The PPARβ/δ Activator GW501516 Prevents the Down-Regulation of AMPK Caused by a High-Fat Diet in Liver and Amplifies the PGC-1α-Lipin 1-PPARα Pathway Leading to Increased Fatty Acid Oxidation

Metabolic syndrome-associated dyslipidemia is mainly initiated by hepatic overproduction of the plasma lipoproteins carrying triglycerides. Here we examined the effects of the peroxisome proliferator-activated receptors (PPAR)-β/δ activator GW501516 on high-fat diet (HFD)-induced hypertriglyceridemia and hepatic fatty acid oxidation. Exposure to the HFD caused hypertriglyceridemia that was accompanied by reduced hepatic mRNA levels of PPAR-γ coactivator 1 (PGC-1)-α and lipin 1, and these effects were prevented by GW501516 treatment. GW501516 treatment also increased nuclear lipin 1 protein levels, leading to amplification in the PGC-1α-PPARα signaling system, as demonstrated by the increase in PPARα levels and PPARα-DNA binding activity and the increased expression of PPARα-target genes involved in fatty acid oxidation. These effects of GW501516 were accompanied by an increase in plasma β-hydroxybutyrate levels, demonstrating enhanced hepatic fatty acid oxidation. Moreover, GW501516 increased the levels of the hepatic endogenous ligand for PPARα, 16:0/18:1-phosphatidilcholine and markedly enhanced the expression of the hepatic Vldl receptor. Interestingly, GW501516 prevented the reduction in AMP-activated protein kinase (AMPK) phosphorylation and the increase in phosphorylated levels of ERK1/2 caused by HFD. In addition, our data indicate that the activation of AMPK after GW501516 treatment in mice fed HFD might be the result of an increase in the AMP to ATP ratio in hepatocytes. These findings indicate that the hypotriglyceridemic effect of GW501516 in HFD-fed mice is accompanied by an increase in phospho-AMPK levels and the amplification of the PGC-1α-lipin 1-PPARα pathway.

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RS4-type resistant starch prevents high-fat diet-induced obesity via increased hepatic fatty acid oxidation and decreased postprandial GIP in C57BL/6J mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00468.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. E652-E662 ◽

Cited By ~ 41

Author(s):

Akira Shimotoyodome ◽

Junko Suzuki ◽

Daisuke Fukuoka ◽

Ichiro Tokimitsu ◽

Tadashi Hase

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Resistant Starch ◽

High Fat Diet ◽

Acid Oxidation ◽

High Fat ◽

Fat Utilization ◽

Hepatic Fatty Acid ◽

Diet Induced Obesity ◽

Hepatic Fatty Acid Oxidation

Chemically modified starches (CMS) are RS4-type resistant starch, which shows a reduced availability, as well as high-amylose corn starch (HACS, RS2 type), compared with the corresponding unmodified starch. Previous studies have shown that RS4 increases fecal excretion of bile acids and reduces zinc and iron absorption in rats. The aim of this study was to investigate the effects of dietary RS4 supplementation on the development of diet-induced obesity in mice. Weight- and age-matched male C57BL/6J mice were fed for 24 wk on a high-fat diet containing unmodified starch, hydroxypropylated distarch phosphate (RS4), or HACS (RS2). Those fed the RS4 diet had significantly lower body weight and visceral fat weight than those fed either unmodified starch or the RS2 diet. Those fed the RS4 diet for 4 wk had a significantly higher hepatic fatty acid oxidation capacity and related gene expression and lower blood insulin than those fed either unmodified starch or the RS2 diet. Indirect calorimetry showed that the RS4 group exhibited higher energy expenditure and fat utilization compared with the RS2 group. When gavaged with fat (trioleate), RS4 stimulated a lower postprandial glucose-dependent insulinotropic polypeptide (GIP; incretin) response than RS2. Higher blood GIP levels induced by chronic GIP administration reduced fat utilization in high-fat diet-fed mice. In conclusion, dietary supplementation with RS4-type resistant starch attenuates high-fat diet-induced obesity more effectively than RS2 in C57BL/6J mice, which may be attributable to lower postprandial GIP and increased fat catabolism in the liver.

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High-fat diet from perilla oil induces insulin resistance despite lower serum lipids and increases hepatic fatty acid oxidation in rats

Lipids in Health and Disease ◽

10.1186/1476-511x-13-15 ◽

2014 ◽

Vol 13 (1) ◽

pp. 15 ◽

Cited By ~ 18

Author(s):

Tao Zhang ◽

Shuang Zhao ◽

Wei Li ◽

Lanzhi Ma ◽

Ming Ding ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

High Fat Diet ◽

Serum Lipids ◽

Acid Oxidation ◽

High Fat ◽

Lower Serum ◽

Hepatic Fatty Acid ◽

Hepatic Fatty Acid Oxidation

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Interrelated effects of dihomo-γ-linolenic and arachidonic acids, and sesamin on hepatic fatty acid synthesis and oxidation in rats

British Journal Of Nutrition ◽

10.1017/s0007114512000141 ◽

2012 ◽

Vol 108 (11) ◽

pp. 1980-1993 ◽

Cited By ~ 5

Author(s):

Takashi Ide ◽

Yoshiko Ono ◽

Hiroshi Kawashima ◽

Yoshinobu Kiso

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Dietary Fat ◽

Acid Synthesis ◽

Acid Oxidation ◽

Mrna Levels ◽

Lipogenic Enzymes ◽

Hepatic Fatty Acid ◽

Hepatic Fatty Acid Oxidation ◽

Maize Oil

Interrelated effects of dihomo-γ-linolenic acid (DGLA) and arachidonic acid (ARA), and sesamin, a sesame lignan, on hepatic fatty acid synthesis and oxidation were examined in rats. Rats were fed experimental diets supplemented with 0 or 2 g/kg sesamin (1:1 mixture of sesamin and episesamin), containing 100 g/kg of maize oil or fungal oil rich in DGLA or ARA for 16 d. Among the groups fed sesamin-free diets, oils rich in DGLA or ARA, especially the latter, compared with maize oil strongly reduced the activity and mRNA levels of various lipogenic enzymes. Sesamin, irrespective of the type of fat, reduced the parameters of lipogenic enzymes except for malic enzyme. The type of dietary fat was rather irrelevant in affecting hepatic fatty acid oxidation among rats fed the sesamin-free diets. Sesamin increased the activities of enzymes involved in fatty acid oxidation in all groups of rats given different fats. The extent of the increase depended on the dietary fat type, and the values became much higher with a diet containing sesamin and oil rich in ARA in combination than with a diet containing lignan and maize oil. Analyses of mRNA levels revealed that the combination of sesamin and oil rich in ARA compared with the combination of lignan and maize oil markedly increased the gene expression of various peroxisomal fatty acid oxidation enzymes but not mitochondrial enzymes. The enhancement of sesamin action on hepatic fatty acid oxidation was also confirmed with oil rich in DGLA but to a lesser extent.

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