Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Nam Ho Jeoung, Robert Harris

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93 Citations (Scopus)

Abstract

The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4-/- mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4-/- mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4-/- mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4-/- mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4-/- mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4 -/- mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4-/- mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4-/- mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.

Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume295
Issue number1
DOIs
StatePublished - Jul 2008

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Obese Mice
Nutrition
Blood Glucose
Diet
Glucose
Diaphragms
Diaphragm
Pyruvate Dehydrogenase Complex
Insulin
Liver
Oxidation
Muscle
Insulin Resistance
pyruvate dehydrogenase kinase 4
Fatty Acids
Fats
High Fat Diet
Ketone Bodies
Branched Chain Amino Acids
Kidney

Keywords

  • Branched-chain amino acids
  • Diet-induced obesity
  • Fatty acid oxidation
  • Glucose oxidation
  • Pyruvate dehydrogenase kinase-4-knockout mice

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Biochemistry

Cite this

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abstract = "The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4-/- mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4-/- mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4-/- mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4-/- mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4-/- mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4 -/- mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4-/- mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4-/- mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.",
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