Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding

Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, 15 N 2030 East, Bldg 533, Rm 3110B, Salt Lake City, UT 84112, USA.
Cardiovascular Research (Impact Factor: 5.94). 02/2009; 82(2):351-60. DOI: 10.1093/cvr/cvp017
Source: PubMed


Diet-induced obesity is associated with increased myocardial fatty acid (FA) utilization, insulin resistance, and cardiac dysfunction. The study was designed to test the hypothesis that impaired glucose utilization accounts for initial changes in FA metabolism.
Ten-week-old C57BL6J mice were fed a high-fat diet (HFD, 45% calories from fat) or normal chow (4% calories from fat). Cardiac function and substrate metabolism in isolated working hearts, glucose uptake in isolated cardiomyocytes, mitochondrial function, insulin-stimulated protein kinase B (Akt/PKB) and Akt substrate (AS-160) phosphorylation, glucose transporter 4 (GLUT4) translocation, pyruvate dehydrogenase (PDH) activity, and mRNA levels for metabolic genes were determined after 2 or 5 weeks of HFD. Two weeks of HFD reduced basal rates of glycolysis and glucose oxidation and prevented insulin stimulation of glycolysis in hearts and reduced insulin-stimulated glucose uptake in cardiomyocytes. Insulin-stimulated Akt/PKB and AS-160 phosphorylation were preserved, and PDH activity was unchanged. GLUT4 content was reduced by 55% and GLUT4 translocation was significantly attenuated. HFD increased FA oxidation rates and myocardial oxygen consumption (MVO2), which could not be accounted for by mitochondrial uncoupling or by increased expression of peroxisome proliferator activated receptor-alpha (PPAR-alpha) target genes, which increased only after 5 weeks of HFD.
Rates of myocardial glucose utilization are altered early in the course of HFD because of reduced GLUT4 content and GLUT4 translocation despite normal insulin signalling to Akt/PKB and AS-160. The reciprocal increase in FA utilization is not due to PPAR-alpha-mediated signalling or mitochondrial uncoupling. Thus, the initial increase in myocardial FA utilization in response to HFD likely results from impaired glucose transport that precedes impaired insulin signalling.

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Available from: Sihem Boudina, May 28, 2014
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    • "In animal models, cardiac energetics is usually assessed ex vivo in isolated perfused heart setups by measuring cardiac power and oxygen consumption to calculate cardiac energy efficiency [19] [20]. Reduced cardiac efficiency has been observed in rodents with diet-induced obesity [15] [21], obese ob/ob mice [16] [20] [22], and diabetic db/db mice [19] [20] [23]. Unfortunately, the ex vivo setup does not entirely mimic the complexity of the in vivo situation as the ex vivo heart is usually perfused with glucose and FA at a constant concentration, while in obesity the in vivo heart is exposed to a hyperlipidemic and, possibly, a hyperinsulinemic environment, which affects the choice of substrates. "
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    ABSTRACT: Obesity is often associated with abnormalities in cardiac morphology and function. This study tested the hypothesis that obesity-related cardiomyopathy is caused by impaired cardiac energetics. In a mouse model of high-fat diet (HFD)-induced obesity, we applied in vivo cardiac 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) to investigate cardiac energy status and function, respectively. The measurements were complemented by ex vivo determination of oxygen consumption in isolated cardiac mitochondria, the expression of proteins involved in energy metabolism, and markers of oxidative stress and calcium homeostasis. We also assessed whether HFD induced myocardial lipid accumulation using in vivo 1H MRS, and if this was associated with apoptosis and fibrosis. Twenty weeks of HFD feeding resulted in early stage cardiomyopathy, as indicated by diastolic dysfunction and increased left ventricular mass, without any effects on systolic function. In vivo cardiac phosphocreatine-to-ATP ratio and ex vivo oxygen consumption in isolated cardiac mitochondria were not reduced after HFD feeding, suggesting that the diastolic dysfunction was not caused by impaired cardiac energetics. HFD feeding promoted mitochondrial adaptations for increased utilization of fatty acids, which was however not sufficient to prevent the accumulation of myocardial lipids and lipid intermediates. Myocardial lipid accumulation was associated with oxidative stress and fibrosis, but not apoptosis. Furthermore, HFD feeding strongly reduced the phosphorylation of phospholamban, a prominent regulator of cardiac calcium homeostasis and contractility. In conclusion, HFD-induced early stage cardiomyopathy in mice is associated with lipotoxicity-associated oxidative stress, fibrosis, and disturbed calcium homeostasis, rather than impaired cardiac energetics.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 10/2014; 1841(10). DOI:10.1016/j.bbalip.2014.07.016 · 5.16 Impact Factor
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    • "The PPAR transcription factor family is extensively known to regulate cardiac metabolism, mainly through PPARα and PPARβ/δ isoforms together with PGC-1α coactivator [69]. PPARα/PGC-1α leads to transcriptional induction of pyruvate dehydrogenase kinase-4 (PDK4), FAT/CD36 transporter, and FFA oxidation enzymes [70], thereby facilitating mitochondrial FFA import and β-oxidation-dependent metabolism in expenses of glucose assimilation. Thus, NF-κB and p38-mediated PPARα/PGC-1α inhibition has been described as an important pathological mechanism in DCM progression [71]. "
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    ABSTRACT: Diabetic cardiomyopathy is defined as a ventricular dysfunction initiated by alterations in cardiac energy substrates in the absence of coronary artery disease and hypertension. Hyperglycemia, hyperlipidemia, and insulin resistance are major inducers of the chronic low-grade inflammatory state that characterizes the diabetic heart. Cardiac Toll-like receptors and inflammasome complexes may be key inducers for inflammation probably through NF-κB activation and ROS overproduction. However, metabolic dysregulated factors such as peroxisome proliferator-activated receptors and sirtuins may serve as therapeutic targets to control this response by mitigating both Toll-like receptors and inflammasome signaling.
    International Journal of Endocrinology 03/2014; 2014:847827. DOI:10.1155/2014/847827 · 1.95 Impact Factor
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    • "Diet-induced declines in the active fraction of PDH have also been reported [15,17,18]. Dietary durations of greater than one month were required, however, to observe these changes [7,10,15,16,18] suggestive of a downstream consequence rather than an initiating event in diminished glucose utilization. There are, however, reports that PDK4 [13,17] and PDH [17] exhibit changes within a few weeks of initiating a high fat diet. "
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    ABSTRACT: Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production.
    PLoS ONE 10/2013; 8(10):e77280. DOI:10.1371/journal.pone.0077280 · 3.23 Impact Factor
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