CREB regulates hepatic gluconeogenesis through the coactivator PGC-1

Abstract

When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pathways act synergistically to induce gluconeogenesis (glucose synthesis), although the underlying mechanism has not been determined. 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 hypoglycaemia [corrected] and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes. In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativity 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 liver contributes importantly to the pathogenesis of this disease.

Nuclear receptors, mitochondria and lipid metabolism

“…The activities are most notable in highly metabolic tissues, such as brown adipose tissue, heart, skeletal muscle, liver and the CNS, where PGC-1a regulates the central characteristics of these differentiated tissues: thermogenesis, contractile force, oxidative fiber types, gluconeogenesis and beta-oxidation, and emerging roles in the CNS such as ROS adaptation and apoptosis. (Puigserver et al 1998;Herzig et al 2001;Lin et al 2002;Puigserver et al 2003;Rhee et al 2003;Arany et al 2005;St-Pierre et al 2006;Handschin et al 2007). While named for its interaction with PPARγ, many of these PGC-1-dependent adaptations appear to be largely dependent on ERRs and other metabolic transcription factors that are independent of PPAR/RXR Rhee et al 2003;Schilling et al 2006;Alaynick et al 2007;Huss et al 2007;Villena et al 2007).…”

Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes

“…Contrary to the decrease of PPARGC1A expression in the skeletal muscle of patients with type 2 diabetes, PPARGC1A expression in the liver has been shown to be elevated in animal models of diabetes [8][9][10][11]. Tissue-specific regulation of metabolic pathways through PPARGC1A may take place in the skeletal muscle and liver.…”

“…The rate of gluconeogenesis is controlled by key enzymes, including phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase (G6PC), in response to environmental and hormonal stimuli. Transcriptional activation of the PEPCK promoter requires coactivation of glucocorticoid receptors and the liver-enriched transcription factor hepatic nuclear factor-4α (HNF4A) by PGC-1α, indicating that PGC-1α is a key regulator of gluconeogenesis as well as of OXPHOS [8][9][10].…”

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

“…PPARGC1A also plays a key role in the regulation of hepatic glucose output through the control of gluconeogenesis [4,5], and modulates the expression of the insulin-regulated glucose transporter GLUT4 through an interaction with the transcription factor MADS box transcription enhancer factor 2, polypeptide C (also known as MEF2C) [6]. Moreover, decreased PPARGC1A expression was detected in muscle of individuals with diabetes and in unaffected subjects with a family history of diabetes [7].…”