This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gluconeogenesis (GNG) is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Several transcription factors and coactivators have been shown to regulate this process, however, the underlying mechanisms have not been fully elucidated. We recently found that a calcium-responsive kinase calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in the liver of leptin-deficient (ob/ob) mice, a model of severe insulin resistance and diabetes. Treatment of ob/ob mice with a specific CaMKII inhibitor decreased hepatic CaMKII activity, lowered fasting blood glucose, and decreased the expression of the gluconeogenic genes, G6Pase and PEPCK. We next explored GNG in primary hepatocytes, which express CaMKIIg, from WT vs. Camk2g-/- mice. We demonstrated that CaMKII plays an essential role in the regulation of fasting gluconeogenesis. We found that the CaMKIIg-deficient hepatocytes have a marked decrease in the expression of G6Pase and PEPCK induced by forskolin, a glucagon mimetic and cAMP activator, and lower levels of nuclear FoxO1, which transcriptionally induces GNG genes. Moreover, primary hepatocytes transduced with adenovirus containing constitutively active CaMKII have increased expression levels of G6Pase and PEPCK mRNA compared with controls. In support of a role for CaMKIIg in fasting GNG in vivo, we found that fasted Camk2g-/- mice had lower blood glucose levels;lower conversion of pyruvate to glucose;blunted induction of hepatic GNG genes;and lower levels of FoxO1 in hepatic nuclei compared with WT mice. These data suggest that ER stress-induced activation of CaMKIIg in liver during obesity and fasting contributes to increased hepatic glucose production and hyperglycemia. This concept raises the possibility that therapeutic targeting of hepatic CaMKIIg may have particular benefit in glucose homeostasis in insulin-resistant subjects.
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