Thomas S A, Palmiter R D
Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle 98195-7370, USA.
Nature. 1997 May 1;387(6628):94-7. doi: 10.1038/387094a0.
Adrenaline and noradrenaline, the main effectors of the sympathetic nervous system and adrenal medulla, respectively, are thought to control adiposity and energy balance through several mechanisms. They promote catabolism of triglycerides and glycogen, stimulate food intake when injected into the central nervous system, activate thermogenesis in brown adipose tissue, and regulate heat loss through modulation of peripheral vasoconstriction and piloerection. Thermogenesis in brown adipose tissue occurs in response to cold and overeating (diet induced), and there is an inverse relationship between diet-induced thermogenesis and obesity both in humans and in animal models. As a potential model for obesity, we generated mice that cannot synthesize noradrenaline or adrenaline by inactivating the gene that encodes dopamine beta-hydroxylase. These mice are cold intolerant because they have impaired peripheral vasoconstriction and are unable to induce thermogenesis in brown adipose tissue through uncoupling protein (UCP1). The mutants have increased food intake but do not become obese because their basal metabolic rate is also elevated. The unexpected increase in basal metabolic rate is not due to hyperthyroidism, compensation by the widely expressed uncoupling protein UCP2, or shivering.
肾上腺素和去甲肾上腺素分别是交感神经系统和肾上腺髓质的主要效应器，它们被认为通过多种机制控制肥胖和能量平衡。它们促进甘油三酯和糖原的分解代谢，注入中枢神经系统时刺激食物摄入，激活棕色脂肪组织中的产热作用，并通过调节外周血管收缩和竖毛来调节热量散失。棕色脂肪组织中的产热作用是对寒冷和暴饮暴食（饮食诱导）的反应，在人类和动物模型中，饮食诱导的产热作用与肥胖之间存在负相关。作为肥胖的潜在模型，我们通过使编码多巴胺β-羟化酶的基因失活，培育出了无法合成去甲肾上腺素或肾上腺素的小鼠。这些小鼠不耐寒，因为它们的外周血管收缩受损，并且无法通过解偶联蛋白（UCP1）在棕色脂肪组织中诱导产热。这些突变体的食物摄入量增加，但不会变得肥胖，因为它们的基础代谢率也升高了。基础代谢率的意外升高并非由于甲状腺功能亢进、广泛表达的解偶联蛋白UCP2的代偿作用或颤抖。
