Metabolic dysregulation in the SHROB rat reflects abnormal expression of transcription factors and enzymes that regulate carbohydrate metabolism.
The Koletsky (SHROB) strain of rats is spontaneously hypertensive and displays insulin resistance, hyperglucagonemia and hypertriglyceridemia but is normoglycemic under fasting conditions. The aim of this study was to unravel the pattern of expression of genes encoding key regulatory enzymes involved in carbohydrate metabolism in the liver and kidney that may be impacted in this strain. We found that SHROB animals have decreased beta-adrenergic receptor density and, consequently, blunted increases in cAMP levels in response to beta-adrenergic agonists. They also have lower levels of hepatic as well as renal phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) mRNA and protein than their lean littermates. Expression of the genes for glycogen phosphorylase and glycogen synthase was also decreased. Hepatocytes from the SHROB animals exhibited glycogen depletion of only 50% compared to 86% by hepatocytes from lean littermates when challenged with either glucagon or forskolin to stimulate adenylyl cyclase. The expression of C/EBPalpha and C/EBPbeta, two key transcription factors that are essential for the coordinated expression of genes involved in glucose homeostasis, was depressed in livers of the SHROB rats, as were levels of HNF-4alpha, PPARalpha and PGC-1alpha. We conclude that overproduction of glucose is prevented in the SHROB rats by decreased expression of the genes for glycogen phosphorylase and the gluconeogenic enzymes PEPCK and G6Pase, which may prevent progression to diabetes in this model.
Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4935, USA.
Chuan
C
Xu
Ifeanyi J
IJ
Arinze
Janean
J
Johnson
Tertius T
TT
Tuy
Frederic
F
Bone
Paul
P
Ernsberger
Duna
D
Massillon
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D050260:Carbohydrate Metabolism / Q000235:genetics; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004798:Enzymes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D004798:Enzymes; D006728:Hormones; D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D014157:Transcription Factors; D000242:Cyclic AMP