Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPAR-Dependent Switch From Lipogenesis to Fat Oxidation
Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPAR-Dependent Switch From Lipogenesis to Fat Oxidation
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DOI：
10.2337/db14-1213
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发表时间：
2015-07-01
期刊：
影响因子：
7.7
通讯作者：
Bakker, Barbara M.
中科院分区：
文献类型：
--
作者：
den Besten, Gijs;Bleeker, Aycha;Bakker, Barbara M.
短链脂肪酸（SCFAs）是膳食纤维发酵的主要产物，被认为可以促进与纤维相关的代谢综合征预防。在这里，我们表明，膳食SCFAs诱导过氧化物酶体增殖物激活受体（PPAR）依赖开关从脂质合成利用。膳食SCFA补充剂通过降低PPAR表达和活性预防和逆转高脂饮食诱导的小鼠代谢异常。这增加了线粒体解偶联蛋白2的表达，并提高了AMP与ATP的比率，从而通过AMPK刺激肝脏和脂肪组织的氧化代谢。脂肪特异性破坏PPAR的小鼠中不存在SCFA诱导的体重减轻和胰岛素敏感性刺激。同样，SCFA诱导的肝脏脂肪变性减少在缺乏肝脏PPAR的小鼠中不存在。这些结果表明，脂肪和肝脏的过氧化物酶体增殖物激活受体是关键介质的有益效果的SCFAs对代谢综合征，具有明显不同的和互补的作用。我们的研究结果表明，SCFAs可能在治疗上用作廉价和选择性的PPAR调节剂。
Short-chain fatty acids (SCFAs) are the main products of dietary fiber fermentation and are believed to drive the fiber-related prevention of the metabolic syndrome. Here we show that dietary SCFAs induce a peroxisome proliferator-activated receptor- (PPAR)-dependent switch from lipid synthesis to utilization. Dietary SCFA supplementation prevented and reversed high-fat diet-induced metabolic abnormalities in mice by decreasing PPAR expression and activity. This increased the expression of mitochondrial uncoupling protein 2 and raised the AMP-to-ATP ratio, thereby stimulating oxidative metabolism in liver and adipose tissue via AMPK. The SCFA-induced reduction in body weight and stimulation of insulin sensitivity were absent in mice with adipose-specific disruption of PPAR. Similarly, SCFA-induced reduction of hepatic steatosis was absent in mice lacking hepatic PPAR. These results demonstrate that adipose and hepatic PPAR are critical mediators of the beneficial effects of SCFAs on the metabolic syndrome, with clearly distinct and complementary roles. Our findings indicate that SCFAs may be used therapeutically as cheap and selective PPAR modulators.