scholarly journals High-Fat/Low-Carbohydrate Diet Reduces Insulin-Stimulated Carbohydrate Oxidation but Stimulates Nonoxidative Glucose Disposal in Humans: An Important Role for Skeletal Muscle Pyruvate Dehydrogenase Kinase 4

2007 ◽  
Vol 92 (1) ◽  
pp. 284-292 ◽  
Author(s):  
K. Chokkalingam ◽  
K. Jewell ◽  
L. Norton ◽  
J. Littlewood ◽  
L. J. C. van Loon ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Glycogen Storage ◽  
Pyruvate Dehydrogenase Kinase ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Complex Activity ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Low Carbohydrate

Abstract Aim: The aim of this report was to study the effect of high-fat (HF)/low-carbohydrate (CHO) diet on regulation of substrate metabolism in humans. Methods: Ten healthy men consumed either a HF (75% energy as fat) or control (35%) diet for 6 d in random order. On d 7, blood glucose disappearance rate (Rd) was determined before and during a hyperinsulinemic euglycemic clamp. Substrate oxidation was determined by indirect calorimetry. Muscle biopsies were obtained prediet, postdiet, and postclamps. Results: Rd was similar under basal conditions but slightly elevated (∼10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by ∼40%, P < 0.05) and clamp conditions (by ∼20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by ∼25%, P < 0.05). Muscle pyruvate dehydrogenase complex activity was blunted under basal and clamp conditions after HF compared with control (P < 0.05) and was accompanied by an approximately 2-fold increase (P < 0.05) in pyruvate dehydrogenase kinase 4 (PDK4) mRNA and protein expression. Conclusion: Short-term HF/low-CHO dietary intake did not induce whole-body insulin resistance, but caused a shift in im glucose metabolism from oxidation to glycogen storage. Insulin-stimulated CHO oxidation and muscle pyruvate dehydrogenase complex activity were blunted after the HF diet. Up-regulation of muscle PDK4 expression was an early molecular adaptation to these changes, and we showed for the first time in healthy humans, unlike insulin-resistant individuals, that insulin can suppress PDK4 but not PDK2 gene expression in skeletal muscle.

scholarly journals Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex

1998 ◽  
Vol 329 (1) ◽  
pp. 191-196 ◽  
Author(s):  
Melissa M. BOWKER-KINLEY ◽  
I. Wilhelmina DAVIS ◽  
Pengfei WU ◽  
A. Robert HARRIS ◽  
M. Kirill POPOV
Keyword(s):  
Tissue Distribution ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Synthetic Analogue ◽  
Complex Activity ◽  
Acetyl Coa ◽  
Tissue Specific ◽  
Specific Regulation ◽  
Dehydrogenase Complex

Tissue distribution and kinetic parameters for the four isoenzymes of pyruvate dehydrogenase kinase (PDK1, PDK2, PDK3 and PDK4) identified thus far in mammals were analysed. It appeared that expression of these isoenzymes occurs in a tissue-specific manner. The mRNA for isoenzyme PDK1 was found almost exclusively in rat heart. The mRNA for PDK3 was most abundantly expressed in rat testis. The message for PDK2 was present in all tissues tested but the level was low in spleen and lung. The mRNA for PDK4 was predominantly expressed in skeletal muscle and heart. The specific activities of the isoenzymes varied 25-fold, from 50 nmol/min per mg for PDK2 to 1250 nmol/min per mg for PDK3. Apparent Ki values of the isoenzymes for the synthetic analogue of pyruvate, dichloroacetate, varied 40-fold, from 0.2 mM for PDK2 to 8 mM for PDK3. The isoenzymes were also different with respect to their ability to respond to NADH and NADH plus acetyl-CoA. NADH alone stimulated the activities of PDK1 and PDK2 by 20 and 30% respectively. NADH plus acetyl-CoA activated these isoenzymes nearly 200 and 300%. Under comparable conditions, isoenzyme PDK3 was almost completely unresponsive to NADH, and NADH plus acetyl-CoA caused inhibition rather than activation. Isoenzyme PDK4 was activated almost 2-fold by NADH, but NADH plus acetyl-CoA did not activate above the level seen with NADH alone. These results provide the first evidence that the unique tissue distribution and kinetic characteristics of the isoenzymes of PDK are among the major factors responsible for tissue-specific regulation of the pyruvate dehydrogenase complex activity.

scholarly journals Activation of Liver X Receptor Regulates Substrate Oxidation in White Adipocytes

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4104-4113 ◽  
Author(s):  
Britta M. Stenson ◽  
Mikael Rydén ◽  
Knut R. Steffensen ◽  
Kerstin Wåhlén ◽  
Amanda T. Pettersson ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Substrate Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Tissue Mass ◽  
Metabolic Complications ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
White Adipocytes ◽  
X Receptors

Abstract Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial β-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial β-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial β-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.

scholarly journals Coenzyme A–mediated degradation of pyruvate dehydrogenase kinase 4 promotes cardiac metabolic flexibility after high-fat feeding in mice

2018 ◽  
Vol 293 (18) ◽  
pp. 6915-6924 ◽  
Author(s):  
Christopher Schafer ◽  
Zachary T. Young ◽  
Catherine A. Makarewich ◽  
Abdallah Elnwasany ◽  
Caroline Kinter ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Coenzyme A ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Flexibility ◽  
High Fat ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Fat Feeding

Enzymatic regulation of glucose disposal in human skeletal muscle after a high-fat, low-carbohydrate diet

2005 ◽  
Vol 98 (1) ◽  
pp. 100-107 ◽  
Author(s):  
Tanya L. Pehleman ◽  
Sandra J. Peters ◽  
George J. F. Heigenhauser ◽  
Lawrence L. Spriet
Keyword(s):  
Skeletal Muscle ◽  
Active Form ◽  
Whole Body ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Vastus Lateralis Muscle ◽  
High Fat ◽  
Carbohydrate Diet ◽  
Low Carbohydrate Diet ◽  
Low Carbohydrate

Whole body glucose disposal and skeletal muscle hexokinase, glycogen synthase (GS), pyruvate dehydrogenase (PDH), and PDH kinase (PDK) activities were measured in aerobically trained men after a standardized control diet (Con; 51% carbohydrate, 29% fat, and 20% protein of total energy intake) and a 56-h eucaloric, high-fat, low-carbohydrate diet (HF/LC; 5% carbohydrate, 73% fat, and 22% protein). An oral glucose tolerance test (OGTT; 1 g/kg) was administered after the Con and HF/LC diets with vastus lateralis muscle biopsies sampled pre-OGTT and 75 min after ingestion of the oral glucose load. The 90-min area under the blood glucose and plasma insulin concentration vs. time curves increased by 2-fold and 1.25-fold, respectively, after the HF/LC diet. The pre-OGTT fraction of GS in its active form and the maximal activity of hexokinase were not affected by the HF/LC diet. However, the HF/LC diet increased PDK activity (0.19 ± 0.05 vs. 0.08 ± 0.02 min−1) and decreased PDH activation (0.38 ± 0.08 vs. 0.79 ± 0.10 mmol acetyl-CoA·kg wet muscle−1·min−1) before the OGTT vs. Con. During the OGTT, GS and PDH activation increased by the same magnitude in both diets, such that PDH activation remained lower during the HF/LC OGTT (0.60 ± 0.11 vs. 1.04 ± 0.09 mmol acetyl-CoA·kg−1·min−1). These data demonstrate that the decreased glucose disposal during the OGTT after the 56-h HF/LC diet was in part related to decreased oxidative carbohydrate disposal in skeletal muscle and not to decreased glycogen storage. The rapid increase in PDK activity during the HF/LC diet appeared to account for the reduced potential for oxidative carbohydrate disposal.

scholarly journals Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species

2012 ◽  
Vol 287 (42) ◽  
pp. 35153-35160 ◽  
Author(s):  
Thomas R. Hurd ◽  
Yvonne Collins ◽  
Irina Abakumova ◽  
Edward T. Chouchani ◽  
Bartlomiej Baranowski ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Reactive Oxygen ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Oxygen Species ◽  
Complex Activity ◽  
Cycle Enzyme ◽  
Dehydrogenase Complex

Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H2O2) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H2O2 derives from superoxide (O2̇̄), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O2̇̄ production, such as may occur under nutrient excess and low ATP demand, the increase in O2̇̄ and H2O2 may provide feedback signals to modulate mitochondrial metabolism.

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

2008 ◽  
Vol 295 (1) ◽  
pp. E46-E54 ◽  
Author(s):  
Nam Ho Jeoung ◽  
Robert A. Harris
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Pyruvate Dehydrogenase Kinase ◽  
Wild Type ◽  
High Fat ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Liver And Kidney

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.

scholarly journals Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Sun Joo Lee ◽  
Ji Yun Jeong ◽  
Chang Joo Oh ◽  
Sungmi Park ◽  
Joon-Young Kim ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Direct Interaction ◽  
Pathologic Response ◽  
Pyruvate Dehydrogenase Kinase ◽  
Phosphate Homeostasis ◽  
Mortality And Morbidity ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Dehydrogenase Complex

Abstract Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification.

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