Enhancement of Muscle Mitochondrial Oxidative Capacity and Alterations in Insulin Action Are Lipid Species Dependent
ABSTRACT Medium-chain fatty acids (MCFAs) have been reported to be less obesogenic than long-chain fatty acids (LCFAs); however, relatively little is known regarding their effect on insulin action. Here, we examined the tissue-specific effects of MCFAs on lipid metabolism and insulin action.
C57BL6/J mice and Wistar rats were fed either a low-fat control diet or high-fat diets rich in MCFAs or LCFAs for 4-5 weeks, and markers of mitochondrial oxidative capacity, lipid levels, and insulin action were measured.
Mice fed the MCFA diet displayed reduced adiposity and better glucose tolerance than LCFA-fed animals. In skeletal muscle, triglyceride levels were increased by the LCFA diet (77%, P < 0.01) but remained at low-fat diet control levels in the MCFA-fed animals. The LCFA diet increased (20-50%, P < 0.05) markers of mitochondrial metabolism in muscle compared with low-fat diet-fed controls; however; the increase in oxidative capacity was substantially greater in MCFA-fed animals (50-140% versus low-fat-fed controls, P < 0.01). The MCFA diet induced a greater accumulation of liver triglycerides than the LCFA diet, likely due to an upregulation of several lipogenic enzymes. In rats, isocaloric feeding of MCFA or LCFA high-fat diets induced hepatic insulin resistance to a similar degree; however, insulin action was preserved at the level of low-fat diet-fed controls in muscle and adipose from MCFA-fed animals.
MCFAs reduce adiposity and preserve insulin action in muscle and adipose, despite inducing steatosis and insulin resistance in the liver. Dietary supplementation with MCFAs may therefore be beneficial for preventing obesity and peripheral insulin resistance.
Full-textDOI: · Available from: Ji-Ming Ye, May 27, 2015
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ABSTRACT: Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine.Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.024 · 10.40 Impact Factor
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ABSTRACT: The unfolded protein response (UPR) pathways have been implicated in the development of hepatic insulin resistance during high fructose (HFru) feeding. The present study investigated their roles in initiating impaired insulin signaling transduction in the liver induced by HFru feeding in mice. HFru feeding resulted in hepatic steatosis, increased de novo lipogenesis and activation of two arms of the UPR pathways (IRE1/XBP1 and PERK/eIF2α) in similar patterns from 3days to 8weeks. In order to identify the earliest trigger of impaired insulin signaling in the liver, we fed mice with the HFru diet for one day and revealed that only the IRE1 branch was activated (by 2-fold) and insulin-mediated Akt phosphorylation was blunted (~25%) in the liver. There were significant increases in phosphorylation of JNK (~50%) and IRS at serine site (~50%), protein content of ACC and FAS (up to 2.5-fold) and triglyceride level (2-fold) in liver (but not in muscle or fat). Blocking IRE1 activity abolished increases in JNK activity, IRS serine phosphorylation and protected insulin-stimulated Akt phosphorylation without altering hepatic steatosis or PKCε, a key link between lipids and insulin resistance. Our findings together suggest that activation of IRE1-JNK pathway is a key linker of impaired hepatic insulin signaling transduction induced by HFru feeding. Copyright © 2014. Published by Elsevier B.V.Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 11/2014; 1852(1). DOI:10.1016/j.bbadis.2014.11.017 · 5.09 Impact Factor
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ABSTRACT: Mitochondrial dysfunction has been implicated in the development of insulin resistance, however a large variety of association and intervention studies, as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between insulin resistance and diminished mitochondrial function, it is still unclear if a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of insulin resistance. This review will take a journey through the past and summarize the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence will be presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we will discuss if mitochondria are a potential target for the treatment of insulin resistance.11/2014; DOI:10.1530/EC-14-0092