Article

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: 5.81). 02/2009; 82(2):351-60. DOI: 10.1093/cvr/cvp017
Source: PubMed

ABSTRACT 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.

Full-text

Available from: Sihem Boudina, May 28, 2014
0 Followers
 · 
98 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Link to retrieve the chapter: http://link.springer.com/chapter/10.1007/978-3-319-13680-6_6 The adrenergic nervous system plays a crucial role in cardiovascular physiology. Adrenergic receptors, which are extensively distributed throughout the body, essentially mediate cellular communication, allowing cells to sense external signals or to talk each other via neurotransmitters and hormones. These receptors are involved in a plethora of pathophysiological processes and a large amount of studies has demonstrated their participation in cardiovascular metabolism and aging. This chapter represents an updated and systematic appraisal of the literature in this field, summarizing the major findings of research investigating the functional role of neuroendocrine adrenergic system in regulating cardiovascular aging and cardiovascular metabolism.
    Advances in Experimental Medicine and Biology 01/2015; DOI:10.1007/978-3-319-13680-6_6 · 2.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of "IR as an adaptive defense mechanism" and "insulin-induced metabolic stress" may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 03/2015; 64(3):673-86. DOI:10.2337/db14-0694 · 8.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of Nox2 in both high fat-fed murine hearts and palmitate- treated H9C2 cardiomyocytes. Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated cardiomyocytes. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated cardiomyocytes. Palmitate-induced Nox2 activation was dependent on the activation of classical PKCs specifically PKCβII. These findings reveal a novel mechanism linking lipotoxicity with a PKCβ-Nox2 mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in cardiomyocytes. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    The Journal of Lipid Research 12/2014; 56(3). DOI:10.1194/jlr.M055152 · 4.73 Impact Factor