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 components of the insulin signaling pathway may be involved. In this work, we hypothesize 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 activity 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-fat 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 were fed. In addition, both basal and diet-induced GSK-3 activity was higher (2.3- and 3.2-fold, respectively) in the adipose tissue of C57BL/6J mice compared with that in A/J mice. Taken together, our studies suggest an unsuspected link between increased GSK-3 activity and development of insulin resistance and type 2 diabetes in fat tissue of C57BL/6J mice, and implicate GSK-3 as a potential factor contributing to susceptibility of C57BL/6J mice to diet-induced diabetes.
Eldar-Finkelman
H
H
Division of Women's Health, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Schreyer
S A
SA
Shinohara
M M
MM
LeBoeuf
R C
RC
Krebs
E G
EG
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics*; D004032:Diet; D020022:Genetic Predisposition to Disease; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D008297:Male; D051379:Mice; D008805:Mice, Inbred A / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
D011518:Proto-Oncogene Proteins; D038341:Glycogen Synthase Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3