Herzig et al. (2001) demonstrated that mice carrying a targeted disruption of the cAMP response element-binding (CREB) protein gene ( 123810 ), or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycemia and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic program through the nuclear receptor coactivator PGC1, which was demonstrated to be a direct target for CREB regulation in vivo. Overexpression of PGC1 in CREB-deficient mice restored glucose homeostasis and rescued the expression of gluconeogenic genes. In transient assays, PGC1 potentiated glucocorticoid induction of the gene for PEPCK, the rate-limiting enzyme in gluconeogenesis. PGC1 promotes cooperativity between cAMP and glucocorticoid signaling pathways during hepatic gluconeogenesis. Fasting hyperglycemia is strongly correlated with type II diabetes ( 125853 ), so Herzig et al. (2001) concluded that the activation of PGC1 by CREB in liver contributes importantly to the pathogenesis of this disease.