Dolim Lee1, John Le Lay, Klaus H Kaestner. 1. Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-126 Translational Research Center, 3400 Civic Center Boulevard, Philadelphia, PA, 19104-6145, USA.
Abstract
AIMS/HYPOTHESIS: Excessive hepatic glucose production is a hallmark of insulin resistance in type 2 diabetes. The cAMP responsive transcription factor cAMP responsive element binding protein (CREB), thought to be a key activator of the hepatic gluconeogenic gene regulation programme, has been suggested as a therapeutic target to reduce glucose output by the liver. Here, we test directly the requirement for hepatocytic CREB for the maintenance of glucose homeostasis. METHODS: We derived mice with a Creb (also known as Creb1) loxP allele for conditional, cell-type specific gene ablation. Hepatocyte-specific deletion of Creb was induced by injecting Creb (loxP/loxP) mice with Cre recombinase expression adeno-associated virus. RESULTS: Strikingly, we found no difference in fed and fasted glucose levels, or in glucose, insulin and glucagon tolerance in mice fed a normal chow or a high-fat diet. In addition, mRNA levels of liver-specific genes, including several CREB target genes involved in gluconeogenesis, were not affected by CREB deficiency in the liver. CONCLUSION/ INTERPRETATION: Our data show that CREB has no non-redundant functions in hepatic glucose metabolism, and is therefore not likely to be a useful target for the development of glucose-lowering drugs.
AIMS/HYPOTHESIS: Excessive hepatic glucose production is a hallmark of insulin resistance in type 2 diabetes. The cAMP responsive transcription factor cAMP responsive element binding protein (CREB), thought to be a key activator of the hepatic gluconeogenic gene regulation programme, has been suggested as a therapeutic target to reduce glucose output by the liver. Here, we test directly the requirement for hepatocytic CREB for the maintenance of glucose homeostasis. METHODS: We derived mice with a Creb (also known as Creb1) loxP allele for conditional, cell-type specific gene ablation. Hepatocyte-specific deletion of Creb was induced by injecting Creb (loxP/loxP) mice with Cre recombinase expression adeno-associated virus. RESULTS: Strikingly, we found no difference in fed and fasted glucose levels, or in glucose, insulin and glucagon tolerance in mice fed a normal chow or a high-fat diet. In addition, mRNA levels of liver-specific genes, including several CREB target genes involved in gluconeogenesis, were not affected by CREB deficiency in the liver. CONCLUSION/ INTERPRETATION: Our data show that CREB has no non-redundant functions in hepatic glucose metabolism, and is therefore not likely to be a useful target for the development of glucose-lowering drugs.
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