Conditional, tissue-specific expression of Q205L Gαi2 in vivo mimics insulin activation of c-Jun N-terminal kinase and p38 kinase

Deficiency of the G-protein subunit G alpha(i2) impairs insulin action (Moxham, C, M,, and MaIbon, 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 G alpha(i2) was achieved in mice harboring the transgene, Expression of Q205L Get, was detected in skeletal muscle, liver, and adipose tissue of transgenic mice. Whereas the G alpha(i2)-deficient mice displayed blunted insulin action, the Q205L G alpha(i2)-expressing mice displayed enhanced insulin-like effects. Glycogen synthase in skeletal muscle was found to be activated in Q205L G alpha(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 G alpha(i2) ERK1,2, in contrast, are unaffected in the Q205L G alpha(i2)-expressing mice, Insulin, like expression of Q205L G alpha(i2), activates both 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 G alpha(i2), deficiency provokes insulin resistance, expression of Q205L constitutively active G alpha(i2) mimics insulin action in vivo, sharing with insulin the activation of two mitogen-activated protein kinase members, p38 and c-Jun N-terminal kinases.