scholarly journals The activity of the pyruvate dehydrogenase complex in heart and liver from mice during the development of obesity and insulin resistance

1987 ◽  
Vol 243 (2) ◽  
pp. 549-553 ◽  
Author(s):  
I D Caterson ◽  
L D Astbury ◽  
P F Williams ◽  
M A Vanner ◽  
G J Cooney ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pyruvate Dehydrogenase ◽  
Serum Insulin ◽  
Pyruvate Dehydrogenase Complex ◽  
Active Form ◽  
Whole Body ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Gold Thioglucose ◽  
Mitochondrial Fatty Acid

The amount of pyruvate dehydrogenase in the active form (PDHa) was increased 1.7-fold compared with controls in heart muscle of mice 1 week after induction of obesity with a single injection of gold-thioglucose. At 4 weeks post injection, the amount of PDHa was decreased to 32% of control, a value which was observed in later stages of the obesity syndrome. In contrast, liver PDHa was increased and remained at an increased activity during the development of obesity. Despite normal post-prandial serum insulin contents, liver membrane insulin-receptor numbers were decreased 1 week after gold-thioglucose injection, and there was no change in receptor affinity. The decrease in heart PDHa in the obese animals was reversed by a single dose of 2-tetradecylglycidic acid, but this inhibitor of mitochondrial fatty acid oxidation did not affect liver PDHa in these animals. These early and diverse changes in PDHa argue for a multifactorial aetiology in the development of the whole-body insulin resistance seen in older gold-thioglucose-treated obese animals.

scholarly journals Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function

2020 ◽  
Author(s):  
Ada Admin ◽  
Federico Cividini ◽  
Brian T Scott ◽  
Jorge Suarez ◽  
Darren E. Casteel ◽  
...  
Keyword(s):  
Contractile Function ◽  
Pyruvate Dehydrogenase Complex ◽  
Dominant Negative ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Cardiac Contractile Function ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Type 2 Diabetic

The contribution of altered mitochondrial Ca<sup>2+</sup> handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. Here, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9 (dCas9)-based gene promoter pull-down approach coupled with mass spectrometry we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor co-repressor 2 (Ncor2) repression, and ChIP assays identified PPARα as a mediator of MCUb gene expression in T2D cardiomyocytes. Upregulation of MCUb limits mitochondrial matrix Ca<sup>2+</sup> uptake and impairs mitochondrial energy production via glucose oxidation, by depressing Pyruvate Dehydrogenase Complex (PDC) activity. Gene therapy displacement of endogenous MCUb with a dominant-negative MCUb transgene (MCUb<sup>W246R/V251E</sup>) <i>in vivo</i> rescued T2D cardiomyocytes from metabolic inflexibility, and stimulated cardiac contractile function and adrenergic responsiveness by enhancing phospholamban (PLN) phosphorylation via Protein Kinase A (PKA). We conclude that MCUb represents one newly-discovered molecular effector at the interface of metabolism and cardiac function, and its repression improves the outcome of the chronically-stressed diabetic heart.

scholarly journals Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function

2020 ◽  
Author(s):  
Ada Admin ◽  
Federico Cividini ◽  
Brian T Scott ◽  
Jorge Suarez ◽  
Darren E. Casteel ◽  
...  
Keyword(s):  
Contractile Function ◽  
Pyruvate Dehydrogenase Complex ◽  
Dominant Negative ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Cardiac Contractile Function ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Type 2 Diabetic

The contribution of altered mitochondrial Ca<sup>2+</sup> handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. Here, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9 (dCas9)-based gene promoter pull-down approach coupled with mass spectrometry we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor co-repressor 2 (Ncor2) repression, and ChIP assays identified PPARα as a mediator of MCUb gene expression in T2D cardiomyocytes. Upregulation of MCUb limits mitochondrial matrix Ca<sup>2+</sup> uptake and impairs mitochondrial energy production via glucose oxidation, by depressing Pyruvate Dehydrogenase Complex (PDC) activity. Gene therapy displacement of endogenous MCUb with a dominant-negative MCUb transgene (MCUb<sup>W246R/V251E</sup>) <i>in vivo</i> rescued T2D cardiomyocytes from metabolic inflexibility, and stimulated cardiac contractile function and adrenergic responsiveness by enhancing phospholamban (PLN) phosphorylation via Protein Kinase A (PKA). We conclude that MCUb represents one newly-discovered molecular effector at the interface of metabolism and cardiac function, and its repression improves the outcome of the chronically-stressed diabetic heart.

scholarly journals Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione

Aging Cell ◽  
2013 ◽  
Vol 12 (3) ◽  
pp. 415-425 ◽  
Author(s):  
Dan Nguyen ◽  
Susan L. Samson ◽  
Vasumathi T. Reddy ◽  
Erica V. Gonzalez ◽  
Rajagopal V. Sekhar
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Protective Role ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid

The activity of the pyruvate dehydrogenase complex in heart muscle in the previously obese mouse model

1986 ◽  
Vol 6 (12) ◽  
pp. 1071-1075 ◽  
Author(s):  
Kate Steinbeck ◽  
Ian D. Caterson ◽  
John R. Turtle
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Heart Muscle ◽  
Food Restriction ◽  
Serum Insulin ◽  
Pyruvate Dehydrogenase Complex ◽  
Active Form ◽  
Insulin Level ◽  
Serum Glucose ◽  
Obese Mouse ◽  
Dehydrogenase Complex

Obese gold thioglucose injected mice were reduced to lean control weight by food restriction. When pair fed with lean controls these animals then gained weight (were metabolically more efficient). Serum glucose was also elevated in this group (14.5±0.4 (14) vs 12.1±0.3 mmol/L, p<0.001). If previously obese animals were weight maintained with lean controls (by mild food restriction), serum glucose remained at control levels. The activity of the pyruvate dehydrogenase complex in heart muscle was decreased in both obese and pair fed previously obese, whilst it was similar to that of lean controls in the weight maintained previously obese and in obese mice actually dieted. In all obese and previously obese animals serum insulin was elevated. In hearts from control animals subjected to mild food restriction the pyruvate dehydrogenase complex was activated (11.53±1.80 (5) vs 3.34±0.62 (9) U/g dry weight), despite a reduced serum insulin level (42±2 vs 74±10 μU/ml, p<0.01). These diverse changes in the proportion of the pyruvate dehydrogenase complex in the active form and insulin levels argue for a persistent alteration in the sensitivity of the pyruvate dehydrogenase complex to insulin in obesity, as well as indicating that glucose metabolism in obese animals is altered by both body weight and diet amount.

scholarly journals Acute or Chronic Upregulation of Mitochondrial Fatty Acid Oxidation Has No Net Effect on Whole-Body Energy Expenditure or Adiposity

2010 ◽  
Vol 11 (1) ◽  
pp. 70-76 ◽  
Author(s):  
Kyle L. Hoehn ◽  
Nigel Turner ◽  
Michael M. Swarbrick ◽  
Donna Wilks ◽  
Elaine Preston ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Expenditure ◽  
Fatty Acid Oxidation ◽  
Whole Body ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Body Energy

scholarly journals Diurnal patterns of cardiac and hepatic pyruvate dehydrogenase complex activity in gold-thioglucose-obese mice

1993 ◽  
Vol 295 (3) ◽  
pp. 731-734 ◽  
Author(s):  
J M Bryson ◽  
G J Cooney ◽  
V R Wensley ◽  
S C Blair ◽  
I D Caterson
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Serum Insulin ◽  
Pyruvate Dehydrogenase Complex ◽  
Fold Increase ◽  
Hepatic Lipogenesis ◽  
Obese Mice ◽  
Diurnal Pattern ◽  
Complex Activity ◽  
Gold Thioglucose ◽  
Dehydrogenase Complex

The diurnal pattern of the activity of the pyruvate dehydrogenase complex (PDHC) was studied in the heart and liver of gold-thioglucose (GTG)-obese mice and age-matched controls. The diurnal pattern of lipogenesis was also measured in the liver. Both lean and obese mice had one main eating period, from 20:00 to 24:00 h. Eating produced no change in serum glucose of control mice but there was a significant rise in serum insulin and triacylglycerols. There was also a 3-fold increase in cardiac PDHC activity and a 3-fold increase in hepatic lipogenesis in the control mice, but little change in hepatic PDHC activity. GTG-obese mice were hyperglycaemic, hyperinsulinaemic and hypertriglyceridaemic at all times studied, with significant increases in these parameters being seen in response to eating. Eating produced little change in cardiac PDHC activity, but there was a 5-fold increase in hepatic PDHC activity, paralleled by a 10-fold increase in hepatic lipogenesis. Hepatic PDHC activity was significantly higher in GTG-obese mice at all times except 16:00 h. The simultaneous rise of hepatic PDHC activity, lipogenesis and serum triacylglycerols in GTG-obese mice suggests an increased utilization of glucose for lipogenesis. The lack of change in heart PDHC activity in GTG-obese mice over 24 h suggests that a general decrease in PDHC activity may contribute to the development of the glucose intolerance and insulin resistance of obesity and non-insulin-dependent diabetes. However, it appears that a different level of metabolic control allows hepatic PDHC activity of the same obese animals to increase in response to hyperinsulinaemia and contribute to the higher rates of lipogenesis seen in obese mice.

scholarly journals CORRECTING GLUTATHIONE DEFICIENCY AND MITOCHONDRIAL DYSFUNCTION IN OLDER HUMANS: A RANDOMIZED CLINICAL TRIAL

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S416-S416
Author(s):  
Rajagopal V Sekhar ◽  
Premranjan Kumar ◽  
Jean W Hsu ◽  
James Suliburk ◽  
George E Taffet ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Physical Function ◽  
Gait Speed ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Double Blind ◽  
Mitochondrial Fatty Acid ◽  
Glutathione Deficiency

Abstract Aging is associated with impaired mitochondrial fatty-acid oxidation (MFO) due to unknown mechanisms, and interventions are lacking. We hypothesized that impaired MFO in aging occurs due to Glutathione-deficiency and tested this in a randomized, placebo-controlled double-blind clinical-trial in 24 older-humans (71.1y) and 12 young-controls (25.5y) using calorimetry, muscle-biopsy and tracer-protocols. Older-humans received either GlyNAC (Glycine 1.33mmol/kg/d and N-acetylcysteine 0.83mmol/kg/d as Glutathione precursors) or isonitrogenous-placebo for 16-weeks; young-controls received GlyNAC for 2-weeks. Compared to young-controls, older humans had significantly lower Glutathione, impaired MFO, lower gait-speed and physical-function, and higher oxidative-stress, inflammation and insulin-resistance. GlyNAC supplementation in older-humans significantly improved and restored MFO; increased gait-speed (19%,) and physical-function; and decreased oxidative-stress (TBARS 80%), inflammation (IL-6 83%; TNF-alpha 58%), and insulin-resistance (HOMA-IR 68%), but young-controls were unaffected. These data provide proof-of-concept that GlyNAC supplementation could improve the health of older-humans by correcting Glutathione-deficiency and mitochondrial-defects to improve gait-speed, oxidative-stress, inflammation and insulin-resistance.

scholarly journals GlyNAC (Glycine and N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 154
Author(s):  
Rajagopal V. Sekhar
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Plasma Ffa ◽  
Underlying Mechanisms

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA (free-fatty acid) concentrations in humans with T2D remains unknown. This manuscript reports the effect of supplementing GlyNAC for 14-days on MFO, MGO, IR and FFA in 10 adults with T2D and 10 unsupplemented non-diabetic controls. Fasted T2D participants had 36% lower MFO (p < 0.001), 106% higher MGO (p < 0.01), 425% higher IR (p < 0.001) and 76% higher plasma FFA (p < 0.05). GlyNAC supplementation significantly improved fasted MFO by 30% (p < 0.001), lowered MGO by 47% (p < 0.01), decreased IR by 22% (p < 0.01) and lowered FFA by 25% (p < 0.01). These results provide proof-of-concept that GlyNAC supplementation could improve mitochondrial dysfunction and IR in patients with T2D, and warrant additional research.

Glucocorticoids promote mitochondrial fatty acid oxidation in the fetal heart

2019 ◽  
Author(s):  
Helena Urquijo ◽  
Emma N Panting ◽  
Roderick N Carter ◽  
Emma J Agnew ◽  
Caitlin S Wyrwoll ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fetal Heart ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid

scholarly journals Quantitation of acyl-CoA and acylcarnitine esters accumulated during abnormal mitochondrial fatty acid oxidation.

1991 ◽  
Vol 266 (34) ◽  
pp. 22932-22938
Author(s):  
R.S. Kler ◽  
S. Jackson ◽  
K. Bartlett ◽  
L.A. Bindoff ◽  
S. Eaton ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid
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