Phosphoenolpyruvate carboxykinase (GTP) gene transcription and hyperglycemia are regulated by glucocorticoids in genetically obese db/db transgenic mice

The molecular mechanisms underlying increased hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene transcription and gluconeogenesis in type II diabetes are largely unknown. To examine the involvement of glucocorticoids and the cis-acting insulin response sequence (IRS, -416/-407) in the genetical...

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Published in:	The Journal of biological chemistry Vol. 272; no. 50; pp. 31475 - 31481
Main Authors:	Friedman, J.E, Sun, Y, Ishizuka, T, Farrell, C.J, McCormack, S.E, Herron, L.M, Hakimi, P, Lechner, P, Yun, J.S
Format:	Journal Article
Language:	English
Published:	United States 12-12-1997
Subjects:	ADN RECOMBINADO ADN RECOMBINE ANIMAL TRANSGENIQUE ANIMALES TRANSGENICOS Animals ANTAGONISTAS DE LAS HORMONAS ANTAGONISTE D'HORMONE ARN MENSAJERO ARN MESSAGER Binding Sites BLOOD PROTEINS C-REACTIVE PROTEIN CORTICOSTERONE DB LOCUS Diabetes Mellitus, Type 2 - enzymology Diabetes Mellitus, Type 2 - genetics DNA - metabolism EXPRESION GENICA EXPRESSION DES GENES FOIE GENE GENE EXPRESSION GENES Genes, Reporter GLUCOCORTICOIDE GLUCOCORTICOIDES GLUCOCORTICOIDS Glucocorticoids - physiology GLUCOSE-6-PHOSPHATASE GLUT2 PROTEIN HIDROLASAS HIGADO HIPERGLUCEMIA HORMONE ANTAGONISTS Hormone Antagonists - pharmacology HYDROLASE HYDROLASES HYPERGLYCAEMIA Hyperglycemia - physiopathology HYPERGLYCEMIE HYPERINSULINEMIA INSULIN Insulin Receptor Substrate Proteins INSULIN RESPONSE ELEMENT INSULINA INSULINE LIASAS LIVER Liver - drug effects Liver - metabolism LOCI LOCUS LYASE LYASES MESSENGER RNA METABOLIC DISORDERS MICE Mice, Inbred C57BL Mice, Obese Mice, Transgenic Mifepristone - pharmacology OVERWEIGHT Phosphatidylinositol 3-Kinases - metabolism Phosphoenolpyruvate Carboxykinase (GTP) - genetics Phosphoproteins - metabolism Promoter Regions, Genetic PROMOTERS PROTEINAS PROTEINAS SANGUINEAS PROTEINE PROTEINE SANGUINE PROTEINS RATON Rats Receptor, Insulin - metabolism RECOMBINANT DNA REPORTER GENES RU 486 SOBREPESO SOURIS SURFACE PROTEINS SURPOIDS TRANSCRIPCION TRANSCRIPTION Transcription, Genetic TRANSFERASAS TRANSFERASE TRANSFERASES TRANSGENIC ANIMALS TRASTORNOS METABOLICOS TROUBLE DU METABOLISME TYROSINE AMINOTRANSFERASE
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Summary:	The molecular mechanisms underlying increased hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene transcription and gluconeogenesis in type II diabetes are largely unknown. To examine the involvement of glucocorticoids and the cis-acting insulin response sequence (IRS, -416/-407) in the genetically obese db/db mouse model, we generated crosses between C57BL/KsJ-db/+ mice and transgenic mice that express -460 or -2000 base pairs of the rat PEPCK gene promoter containing an intact or mutated IRS, linked to a reporter gene. Transgenic mice expressing the intact PEPCK(460)-CRP (C-reactive protein) transgene bred to near homozygosity at the db locus were obese, hyperinsulinemic, and developed fasting hyperglycemia (389 +/- 26 mg/100 ml) between 4 and 10 weeks of age. Levels of CRP reporter gene expression were increased 2-fold despite severe hyperinsulinemia compared with non-diabetic non-obese transgenic mice. Reporter gene expression was also increased 2-fold in transgenic obese diabetic db/db mice bearing a mutation in the IRS, -2000(IRS)-hGx, compared with non-obese non-diabetic transgenic 2000(IRS)-hGx mice. Treatment of obese diabetic db/db transgenic mice with the glucocorticoid receptor blocker RU 486 decreased plasma glucose by 50% and reduced PEPCK, GLUT2, glucose-6-phosphatase, tyrosine aminotransferase, CRP, and hGx reporter gene expression to levels similar to those of non-obese normoglycemic transgenic mice. Taken together, these results establish that -460 bp of 5'-flanking sequence is sufficient to mediate the induction of PEPCK gene transcription in genetically obese db/db mice during the development of hyperglycemia. The results further demonstrate that the mechanism underlying increased expression of gluconeogenic enzymes in the db/db mouse requires the action of glucocorticoids and occurs independently of factors acting through the PEPCK IRS (-416/-407) promoter binding site.
Bibliography:	1997061662 S30 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.272.50.31475