A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain
A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain
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DOI：
10.1152/ajpendo.00361.2010
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发表时间：
2010-11-01
影响因子：
5.1
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Jornayvaz, Francois R.;Jurczak, Michael J.;Shulman, Gerald I.
Jornayvaz FR，Jurczak MJ，Lee HY，Birkenfeld AL，Frederick DW，Zhang D，Zhang X，Samuel VT，Shulman GI。高脂肪、生酮饮食会导致小鼠肝脏胰岛素抵抗，尽管会增加能量消耗并防止体重增加。Am J生理学内分泌代谢酶299：E808-E815,2010。2010年8月31日首次出版；DOI：10.1152/ajpendo.00361.2010。-低碳水化合物、高脂肪生酮饮食(KD)被认为比传统的热量限制更有效地促进减肥，但它们对肝脏葡萄糖和脂肪代谢的影响以及它们可能促进减肥的机制仍存在争议。本研究的目的是探讨KD对肝脏和肌肉胰岛素敏感性、肝脏脂肪代谢、能量消耗和食物摄入量的影响。使用高胰岛素-正常血糖钳夹，我们研究了喂食KD或普通食物(RC)的小鼠的胰岛素作用。用H-1磁共振波谱测定体成分。尽管由于能量消耗增加了17%(P<；0.001)，KD喂养的小鼠比RC喂养的小鼠轻了15%(P<；0.001)，但KD喂养的小鼠表现出严重的肝脏胰岛素抵抗，反映在钳夹期间内源性葡萄糖产生的抑制减少(0%比RC喂养的小鼠的100%，P<；0.001)。肝脏胰岛素抵抗可归因于肝脏二酰甘油含量增加350%(P<；0.001)，导致PKC epsilon激活增加(P<；0.05)，胰岛素受体底物-2酪氨酸磷酸化降低(P<；0.01)。KD喂养的小鼠的食物摄入量减少了56%(P<；0.001)，尽管热量摄入相似，部分原因是血浆N-酰基磷脂酰乙醇胺浓度增加了三倍以上(P<；0.05)。总而言之，尽管KD可以防止小鼠体重增加，但由于肝脏二甘油含量增加，KD会导致肝脏胰岛素抵抗。考虑到非酒精性脂肪性肝病在2型糖尿病发展中的关键作用，以及KD在肥胖治疗中的广泛使用，这些结果可能具有潜在的重要临床意义。
Jornayvaz FR, Jurczak MJ, Lee HY, Birkenfeld AL, Frederick DW, Zhang D, Zhang X, Samuel VT, Shulman GI. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Am J Physiol Endocrinol Metab 299: E808-E815, 2010. First published August 31, 2010; doi: 10.1152/ajpendo.00361.2010.-Low-carbohydrate, high-fat ketogenic diets (KD) have been suggested to be more effective in promoting weight loss than conventional caloric restriction, whereas their effect on hepatic glucose and lipid metabolism and the mechanisms by which they may promote weight loss remain controversial. The aim of this study was to explore the role of KD on liver and muscle insulin sensitivity, hepatic lipid metabolism, energy expenditure, and food intake. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in mice fed a KD or regular chow (RC). Body composition was assessed by H-1 magnetic resonance spectroscopy. Despite being 15% lighter (P < 0.001) than RC-fed mice because of a 17% increase in energy expenditure (P < 0.001), KD-fed mice manifested severe hepatic insulin resistance, as reflected by decreased suppression (0% vs. 100% in RC-fed mice, P < 0.01) of endogenous glucose production during the clamp. Hepatic insulin resistance could be attributed to a 350% increase in hepatic diacylglycerol content (P < 0.001), resulting in increased activation of PKC epsilon (P < 0.05) and decreased insulin receptor substrate-2 tyrosine phosphorylation (P < 0.01). Food intake was 56% (P < 0.001) lower in KD-fed mice, despite similar caloric intake, and could partly be attributed to a more than threefold increase (P < 0.05) in plasma N-acylphosphatidylethanolamine concentrations. In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications.