Unger R H, Zhou Y T
Department of Internal Medicine, Gifford Laboratories, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75390-8854, USA.
Diabetes. 2001 Feb;50 Suppl 1:S118-21. doi: 10.2337/diabetes.50.2007.s118.
A recently identified function of leptin is to protect nonadipose tissues from the nonoxidative metabolic products of long-chain fatty acids (FAs) during periods of overnutrition by increasing the beta-oxidative metabolism of surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as ceramide increase in nonadipose tissues, including the pancreatic islets and heart, and cause nitric oxide-mediated lipotoxicity and lipoapoptosis. The triacylglycerol content in nonadipocytes provides a useful index of overall nonoxidative metabolism. In normal animal tissue, triacylglycerol is maintained within a narrow range; even when the caloric intake is excessive, compensatory FA-induced upregulation of oxidation prevents overaccumulation. However, if leptin is deficient or if leptin receptors (Ob-R) are nonfunctional, this autoregulatory system does not operate, and triacylglycerol content rises in nonadipose tissues. This provides a source of excess FAs that enter potentially toxic pathways of nonoxidative metabolism leading to apoptosis of certain tissues. FA overload in skeletal muscle causes insulin resistance; in myocardium, it impairs cardiac function; and in pancreatic islets, it causes beta-cell dysfunction, apoptosis, and diabetes. All abnormalities in these tissues can be blocked by troglitazone, an inhibitor of FA accumulation.
瘦素最近被发现的一个功能是，在营养过剩期间，通过增加多余脂肪酸（FAs）的β-氧化代谢并减少脂肪生成，来保护非脂肪组织免受长链脂肪酸的非氧化代谢产物的影响。当这个保护系统失效时，非氧化代谢的有害产物如神经酰胺会在包括胰岛和心脏在内的非脂肪组织中增加，并导致一氧化氮介导的脂毒性和脂肪凋亡。非脂肪细胞中的三酰甘油含量提供了一个整体非氧化代谢的有用指标。在正常动物组织中，三酰甘油维持在一个狭窄的范围内；即使热量摄入过多，脂肪酸诱导的氧化代偿性上调也能防止过度积累。然而，如果瘦素缺乏或瘦素受体（Ob-R）无功能，这种自动调节系统就不会起作用，非脂肪组织中的三酰甘油含量就会升高。这就提供了过量脂肪酸的来源，这些脂肪酸进入潜在的非氧化代谢毒性途径，导致某些组织的凋亡。骨骼肌中的脂肪酸过载会导致胰岛素抵抗；在心肌中，它会损害心脏功能；在胰岛中，它会导致β细胞功能障碍、凋亡和糖尿病。这些组织中的所有异常都可以被曲格列酮（一种脂肪酸积累抑制剂）阻断。
