Havel P J
Department of Nutrition, University of California, Davis 95616, USA.
Proc Nutr Soc. 2000 Aug;59(3):359-71. doi: 10.1017/s0029665100000410.
Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor alpha, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based on in vitro studies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity.
脂肪组织具有复杂的代谢和内分泌功能。脂肪组织产生的内分泌产物包括肿瘤坏死因子α、白细胞介素6、酰化刺激蛋白和瘦素。本综述将主要关注调节瘦素产生和作用的机制，以及这种调节在能量平衡控制中的意义。瘦素在中枢神经系统中起作用，它与许多下丘脑神经肽系统相互作用，以调节摄食行为和能量消耗。瘦素基因或瘦素受体发生突变的动物和人类受试者出现极度肥胖，这表明正常的瘦素产生和作用对于维持能量平衡至关重要。胰岛素是脂肪组织产生瘦素的主要调节因子。给人类受试者输注胰岛素会增加循环中的瘦素浓度。胰岛素缺乏的糖尿病啮齿动物血浆瘦素水平明显降低，而低瘦素水平会导致糖尿病性多食。基于体外研究，胰岛素刺激瘦素产生的作用似乎涉及葡萄糖代谢增加。阻断葡萄糖转运或糖酵解会抑制分离的脂肪细胞中瘦素的表达和分泌。有证据表明，葡萄糖无氧代谢生成乳酸不会刺激瘦素产生。脂肪组织中胰岛素介导的葡萄糖代谢改变可能介导能量限制降低循环瘦素水平以及再喂养增加循环瘦素水平的作用。葡萄糖代谢的变化也可能解释了以下观察结果：相对于高碳水化合物餐，高脂肪餐会降低人类受试者24小时循环瘦素水平，这表明一种可能导致高脂肪饮食促进能量摄入增加、体重增加和肥胖的机制。在能量限制期间观察到的循环瘦素降低与人类受试者饥饿感增加有关。因此，在能量限制的减肥方案中瘦素的降低可能导致体重强烈的反弹倾向。更好地理解调节瘦素产生和作用的精确机制可能会带来治疗肥胖的新方法。
