Williams G, Harrold J A, Cutler D J
Department of Medicine, The University of Liverpool, UK.
Proc Nutr Soc. 2000 Aug;59(3):385-96. doi: 10.1017/s0029665100000434.
The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of 'feeding' and 'satiety' centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY 'feeding' receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as alpha-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as 'agouti' protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.
下丘脑是许多控制能量平衡和体重的外周信号及神经通路的焦点。研究重点已从“进食”和“饱腹感”中枢的解剖学概念，转向调节进食行为和能量消耗的特定神经递质。我们选择了三个例子来说明下丘脑神经递质的生理作用及其作为开发治疗肥胖和其他营养紊乱新药靶点的潜力。神经肽Y（NPY）由下丘脑弓状核（ARC）的神经元表达，这些神经元投射到包括室旁核（PVN）在内的重要食欲调节核团。注入PVN的NPY是已知最有效的中枢食欲刺激剂，还能抑制产热；反复给药会迅速导致肥胖。ARC的NPY神经元受饥饿刺激，可能由循环中瘦素和胰岛素水平下降介导（二者均抑制这些神经元），并在这种及其他能量缺乏状态下导致饥饿感增加。因此，它们通过稳态作用来纠正负能量平衡。ARC的NPY神经元还介导ob/ob和db/db小鼠以及fa/fa大鼠的食欲亢进和肥胖，在这些动物中，由于影响瘦素或其受体的突变，瘦素抑制作用丧失。Y5受体拮抗剂（目前被认为是NPY的“进食”受体）具有抗肥胖作用。黑皮质素-4受体（MC4-R）在下丘脑的各个区域表达，包括腹内侧核和ARC。α-黑素细胞刺激素（阿黑皮素原的一种裂解产物，在ARC神经元中表达）等激动剂激活MC4-R会抑制进食并导致体重减轻。相反，“刺鼠”蛋白和刺鼠基因相关肽（AGRP）等MC4-R拮抗剂会刺激进食并导致肥胖。刺鼠蛋白在下丘脑的异位表达会导致AVY小鼠肥胖，而AGRP与ARC中的NPY神经元共同表达。合成的MC4-R激动剂最终可能会在人类受试者中用作抗肥胖药物。食欲素A和B源自前食欲素原，在下丘脑外侧区（LHA）的特定神经元中表达。中枢注射食欲素A会刺激进食，前食欲素原mRNA受禁食和低血糖上调。LHA在接收来自肠道和肝脏的感觉信号以及感知葡萄糖方面很重要，食欲素神经元可能参与因血浆葡萄糖下降而刺激进食。
