Gremlich Sandrine, Nolan Christopher, Roduit Raphaël, Burcelin Rémy, Peyot Marie-Line, Delghingaro-Augusto Viviane, Desvergne Béatrice, Michalik Liliane, Prentki Marc, Wahli Walter
Center for Integrative Genomics, University of Lausanne, Switzerland.
Endocrinology. 2005 Jan;146(1):375-82. doi: 10.1210/en.2004-0667. Epub 2004 Sep 30.
The cellular response to fasting and starvation in tissues such as heart, skeletal muscle, and liver requires peroxisome proliferator-activated receptor-alpha (PPARalpha)-dependent up-regulation of energy metabolism toward fatty acid oxidation (FAO). PPARalpha null (PPARalphaKO) mice develop hyperinsulinemic hypoglycemia in the fasting state, and we previously showed that PPARalpha expression is increased in islets at low glucose. On this basis, we hypothesized that enhanced PPARalpha expression and FAO, via depletion of lipid-signaling molecule(s) for insulin exocytosis, are also involved in the normal adaptive response of the islet to fasting. Fasted PPARalphaKO mice compared with wild-type mice had supranormal ip glucose tolerance due to increased plasma insulin levels. Isolated islets from the PPARalpha null mice had a 44% reduction in FAO, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion. In normal rats, fasting for 24 h increased islet PPARalpha, carnitine palmitoyltransferase 1, and uncoupling protein-2 mRNA expression by 60%, 62%, and 82%, respectively. The data are consistent with the view that PPARalpha, via transcriptionally up-regulating islet FAO, can reduce insulin secretion, and that this mechanism is involved in the normal physiological response of the pancreatic islet to fasting such that hypoglycemia is avoided.
心脏、骨骼肌和肝脏等组织对禁食和饥饿的细胞反应需要过氧化物酶体增殖物激活受体α（PPARα）依赖性上调能量代谢以促进脂肪酸氧化（FAO）。PPARα基因敲除（PPARαKO）小鼠在禁食状态下会出现高胰岛素血症性低血糖，我们之前发现低葡萄糖水平时胰岛中PPARα的表达会增加。在此基础上，我们推测，通过消耗用于胰岛素胞吐的脂质信号分子，增强的PPARα表达和FAO也参与胰岛对禁食的正常适应性反应。与野生型小鼠相比，禁食的PPARαKO小鼠由于血浆胰岛素水平升高而具有超常的腹腔注射葡萄糖耐量。来自PPARα基因敲除小鼠的分离胰岛的FAO减少了44%，葡萄糖利用和氧化正常，且葡萄糖诱导的胰岛素分泌增强。在正常大鼠中，禁食24小时分别使胰岛PPARα、肉碱棕榈酰转移酶1和解偶联蛋白2的mRNA表达增加了60%、62%和82%。这些数据与以下观点一致：PPARα通过转录上调胰岛FAO可减少胰岛素分泌，且该机制参与胰岛对禁食的正常生理反应，从而避免低血糖。
