Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification

Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that ‘Western’ and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, ‘Western’ or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4–8 weeks), intermediate (16–24 weeks) or long (32–48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.

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Interactions between CD36 and global intestinal alkaline phosphatase in mouse small intestine and effects of high-fat diet

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00235.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. R1738-R1747 ◽

Cited By ~ 31

Author(s):

Matthew Lynes ◽

Sonoko Narisawa ◽

José Luis Millán ◽

Eric P. Widmaier

Keyword(s):

Fatty Acid ◽

High Fat Diet ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Dependent Manner ◽

High Fat ◽

Intestinal Alkaline Phosphatase ◽

Mouse Small Intestine ◽

Mouse Intestine ◽

Plasma Leptin

The mechanisms of the saturable component of long-chain fatty acid (LCFA) transport across the small intestinal epithelium and its regulation by a high-fat diet (HFD) are uncertain. It is hypothesized here that the putative fatty acid translocase/CD36 and intestinal alkaline phosphatases (IAPs) function together to optimize LCFA transport. Phosphorylated CD36 (pCD36) was expressed in mouse enterocytes and dephosphorylated by calf IAP (CIAP). Uptake of fluorescently tagged LCFA into isolated enteroctyes was increased when cells were treated with CIAP; this was blocked with a specific CD36 inhibitor. pCD36 colocalized in enterocytes with the global IAP (gIAP) isozyme and, specifically, coimmunoprecipitated with gIAP, but not the duodenal-specific isozyme (dIAP). Purified recombinant gIAP dephosphorylated immunoprecipitated pCD36, and antiserum to gIAP decreased initial LCFA uptake in enterocytes. Body weight, adiposity, and plasma leptin and triglycerides were significantly increased in HFD mice compared with controls fed a normal-fat diet. HFD significantly increased immunoreactive CD36 and gIAP, but not dIAP, in jejunum, but not duodenum. Uptake of LCFA was increased in a CD36-dependent manner in enterocytes from HFD mice. It is concluded that CD36 exists in its phosphorylated and dephosphorylated states in mouse enterocytes, that pCD36 is a substrate of gIAP, and that dephosphorylation by IAPs results in increased LCFA transport capability. HFD upregulates CD36 and gIAP in parallel and enhances CD36-dependent fatty acid uptake. The interactions between these proteins may be important for efficient fat transport in mouse intestine, but whether the changes in gIAP and CD36 in enterocytes contribute to HFD-induced obesity remains to be determined.

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Influence of high fat diet and resveratrol supplementation on placental fatty acid uptake in the Japanese macaque

Placenta ◽

10.1016/j.placenta.2015.06.002 ◽

2015 ◽

Vol 36 (8) ◽

pp. 903-910 ◽

Cited By ~ 19

Author(s):

P. O'Tierney-Ginn ◽

V. Roberts ◽

M. Gillingham ◽

J. Walker ◽

P.A. Glazebrook ◽

...

Keyword(s):

Fatty Acid ◽

High Fat Diet ◽

Japanese Macaque ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

High Fat

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Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Molecular and Cellular Biology ◽

10.1128/mcb.00138-16 ◽

2016 ◽

Vol 36 (21) ◽

pp. 2715-2727 ◽

Cited By ~ 22

Author(s):

Wojciech G. Garbacz ◽

Peipei Lu ◽

Tricia M. Miller ◽

Samuel M. Poloyac ◽

Nicholas S. Eyre ◽

...

Keyword(s):

Fatty Acid ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Glycogen Synthesis ◽

Metabolic Stress ◽

Density Lipoprotein ◽

Fatty Acid Uptake ◽

Arachidonic Acid Metabolite ◽

Acid Uptake ◽

High Fat

The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome.

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Metallothionein Prevents High-Fat Diet Induced Cardiac Contractile Dysfunction: Role of Peroxisome Proliferator Activated Receptor Coactivator 1 and Mitochondrial Biogenesis

Diabetes ◽

10.2337/db06-1596 ◽

2007 ◽

Vol 56 (9) ◽

pp. 2201-2212 ◽

Cited By ~ 103

Author(s):

F. Dong ◽

Q. Li ◽

N. Sreejayan ◽

J. M. Nunn ◽

J. Ren

Keyword(s):

Mitochondrial Biogenesis ◽

High Fat Diet ◽

Contractile Dysfunction ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Cardiac Contractile ◽

Cardiac Contractile Dysfunction

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Adipocyte-specific Inactivation of Acyl-CoA Synthetase Fatty Acid Transport Protein 4 (Fatp4) in Mice Causes Adipose Hypertrophy and Alterations in Metabolism of Complex Lipids under High Fat Diet

Journal of Biological Chemistry ◽

10.1074/jbc.m111.226530 ◽

2011 ◽

Vol 286 (41) ◽

pp. 35578-35587 ◽

Cited By ~ 32

Author(s):

Lena-Solveig Lenz ◽

Jana Marx ◽

Walee Chamulitrat ◽

Iris Kaiser ◽

Hermann-Josef Gröne ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

High Fat Diet ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Long Chain Fatty Acids ◽

High Fat ◽

Complex Lipids ◽

Long Chain ◽

Chain Fatty Acids

Fatp4 exhibits acyl-CoA synthetase activity and is thereby able to catalyze the activation of fatty acids for further metabolism. However, its actual function in most tissues remains unresolved, and its role in cellular fatty acid uptake is still controversial. To characterize Fatp4 functions in adipocytes in vivo, we generated a mouse line with adipocyte-specific inactivation of the Fatp4 gene (Fatp4A−/−). Under standard conditions mutant mice showed no phenotypical aberrance. Uptake of radiolabeled palmitic and lignoceric acid into adipose tissue of Fatp4A−/− mice was unchanged. When exposed to a diet enriched in long chain fatty acids, Fatp4A−/− mice gained more body weight compared with control mice, although they were not consuming more food. Pronounced obesity was accompanied by a thicker layer of subcutaneous fat and greater adipocyte circumference, although expression of genes involved in de novo lipogenesis was not changed. However, the increase in total fat mass was contrasted by a significant decrease in various phospholipids, sphingomyelin, and cholesteryl esters in adipocytes. Livers of Fatp4-deficient animals under a high fat diet exhibited a higher degree of fatty degeneration. Nonetheless, no evidence for changes in insulin sensitivity and adipose inflammation was found. In summary, the results of this study confirm that Fatp4 is not crucial for fatty acid uptake into adipocytes. Instead, under the condition of a diet enriched in long chain fatty acids, adipocyte-specific Fatp4 deficiency results in adipose hypertrophy and profound alterations in the metabolism of complex lipids.

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Influence of high fat diet sensitivity and resveratrol supplementation on placental fatty acid uptake in the Japanese macaque

Placenta ◽

10.1016/j.placenta.2013.06.187 ◽

2013 ◽

Vol 34 (9) ◽

pp. A62-A63 ◽

Cited By ~ 2

Author(s):

Perrie O'Tierney-Ginn ◽

Victoria Roberts ◽

Kent Thornburg ◽

Kevin Grove ◽

Antonio Frias

Keyword(s):

Fatty Acid ◽

High Fat Diet ◽

Japanese Macaque ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

High Fat

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Gene Expression in Livers of BALB/C and C57BL/6J Mice Fed a High-Fat Diet

Toxicologic Pathology ◽

10.1177/0192623311422078 ◽

2011 ◽

Vol 40 (1) ◽

pp. 71-82 ◽

Cited By ~ 31

Author(s):

Satomi Nishikawa ◽

Jiro Sugimoto ◽

Miyoko Okada ◽

Tetsuya Sakairi ◽

Shiro Takagi

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Mrna Expression ◽

High Fat Diet ◽

Fatty Acid Uptake ◽

Blood Chemistry ◽

Acid Uptake ◽

High Fat ◽

Hepatic Lipid Accumulation ◽

The One

We previously demonstrated that high-fat diet (HFD)–induced hepatic lipid accumulation is more severe in BALB/c mice than in C57BL/6J (B6) mice. To understand the changes in liver metabolism, we studied blood chemistry, gene expression, and histopathological changes of the liver in nine-week HFD-fed BALB/c and B6 mice and one- or four-week HFD-fed BALB/c mice. Serum total cholesterol and triglyceride levels were significantly increased in all HFD-fed groups, and one- and four-week HFD-fed BALB/c groups, respectively. Histopathology revealed that vacuolation of hepatocytes was severe in nine-week HFD-fed BALB/c mice, although it was less severe in the other groups. Microarray analysis of mRNA expression of nine-week HFD-fed BALB/c mice showed up-regulation of genes involved in fatty acid uptake and biosynthesis, such as Cd36, Acaca, Acly, and Fasn. Some changes were observed in the one- and four-week HFD-fed BALB/c groups and the nine-week HFD-fed B6 group, however these changes in mRNA expression were not so marked. In conclusion, the fatty accumulation observed in BALB/c mice may be caused, at least in part, by up-regulation of fatty acid uptake and biosynthesis. Cd36, Acaca, Acly and Fasn may be involved in these metabolic processes.

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Reduced fatty acid uptake aggravates cardiac contractile dysfunction in streptozotocin-induced diabetic cardiomyopathy

Scientific Reports ◽

10.1038/s41598-020-77895-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yogi Umbarawan ◽

Ryo Kawakami ◽

Mas Rizky A. A. Syamsunarno ◽

Norimichi Koitabashi ◽

Hideru Obinata ◽

...

Keyword(s):

Fatty Acid ◽

Total Energy ◽

Diabetic Cardiomyopathy ◽

Energy Supply ◽

Contractile Dysfunction ◽

Acid Uptake ◽

Compensatory Response ◽

Fatty Acid Binding ◽

Cardiac Contractile ◽

Cardiac Contractile Dysfunction

AbstractDiabetes is an independent risk factor for the development of heart failure. Increased fatty acid (FA) uptake and deranged utilization leads to reduced cardiac efficiency and accumulation of cardiotoxic lipids, which is suggested to facilitate diabetic cardiomyopathy. We studied whether reduced FA uptake in the heart is protective against streptozotocin (STZ)-induced diabetic cardiomyopathy by using mice doubly deficient in fatty acid binding protein 4 (FABP4) and FABP5 (DKO mice). Cardiac contractile dysfunction was aggravated 8 weeks after STZ treatment in DKO mice. Although compensatory glucose uptake was not reduced in DKO-STZ hearts, total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. Tracer analysis with 13C6-glucose revealed that accelerated glycolysis in DKO hearts was strongly suppressed by STZ treatment. Levels of ceramides, cardiotoxic lipids, were similarly elevated by STZ treatment. These findings suggest that a reduction in total energy supply by reduced FA uptake and suppressed glycolysis could account for exacerbated contractile dysfunction in DKO-STZ hearts. Thus, enhanced FA uptake in diabetic hearts seems to be a compensatory response to reduced energy supply from glucose, and therefore, limited FA use could be detrimental to cardiac contractile dysfunction due to energy insufficiency.

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