Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice

Although the precise mechanisms contributing to insulin resistance and type 2 diabetes are unknown, it is believed that defects in downstream componen ts of the insulin signaling pathway may be involved. In this work, we hypot hesize that a serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), may be pertinent in this regard. To test this hypothesis, we examined GSK-3 activity in two inbred mouse strains known to be susceptible (C57BL/6J) or resistant (A/J) to diet-induced obesity and diabetes. Examination of GSK-3 in fat, liver, and muscle tissues of C57BL/6J mice revealed that GSK-3 act ivity increased twofold in the epididymal fat tissue and remained unchanged in muscle and liver of mice fed a high-fat diet, compared with their low-f at diet-fed counterparts. In contrast, GSK-3 activity did not change in the epididymal fat tissue of A/J mice, regardless of the type of diet they wer e fed. In addition, both basal and diet-induced GSK-3 activity tvas higher (2.3- and 3.2-fold, respectively) in the adipose tissue of C57BL/6J mice co mpared with that in A/J mice, Taken together, our studies suggest an unsusp ected Link between increased GSK-3 activity and development of insulin resi stance and type 2 diabetes in fat tissue of C57BL/6J mice, and implicate GS K-3 as a potential factor contributing to susceptibility of C57BL/6J mice t o diet-induced diabetes.