Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice.

Aging is associated with the development of chronic diseases such as insulin resistance and type 2 diabetes. A reduction in mitochondrial fat oxidation is postulated to be a key factor contributing to the progression of these diseases. Our aim was to investigate the contribution of impaired mitochondrial fat oxidation toward age-related disease.

Activating PPARα prevents post-ischemic contractile dysfunction in hypertrophied neonatal hearts.

Rationale: Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid β-oxidation rates.

Objective: We determined whether stimulating fatty acid β-oxidation with GW7647, a peroxisome proliferator-activated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy.

Effect of fatty acids on human bone marrow mesenchymal stem cell energy metabolism and survival.

Successful stem cell therapy requires the optimal proliferation, engraftment, and differentiation of stem cells into the desired cell lineage of tissues. However, stem cell therapy clinical trials to date have had limited success, suggesting that a better understanding of stem cell biology is needed. This includes a better understanding of stem cell energy metabolism because of the importance of energy metabolism in stem cell proliferation and differentiation.

Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox.

Recent studies suggest improved outcomes and survival in obese heart failure patients (i.e., the obesity paradox), although obesity and heart failure unfavorably alter cardiac function and metabolism.

Trimetazidine therapy prevents obesity-induced cardiomyopathy in mice.

Obesity is a significant risk factor for the development of cardiovascular disease. Inhibiting fatty acid oxidation has emerged as a novel approach for the treatment of ischemic heart disease. Our aim was to determine whether pharmacologic inhibition of 3-ketoacyl-coenzyme A thiolase (3-KAT), which catalyzes the final step of fatty acid oxidation, could improve obesity-induced cardiomyopathy.

Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling.

Aims: Lysine acetylation is a novel post-translational pathway that regulates the activities of enzymes involved in both fatty acid and glucose metabolism. We examined whether lysine acetylation controls heart glucose and fatty acid oxidation in high-fat diet (HFD) obese and SIRT3 knockout (KO) mice.

Methods And Results: C57BL/6 mice were placed on either a HFD (60% fat) or a low-fat diet (LFD; 4% fat) for 16 or 18 weeks.

Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice.

There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. Although inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart disease and heart failure, reduced muscle fatty acid oxidation rates may contribute to the development of obesity-associated insulin resistance. Our aim was to determine whether treatment with the antianginal agent trimetazidine, which inhibits fatty acid oxidation in the heart secondary to inhibition of 3-ketoacyl-CoA thiolase (3-KAT), may have off-target effects on glycemic control in obesity.

Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation.

Aims: To determine whether post-infarction LV dysfunction is due to low energy availability or inefficient energy utilization, we compared energy metabolism in normal and failing hearts. We also studied whether improved coupling of glycolysis and glucose oxidation by knockout of malonyl CoA decarboxylase (MCD-KO) would have beneficial effects on LV function and efficiency.

Methods And Results: Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or sham operation (SHAM) procedure.

Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy.

Background: Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear.

Methods And Results: Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC).

The impact of current and novel anti-diabetic therapies on cardiovascular risk.

Type 2 diabetes mellitus (T2DM) has become an overwhelming health condition that is no longer just a threat to developed nations, but to undeveloped nations as well. Current therapies for T2DM are relatively effective in controlling hyperglycemia; examples include metformin, thiazolidinediones, sulfonylurea derivatives, α-glucosidase inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Despite their efficacy in controlling hyperglycemia, due to recent findings of increased cardiovascular risk following treatment with either rosiglitazone or intensive glucose lowering, new guidelines from the US FDA recommend that new therapies for diabetes not only improve glycemia, but exert no adverse cardiovascular effects.

Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice.

Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice.

Pyridine nucleotide regulation of cardiac intermediary metabolism.

The pyridine nucleotides NAD(+) and NADP(+) play a pivotal role in regulating intermediary metabolism in the heart. The intracellular NAD(+)/NADH ratio controls flux through various dehydrogenase enzymes involved in both anaerobic and aerobic metabolism and also regulates posttranslational protein modification. The intracellular NADP(+)/NADPH ratio controls flux through the pentose phosphate pathway (PPP) and the polyol pathway, while also regulating ion channel function and oxidative stress.

A role for period 2 in cardioprotection.

How adenosine receptors protect the ischemic heart is not completely understood. Eckle et al. (2012) now show that signaling through adenosine receptor 2b (Adora2b) stabilizes a circadian rhythm protein, period 2 (Per2), resulting in the stabilization of hypoxia-inducible factor-1α (HIF-1α), upregulation of glycolysis, and cardioprotection from ischemia.

Inhibition of serine palmitoyl transferase I reduces cardiac ceramide levels and increases glycolysis rates following diet-induced insulin resistance.

Objective: Diet-induced obesity (DIO) leads to an accumulation of intra-myocardial lipid metabolites implicated in causing cardiac insulin resistance and contractile dysfunction. One such metabolite is ceramide, and our aim was to determine the effects of inhibiting de novo ceramide synthesis on cardiac function and insulin stimulated glucose utilization in mice subjected to DIO.

Materials And Methods: C57BL/6 mice were fed a low fat diet or subjected to DIO for 12 weeks, and then treated for 4 weeks with either vehicle control or the serine palmitoyl transferase I (SPT I) inhibitor, myriocin.

Ischemia/reperfusion-induced myosin light chain 1 phosphorylation increases its degradation by matrix metalloproteinase 2.

Degradation of myosin light chain 1 (MLC1) by matrix metalloproteinase 2 (MMP-2) during myocardial ischemia/reperfusion (I/R) has been demonstrated. However, the exact mechanisms controlling this process remain unknown. I/R increases the phosphorylation of MLC1, but the consequences of this modification are not known.

Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury.

Aims: During reperfusion of the ischaemic myocardium, fatty acid oxidation rates quickly recover, while glucose oxidation rates remain depressed. Direct stimulation of glucose oxidation via activation of pyruvate dehydrogenase (PDH), or secondary to an inhibition of malonyl CoA decarboxylase (MCD), improves cardiac functional recovery during reperfusion following ischaemia. However, the effects of such interventions on the evolution of myocardial infarction are unknown.

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery.

During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload.

Targeting fatty acid and carbohydrate oxidation--a novel therapeutic intervention in the ischemic and failing heart.

Cardiac ischemia and its consequences including heart failure, which itself has emerged as the leading cause of morbidity and mortality in developed countries are accompanied by complex alterations in myocardial energy substrate metabolism. In contrast to the normal heart, where fatty acid and glucose metabolism are tightly regulated, the dynamic relationship between fatty acid β-oxidation and glucose oxidation is perturbed in ischemic and ischemic-reperfused hearts, as well as in the failing heart. These metabolic alterations negatively impact both cardiac efficiency and function.

Isoproterenol stimulates 5'-AMP-activated protein kinase and fatty acid oxidation in neonatal hearts.

Isoproterenol increases phosphorylation of LKB, 5'-AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC), enzymes involved in regulating fatty acid oxidation. However, inotropic stimulation selectively increases glucose oxidation in adult hearts. In the neonatal heart, fatty acid oxidation becomes a major energy source, while glucose oxidation remains low.

Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption.

Objective: It has been proposed that skeletal muscle insulin resistance arises from the accumulation of intramyocellular lipid metabolites that impede insulin signaling, including diacylglycerol and ceramide. We determined the role of de novo ceramide synthesis in mediating muscle insulin resistance.

Research Design And Methods: Mice were subjected to 12 weeks of diet-induced obesity (DIO), and then treated for 4 weeks with myriocin, an inhibitor of serine palmitoyl transferase-1 (SPT1), the rate-limiting enzyme of de novo ceramide synthesis.

Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation.

Dramatic maturational changes occur in cardiac energy metabolism during cardiac development, differentiation, and postnatal growth. These changes in energy metabolism have important impacts on the ability of the cardiomyocyte to proliferate during early cardiac development, as well as when cardiomyocytes terminally differentiate during later development. During early cardiac development, glycolysis is a major source of energy for proliferating cardiomyocytes.

Targeting intermediary metabolism in the hypothalamus as a mechanism to regulate appetite.

The central nervous system mediates energy balance (energy intake and energy expenditure) in the body; the hypothalamus has a key role in this process. Recent evidence has demonstrated an important role for hypothalamic malonyl CoA in mediating energy balance. Malonyl CoA is generated by the carboxylation of acetyl CoA by acetyl CoA carboxylase and is then either incorporated into long-chain fatty acids by fatty acid synthase, or converted back to acetyl-CoA by malonyl CoA decarboxylase.

High levels of fatty acids increase contractile function of neonatal rabbit hearts during reperfusion following ischemia.

In the neonatal heart the transition from using carbohydrates to using fatty acids has not fully matured and oxidative metabolism/ATP generation may be limiting contractile function after ischemia. This study tested the hypothesis that increasing fatty acid availability increases recovery of left ventricular (LV) work by increasing palmitate oxidation, tricarboxylic acid (TCA) cycle activity, and ATP generation. Isolated working hearts from 7-day-old rabbits were perfused with Krebs solution containing low (0.