Abstract
Blood glucose levels are maintained by the balance between glucose uptake by peripheral tissues and glucose secretion by the liver. Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Here we show that the transcriptional coactivator PGC-1 is strongly induced in liver in fasting mice and in three mouse models of insulin action deficiency: streptozotocin-induced diabetes, ob/ob genotype and liver insulin-receptor knockout. PGC-1 is induced synergistically in primary liver cultures by cyclic AMP and glucocorticoids. Adenoviral-mediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates an entire programme of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, leading to increased glucose output. Full transcriptional activation of the PEPCK promoter requires coactivation of the glucocorticoid receptor and the liver-enriched transcription factor HNF-4alpha (hepatic nuclear factor-4alpha) by PGC-1. These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Amino Acid Motifs
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Blood Glucose / metabolism*
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Cell Line
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Cyclic AMP / metabolism
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DNA-Binding Proteins*
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Diabetes Mellitus, Experimental / blood
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Diabetes Mellitus, Experimental / metabolism
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Fasting
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Gluconeogenesis*
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Hepatocyte Nuclear Factor 4
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Hormones / metabolism
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Insulin / physiology
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Liver / metabolism*
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Male
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Mice
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Mice, Knockout
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Obesity / genetics
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Obesity / metabolism
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Phosphoenolpyruvate Carboxykinase (GTP) / genetics
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Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
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Phosphoproteins / metabolism
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Receptors, Glucocorticoid / metabolism
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Response Elements
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Tumor Cells, Cultured
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Blood Glucose
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DNA-Binding Proteins
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Hepatocyte Nuclear Factor 4
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Hormones
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Insulin
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Phosphoproteins
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RNA, Messenger
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Receptors, Glucocorticoid
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Tcfl4 protein, mouse
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Transcription Factors
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peroxisome-proliferator-activated receptor-gamma coactivator-1
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Cyclic AMP
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Receptor, Insulin
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Phosphoenolpyruvate Carboxykinase (GTP)