The relationship between changes in lipid fuel availability and tissue fructose 2,6-bisphosphate concentrations and pyruvate dehydrogenase complex activities in the fed state

French, T J; Goode, A W; Holness, Mark J.; Maclennan, P. A.; Sugden, Mary C.

doi:10.1042/bj2560935

Cited by 21 publications

(19 citation statements)

References 19 publications

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“…Acetyl CoA is an allosteric activator of the key gluconeogenic enzyme, pyruvate carboxylase [44] while NADH is required for the glyceraldehyde-3-phosphate-dehydrogenase reaction. A further mechanism involves a decrease in the concentration of hepatocyte fructose-2,6-bisphosphate (F-2,6-P2) [29,43], an important positive effector of phosphofructokinase-1 (PFK-1). In the current study, increased provision of glycerol (present in the Intralipid) would be expected to raise hepatocyte glycerol-3-phosphate levels.…”

Section: Discussionmentioning

confidence: 99%

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

1991

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The effects of increased tissue glycogen stores on insulin sensitivity, and on the response of insulin-stimulated glucose utilisation to an acute elevation in plasma fatty acid levels (approximately 1.5 mmol/l), were investigated in conscious rats using the hyperinsulinaemic euglycaemic clamp. Studies were performed in two groups of rats; (a) fasted 24 h; (b) fasted 4.5 h, but infused with glucose for 4 h (0.5 g/h) of this period before the clamp (fed, glucose infused rats). Clamp glucose requirement and 3-3H-glucose turnover were 20-25% lower in the fed, glucose-infused rats. In these rats, elevation of plasma fatty acid levels resulted in impaired suppression of hepatic glucose output (residual hepatic glucose output: 41 +/- 4 vs 8 +/- 6 mumol.min-1.kg-1, p less than 0.001) but did not further decrease 3-3H-glucose turnover. Elevated non-esterified fatty acid levels had no significant effect on glucose kinetics in 24 h fasted rats. In the fed glucose-infused rats, at low plasma fatty acid levels, there was no deposition of glycogen in muscle during the clamp and liver glycogen levels fell. With elevation of non-esterified fatty acid levels muscle glycogen deposition was stimulated in both groups, and there was no fall in liver glycogen during the clamps in the fed glucose-infused rats. Increased non-esterified fatty acid availability during the clamps decreased pyruvate dehydrogenase activity in liver, heart, adipose tissue and quadriceps muscle, in both groups of rats. The findings are consistent with an inhibition of glycolysis in liver, skeletal muscle and heart by increased fatty acid availability.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

1991

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“…Bovine heart pyruvate dehydrogenase activity is inhibited by 100 µM palmitoyl-CoA [31], and the activity of this enzyme is also decreased in liver, kidney, adipose tissue and muscle during fasting, concomitant with an increase in the concentration of non-esterified fatty acids in the blood [32][33][34][35]. Furthermore, the increase in mitochondrial acyl-CoA level correlated well with the concomitant decrease in pyruvate dehydrogenase activity observed in mitochondria from rat adipocytes, suggesting that long-chain acyl-CoA is a common regulator of this enzyme [36].…”

Section: Long-chain Acyl-coa Esters As Regulators Of Energy Metabolismmentioning

confidence: 99%

Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling

Færgeman¹,

Knudsen²

1997

Biochemical Journal

624

477

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The intracellular concentration of free unbound acyl-CoA esters is tightly controlled by feedback inhibition of the acyl-CoA synthetase and is buffered by specific acyl-CoA binding proteins. Excessive increases in the concentration are expected to be prevented by conversion into acylcarnitines or by hydrolysis by acyl-CoA hydrolases. Under normal physiological conditions the free cytosolic concentration of acyl-CoA esters will be in the low nanomolar range, and it is unlikely to exceed 200 nM under the most extreme conditions. The fact that acetyl-CoA carboxylase is active during fatty acid synthesis (Ki for acyl-CoA is 5 nM) indicates strongly that the free cytosolic acyl-CoA concentration is below 5 nM under these conditions. Only a limited number of the reported experiments on the effects of acyl-CoA on cellular functions and enzymes have been carried out at low physiological concentrations in the presence of the appropriate acyl-CoA-buffering binding proteins. Re-evaluation of many of the reported effects is therefore urgently required. However, the observations that the ryanodine-senstitive Ca2+-release channel is regulated by long-chain acyl-CoA esters in the presence of a molar excess of acyl-CoA binding protein and that acetyl-CoA carboxylase, the AMP kinase kinase and the Escherichia coli transcription factor FadR are affected by low nanomolar concentrations of acyl-CoA indicate that long-chain acyl-CoA esters can act as regulatory molecules in vivo. This view is further supported by the observation that fatty acids do not repress expression of acetyl-CoA carboxylase or Δ9-desaturase in yeast deficient in acyl-CoA synthetase.

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“…The decrease in muscle PDH activity during starvation [2426] is considered to play a key role in the starvation-induced decrease in whole body glucose turnover [24,27]. As increased fatty acid availability may play a major role in decreasing muscle PDH activity [26,28] we measured the activity of this enzyme in peripheral tissues both basally and at the end of the glucose clamps.…”

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confidence: 99%

Effects of non-esterified fatty acid availability on insulin stimulated glucose utilisation and tissue pyruvate dehydrogenase activity in the rat

1990

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Summary. Fatty acids in cardiac muscle compete with glucose for oxidation, thereby inhibiting glucose utilisation. It is not clear whether a similar mechanism is important in resting skeletal muscle. We used the hyperinsulinaemic euglycaemic clamp technique in conscious rats fasted for 20 h to examine the effects of increased plasma non-esterifled fatty acid levels (-1 mmol/1) on glucose metabolism. Insulin was infused at 75mU/h (plasma insulin, 2.27 + 0.21 gg/1) or 300 mU/h (16.41 + 0.47 gg/1). An increase in non-esterified fatty acid levels decreased clamp glucose requirement and 3-~H-glucose turnover by 35% (p < 0.001) when the higher insulin dose was used but there was no change at the lower dose. At both insulin infusion rates, clamp blood lactate and pyruvate responses suggested inhibition of muscle glycolysis by elevated plasma non-esterified fatty acid concentrations. Quadriceps muscle glycogen deposition during the clamps was enhanced by increased non-esterified fatty acid availability at the lower insulin dose (p < 0.001) but not at the higher insulin concentration. Activation of pyruvate dehyrogenase during the clamps was partially inhibited by increased plasma non-esterified fatty acid in the heart, adipose tissue and quadriceps muscle. This was evident at both insulin levels in heart but only at the higher insulin concentration in muscle (p < 0.002). The findings are consistent with an inhibition of glycolysis in skeletal muscle of mixed fibre type as a result of increased fatty acid availability. At low rates of glucose flux glycogen synthesis may compensate for decreased glycolysis so that glucose turnover is not decreased. The role of pyruvate dehydrogenase in the "glucose-fatty acid cycle" in muscle may depend on the prevailing plasma insulin concentration and the degree of activation of this enzyme.Key words: Glucose-fatty acid cycle, non-esterified fatty acids, rat, glucose clamp, glycogen, glycogen synthase, pyruvate dehydrogenase, intermediary metabolites, glucose turnover.Inhibition of glucose uptake and oxidation in rat diaphragm and cardiac muscle by increased fatty acid oxidation was first demonstrated by Randle and colleagues [1]. They coined the term "glucose-fatty acid cycle" and suggested that increased availability of non-esterified fatty acids (NEFA) in obesity and diabetes may play an important role in the glucose intolerance and tissue insensitivity to insulin [2].Glucose tolerance was impaired when plasma NEFA concentrations were raised in normal man, by infusion of lipids [3,4] or administration of heparin with a fat meal [5]. As liver and skeletal muscle are quantitatively the most important tissues for disposal of an oral glucose load [6,7], it is necessary to postulate that increased fatty acid availability impairs glucose uptake by these tissues. Decreased insulin-stimulated muscle glucose uptake and impaired suppression of hepatic glucose production by insulin in rats fed a high fat diet for several weeks would support this [8,9]. However, the effects of an acute increase ...

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The relationship between changes in lipid fuel availability and tissue fructose 2,6-bisphosphate concentrations and pyruvate dehydrogenase complex activities in the fed state

Cited by 21 publications

References 19 publications

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling

Effects of non-esterified fatty acid availability on insulin stimulated glucose utilisation and tissue pyruvate dehydrogenase activity in the rat

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