scholarly journals Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin Resistance and Obesity

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5341-5349 ◽  
Author(s):  
Jonathan Buchanan ◽  
Pradip K. Mazumder ◽  
Ping Hu ◽  
Gopa Chakrabarti ◽  
Matthew W. Roberts ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Mouse Models ◽  
Acid Oxidation ◽  
Contractile Dysfunction ◽  
Oxidation Rates ◽  
Myocardial Substrate ◽  
Old Mice

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28–37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased β-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-α regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-α regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

Regulation of myocardial fatty acid oxidation by substrate supply

2001 ◽  
Vol 281 (4) ◽  
pp. H1561-H1567 ◽  
Author(s):  
Sarah L. Longnus ◽  
Richard B. Wambolt ◽  
Rick L. Barr ◽  
Gary D. Lopaschuk ◽  
Michael F. Allard
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Regulatory Pathways ◽  
Oxidation Rates ◽  
Substrate Supply ◽  
Exogenous Substrate ◽  
Malonyl Coa ◽  
Myocardial Substrate

We tested the hypothesis that myocardial substrate supply regulates fatty acid oxidation independent of changes in acetyl-CoA carboxylase (ACC) and 5′-AMP-activated protein kinase (AMPK) activities. Fatty acid oxidation was measured in isolated working rat hearts exposed to different concentrations of exogenous long-chain (0.4 or 1.2 mM palmitate) or medium-chain (0.6 or 2.4 mM octanoate) fatty acids. Fatty acid oxidation was increased with increasing exogenous substrate concentration in both palmitate and octanoate groups. Malonyl-CoA content only rose as acetyl-CoA supply from octanoate oxidation increased. The increases in octanoate oxidation and malonyl-CoA content were independent of changes in ACC and AMPK activity, except that ACC activity increased with very high acetyl-CoA supply levels. Our data suggest that myocardial substrate supply is the primary mechanism responsible for alterations in fatty acid oxidation rates under nonstressful conditions and when substrates are present at physiological concentrations. More extreme variations in substrate supply lead to changes in fatty acid oxidation by the additional involvement of intracellular regulatory pathways.

scholarly journals Identification of a novel malonyl-CoA IC50 for CPT-I: implications for predicting in vivo fatty acid oxidation rates

2012 ◽  
Vol 448 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Brennan K. Smith ◽  
Christopher G. R. Perry ◽  
Timothy R. Koves ◽  
David C. Wright ◽  
Jeffrey C. Smith ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Muscle Fibres ◽  
Inhibition Kinetics ◽  
Oxidation Rates ◽  
Isolated Mitochondria ◽  
Malonyl Coa ◽  
Cpt I

Published values regarding the sensitivity (IC50) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC50 (0.61 compared with 0.034 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC50 (6.3 compared with 0.49 μM) in the presence of 150 μM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC50 that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the in vivo disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes.

Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts

2005 ◽  
Vol 288 (5) ◽  
pp. E900-E906 ◽  
Author(s):  
Rogayah Carroll ◽  
Andrew N. Carley ◽  
Jason R. B. Dyck ◽  
David L. Severson
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Glucose Transporter ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Palmitate Oxidation ◽  
Ampk Phosphorylation

Diabetic db/db mice exhibit profound insulin resistance in vivo, but the specific degree of cardiac insensitivity to insulin has not been assessed. Therefore, the effect of insulin on cardiomyocytes from db/db hearts was assessed by measuring two metabolic responses (deoxyglucose uptake and fatty acid oxidation) and the phosphorylation of two enzymes in the insulin-signaling cascade [Akt and AMP-activated protein kinase (AMPK)]. Maximal insulin-stimulated deoxyglucose transport was reduced to 58 and 40% of control in cardiomyocytes from db/db mice at two ages (6 and 12 wk). Insulin-stimulated deoxyglucose uptake was also reduced in myocytes from transgenic db/db mice overexpressing the insulin-sensitive glucose transporter ( db/db-hGLUT4). Treatment of db/db mice for 1 wk with an insulin-sensitizing peroxisome proliferator-activated receptor-γ agonist (COOH) completely normalized insulin-stimulated deoxyglucose uptake. Insulin had no direct effect on palmitate oxidation by either control or db/db cardiomyocytes, but the combination of insulin and glucose reduced palmitate oxidation, likely an indirect effect secondary to increased glucose uptake. Insulin had no effect on AMPK phosphorylation from either control or db/db cardiomyocytes. Insulin increased the phosphorylation of Akt in all cardiomyocyte preparations (control, db/db, COOH-treated db/db) to the same extent. Thus insulin has selective metabolic actions in mouse cardiomyocytes; deoxyglucose uptake and Akt phosphorylation are increased, but fatty acid oxidation and AMPK phosphorylation are unchanged. Insulin resistance in db/db cardiomyocytes is manifested by reduced insulin-stimulated deoxyglucose uptake.

379-P: Aldose Reductase Inhibition by AT-001 Prevents Diabetic Cardiomyopathy via Reducing Myocardial Fatty Acid Oxidation Rates

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 379-P
Author(s):  
KESHAV GOPAL ◽  
QUTUBA G. KARWI ◽  
SEYED AMIRHOSSEIN TABATABAEI DAKHILI ◽  
CORY S. WAGG ◽  
RICCARDO PERFETTI ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Aldose Reductase ◽  
Diabetic Cardiomyopathy ◽  
Acid Oxidation ◽  
Myocardial Fatty Acid ◽  
Aldose Reductase Inhibition ◽  
Oxidation Rates

Abstract 282: Adropin Enhancement of Cardiac Insulin Sensitivity and Inhibition of Fatty Acid Oxidation are Associated With Improvement of Cardiac Function and Efficiency in Hearts From Fasted Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tariq R Altamimi ◽  
Arata Fukushima ◽  
Liyan Zhang ◽  
Su Gao ◽  
Abhishek Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Insulin Signaling ◽  
Plasma Levels ◽  
Acid Oxidation ◽  
Post Translational Modification ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy

Impaired cardiac insulin signaling and high cardiac fatty acid oxidation rates are characteristics of diabetic cardiomyopathy. Potential roles for liver-derived metabolic factors in mediating cardiac energy homeostasis are underappreciated. Plasma levels of adropin, a liver secreted peptide, increase during feeding and decrease during fasting and diabetes. In skeletal muscle, adropin preferentially promotes glucose over fatty acid oxidation. We therefore determined what effect adropin has on cardiac energy metabolism, insulin signaling and cardiac efficiency. C57Bl/6 mice were fasted to accentuate the differences in adropin plasma levels between animals injected 3 times over 24 hr with either vehicle or adropin (450 nmol/kg i.p.). Despite fasting-induced predominance of fatty acid oxidation measured in isolated working hearts, insulin inhibition of fatty acid oxidation was re-established in adropin-treated mice (from 1022±143 to 517±56 nmol. g dry wt -1 . min -1 , p <0.05) compared to vehicle-treated mice (from 757±104 to 818±103 nmol. g dry wt -1 . min -1 ). Adropin-treated mice hearts showed higher cardiac work over the course of perfusion (p<0.05 vs. vehicle), which was accompanied by improved cardiac efficiency and enhanced phosphorylation of insulin signaling enzymes (tyrosine-IRS-1, AS160, p<0.05). Acute addition of adropin (2nM) to isolated working hearts from non-fasting mice showed a robust stimulation of glucose oxidation compared to vehicle-treated hearts (3025±401 vs 1708±292 nmol. g dry wt -1 . min -1 , p<0.05, respectively) with a corresponding inhibition of palmitate oxidation (325±61 vs 731±160 nmol. g dry wt -1 . min -1 , p<0.05, respectively), even in the presence of insulin. Acute adropin addition to hearts also increased IRS-1 tyrosine-phosphorylation as well as Akt, and GSK3β phosphorylation (p<0.05), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. These results suggest adropin as a putative candidate for the treatment of diabetic cardiomyopathy.

scholarly journals MicroRNA-27b-3p regulates function and metabolism in insulin resistance cells by inhibiting receptor tyrosine kinase-like orphan receptor 1

2018 ◽  
Vol 16 ◽  
pp. 205873921876205
Author(s):  
Yong Liu ◽  
Guohui Wang ◽  
Xiangwu Yang ◽  
Pengzhou Li ◽  
Hao Ling ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Tyrosine Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Receptor Tyrosine Kinase ◽  
Cell Model ◽  
Orphan Receptor ◽  
Acid Oxidation ◽  
Metabolism Disorder

Type 2 diabetes mellitus (T2DM) is associated with insulin resistance-induced lipid and glucose metabolism disorder. The study was aimed to explore the potential functional role of microRNA (miR)-27b-3p in T2DM, as well as underlying mechanisms. An insulin resistance cell model was induced in HepG2 cells and then expression of miR-27b-3p and receptor tyrosine kinase-like orphan receptor 1 (ROR1) was analyzed. The expression of miR-27b-3p was overexpressed or silenced, and the relationship between ROR1 and miR-27b-3p was investigated. Thereafter, the effects of miR-27b-3p on percentage of glucose uptake, fatty acid oxidation and cell cycle were analyzed. The expressions of miR-27b-3p were significantly increased, while the ROR1 levels were statistically decreased in the cells of the model group. Overexpression of miR-27b-3p dramatically decreased the levels of ROR1 and the percentage of glucose uptake, but had no effects on fatty acid oxidation. ROR1 was a target of miR-27b-3p. Moreover, overexpression of miR-27b-3p could remarkably highlight the percentages of cells at G0/G1 phase, but decreased the percentages of cells at S phase. In conclusion, our results suggest that miR-27b-3p regulates the function and metabolism of insulin resistance cells by inhibiting ROR1. miR-27b-3p might be a potential drug target in treating T2DM.

Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation

1999 ◽  
Vol 277 (2) ◽  
pp. E342-E351 ◽  
Author(s):  
John C. Chatham ◽  
Zhi-Ping Gao ◽  
John R. Forder
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Diabetic Rats ◽  
Diabetic Group ◽  
Acid Oxidation ◽  
Oxidation Rates ◽  
Tissue Extracts ◽  
Isotopomer Analysis ◽  
C Nmr

The aim of this study was to investigate the effect of increasing exogenous palmitate concentration on carbohydrate and palmitate oxidation in hearts from control and 1-wk diabetic rats. Hearts were perfused with glucose, [3-13C]lactate, and [U-13C]palmitate. Substrate oxidation rates were determined by combining13C-NMR glutamate isotopomer analysis of tissue extracts with measurements of oxygen consumption. Carbohydrate oxidation was markedly depressed after diabetes in the presence of low (0.1 mM) but not high (1.0 mM) palmitate concentration. Increasing exogenous palmitate concentration 10-fold resulted in a 7-fold increase in the contribution of palmitate to energy production in controls but only a 30% increase in the diabetic group. Consequently, at 0.1 mM palmitate, the rate of fatty acid oxidation was higher in the diabetic group than in controls; however, at 1.0 mM fatty acid oxidation, it was significantly depressed. Therefore, after 1 wk of diabetes, the major differences in carbohydrate and fatty acid metabolism occur primarily at low rather than high exogenous palmitate concentration.

scholarly journals Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

2016 ◽  
Vol 311 (2) ◽  
pp. H347-H363 ◽  
Author(s):  
Arata Fukushima ◽  
Osama Abo Alrob ◽  
Liyan Zhang ◽  
Cory S. Wagg ◽  
Tariq Altamimi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Amino Acid Synthesis ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
The Impact

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

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