CREB regulates hepatic gluconeogenesis through the coactivator PGC-1

When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pa thways act synergistically to induce gluconeogenesis (glucose synthesis), a lthough the underlying mechanism has not been determined(1-4). Here we show that mice carrying a targeted disruption of the cyclic AMP (cAMP) response element binding (CREB) protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hyperglycaemia and reduced expression of g luconeogenic enzymes. CREB was found to induce expression of the gluconeoge nic programme through the nuclear receptor coactivator PGC-1, which is show n here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-dercient mice restored glucose homeostasis and rescued expre ssion of gluconeogenic genes. In transient assays, PGC-1 potentiated glucoc orticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK ), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativit y between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis. Fasting hyperglycaemia is strongly correlated with type II diabetes, so our results suggest that the activation of PGC-1 by CREB in l iver contributes importantly to the pathogenesis of this disease.