Conditional, tissue-specific expression of Q205L Gα(i2) in vivo mimics insulin activation of c-Jun N-terminal kinase and p38 kinase

Deficiency of the G-protein subunit Gα(i2) impairs insulin action (Moxham, C. M., and Malbon, C. C. (1996) Nature 379, 840-844). By using the promoter for the phosphoenolpyruvate carboxykinase gene, conditional, tissue- specific expression of the constitutively active mutant form (Q205L) of Gα(i2) was achieved in mice harboring the transgene. Expression of Q205L Gα(i2) was detected in skeletal muscle, liver, and adipose tissue of transgenic mice. Whereas the Gα(i2)-deficient mice displayed blunted insulin action, the Q205L Gα(i2)-expressing mice displayed enhanced insulin-like effects. Glycogen synthase in skeletal muscle was found to be activated in Q205L Gα(i2)-expressing mice, in the absence of the administration of insulin. Analysis of members of mitogen-activated protein kinase family revealed that both c-Jun N-terminal kinase and p38 are constitutively activated in vivo in the mice that express the Q205L Gα(i2). ERK1,2, in contrast, are unaffected in the Q205L Gα(i2)-expressing mice. Insulin, like expression of Q205L Gα(i2), activates beth p38 and c-Jun N-terminal kinases as well as glycogen synthase. Activation of c-Jun N-terminal and p38 kinases in vivo with anisomycin, however, was insufficient to activate glycogen synthase. Much like Gα(i2) deficiency provokes insulin resistance, expression of Q205L constitutively active Gale mimics insulin action in vivo, sharing with insulin the activation of two mitogen-activated protein kinase members, p38 and cJun N-terminal kinases.