glucose intolerance is unclear. To overcome the limitations of pharmacological GSK-3 inhibitors (not isoform-specific) and tissue-specific genetic models, in the present study, we created novel inducible heterozygous mouse models of GSK-3 inhibition that allowed us to delete the gene globally in an isoform-specific and temporal manner to determine the isoform-specific role of GSK-3 in obesity-induced glucose intolerance. |
