Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.
Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.
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DOI：
10.1371/journal.pbio.1001485
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发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Langin D
中科院分区：
文献类型：
--
作者：
Girousse A;Tavernier G;Valle C;Moro C;Mejhert N;Dinel AL;Houssier M;Roussel B;Besse-Patin A;Combes M;Mir L;Monbrun L;Bézaire V;Prunet-Marcassus B;Waget A;Vila I;Caspar-Bauguil S;Louche K;Marques MA;Mairal A;Renoud ML;Galitzky J;Holm C;Mouisel E;Thalamas C;Viguerie N;Sulpice T;Burcelin R;Arner P;Langin D
部分抑制脂肪组织脂解不会增加脂肪量，而是通过调节脂肪酸周转和诱导脂肪细胞从头脂肪生成来改善葡萄糖代谢和胰岛素敏感性。当需要能量时，白色脂肪组织（WAT）通过刺激脂肪细胞脂解作用提供脂肪酸（FA）供外周组织使用。据推测，FA 在肥胖引起的胰岛素抵抗（糖尿病和心血管疾病的主要危险因素）的发展中发挥着关键作用。然而，长期抑制 WAT 的脂肪动员是否以及如何调节胰岛素敏感性仍不清楚。激素敏感脂肪酶 (HSL) 参与 WAT 三酰甘油分解为 FA。 HSL 单倍体不足和 HSL 抑制剂治疗可改善高脂饮食小鼠的胰岛素耐受性，而不影响体重、脂肪量和 WAT 炎症。体内棕榈酸酯周转分析表明，脂肪分解能力减弱与肥胖 HSL 单倍体不足小鼠外周组织中 FA 摄取和储存的减少有关。 FA 周转的减少伴随着葡萄糖代谢的改善，呼吸商的变化，WAT 和骨骼肌中葡萄糖摄取的增加，以及肝脏中从头脂肪生成和胰岛素信号传导的增强。在人类脂肪细胞中，HSL 基因沉默可改善胰岛素刺激的葡萄糖摄取，从而增加从头脂肪生成并激活同源基因表达。临床研究中，WAT脂肪分解率分别与胰岛素抵抗指标和WAT从头脂肪生成基因表达量呈正相关和负相关。在肥胖个体中，长期抑制脂肪分解会导致 WAT 从头脂肪生成基因表达的诱导。因此，WAT 脂肪分解的减少可以在不增加脂肪量的情况下重塑 FA 通量，并通过细胞自主诱导脂肪细胞从头脂肪生成来改善葡萄糖代谢，这有助于改善胰岛素敏感性。在能量需求时期，哺乳动物体内脂肪储存的动员（即脂肪组织脂解）对于以脂肪酸形式提供能量至关重要。然而，过量的脂肪酸会诱导对胰岛素作用的抵抗，胰岛素的作用是调节骨骼肌和肝脏的葡萄糖代谢。胰岛素抵抗（或低胰岛素敏感性）被认为是 2 型糖尿病和心血管疾病等肥胖并发症的基石。在这项研究中，我们对个体脂肪细胞脂肪分解自然变化的临床观察表明，高脂肪分解率与低胰岛素敏感性相关。此外，对激素敏感性脂肪酶（参与白色脂肪组织脂质分解的酶之一）的部分遗传和药理抑制可改善小鼠的胰岛素敏感性，而不会增加体重和脂肪量。我们在小鼠和人类脂肪细胞中进行了一系列机制研究，结果表明，脂肪分解能力减弱会增加脂肪细胞中葡萄糖合成新脂肪酸的能力，这一途径最近被其他人证明是全身胰岛素敏感性的主要决定因素。总之，部分抑制脂肪组织脂解是治疗肥胖相关胰岛素抵抗的一种可行策略。
Partial inhibition of adipose tissue lipolysis does not increase fat mass but improves glucose metabolism and insulin sensitivity through modulation of fatty acid turnover and induction of fat cell de novo lipogenesis. When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity. In periods of energy demand, mobilization of fat stores in mammals (i.e., adipose tissue lipolysis) is essential to provide energy in the form of fatty acids. In excess, however, fatty acids induce resistance to the action of insulin, which serves to regulate glucose metabolism in skeletal muscle and liver. Insulin resistance (or low insulin sensitivity) is believed to be a cornerstone of the complications of obesity such as type 2 diabetes and cardiovascular diseases. In this study, our clinical observation of natural variation in fat cell lipolysis in individuals reveals that a high lipolytic rate is associated with low insulin sensitivity. Furthermore, partial genetic and pharmacologic inhibition of hormone-sensitive lipase, one of the enzymes involved in the breakdown of white adipose tissue lipids, results in improvement of insulin sensitivity in mice without gain in body weight and fat mass. We undertake a series of mechanistic studies in mice and in human fat cells to show that blunted lipolytic capacity increases the synthesis of new fatty acids from glucose in fat cells, a pathway that has recently been shown by others to be a major determinant of whole body insulin sensitivity. In conclusion, partial inhibition of adipose tissue lipolysis is a plausible strategy in the treatment of obesity-related insulin resistance.
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影响因子：
4.8
作者：
Kienesberger, Petra C.;Lee, Daeho;Kershaw, Erin E.
通讯作者：
Kershaw, Erin E.
DOI：
10.1152/ajpendo.00259.2003
发表时间：
2003-12-01
影响因子：
5.1
作者：
Harada, K;Shen, WJ;Kraemer, FB
通讯作者：
Kraemer, FB
脂肪组织 microRNA 作为人类肥胖中 CCL2 产生的调节因子。
影响因子：
7.7
作者：
Arner E;Mejhert N;Kulyté A;Balwierz PJ;Pachkov M;Cormont M;Lorente-Cebrián S;Ehrlund A;Laurencikiene J;Hedén P;Dahlman-Wright K;Tanti JF;Hayashizaki Y;Rydén M;Dahlman I;van Nimwegen E;Daub CO;Arner P
通讯作者：
Arner P
影响因子：
7.7
作者：
BOLINDER, J;OSTMAN, J;ARNER, P
通讯作者：
ARNER, P
影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
通讯作者：
Zechner, R