生物谷报道：肥胖的根源在于能源摄入过多，但是什么因素使人“吃”得更多？良好的食欲可能是更根本的原因，如果有一天人类能自由控制食欲的话，也就有可能控制肥胖。美国Johns Hopkins大学医学院科学家发现控制食欲的根本机制，这一原创性文章将在12月21日出版的PNAS上。
人类食欲的控制中心在下丘脑，但是下丘脑是如何控制食欲的仍存在争议，先前的研究发现，许多神经肽在其中都发挥着重要作用，如NPY，leptin，但这些因子如何相互作用，并最终形成控制食欲的网络中心，仍不清楚。先前发现下丘脑中的malonyl-CoA 可能是所有因子的平衡中心，在控制能量摄入和代谢中起到核心作用，但是何种因素调节它，缺乏研究（生物谷注：包括NPY，leptin等被确认与食欲直接相关的因子的信号通路都未彻底阐明）。这一研究成果表明中枢神经系统中的葡萄糖的水平和leptin的水平共同调节了下丘脑malonyl-CoA表达，如果仅其中之一，并不能良好地发挥作用。
生物谷专家认为，肥胖的根本机制还远比这复杂，它是外周与中枢系统共同调节的结果，是很多信号通路共同综合的。如外周可以由脂肪细胞释放TNF，leptin等因子，当脂肪细胞过多时，释放这些因子自然上升，这些因子进一步进入中枢，促进中枢神经系统中某些信号启动，降低食欲，从而抑制能量的摄入，减轻脂肪的含量，这是动态平衡的结果。但是外界环境因素，或体内稳态被打破了，使这一调控环路无法正常运转，自然会导致肥胖的发生。肥胖是综合因素的结果，而不仅仅是一两个基因决定的。
Hypothalamic malonyl-CoA has been shown to function in global energy homeostasis by modulating food intake and energy expenditure. Little is known, however, about the regulation of malonyl-CoA concentration in the central nervous system. To address this issue we investigated the response of putative intermediates in the malonyl-CoA pathway to metabolic and endocrine cues, notably those provoked by glucose and leptin. Hypothalamic malonyl-CoA rises in proportion to the carbohydrate content of the diet consumed after food deprivation. Malonyl-CoA concentration peaks 1 h after refeeding or after peripheral glucose administration. This response depends on the dose of glucose administered and is blocked by the i.c.v. administration of an inhibitor of glucose metabolism, 2-deoxyglucose (2-DG). The kinetics of change in hypothalamic malonyl-CoA after glucose administration is coincident with the suppression of phosphorylation of AMP kinase and acetyl-CoA carboxylase. Blockade of glucose utilization in the CNS by i.c.v. 2-DG prevented the effects of glucose on 5'AMP-activated protein kinase, malonyl-CoA, hypothalamic neuropeptide expression, and food intake. Finally, we showed that leptin can increase hypothalamic malonyl-CoA and that the increase is additive with glucose administration. Leptin-deficient ob/ob mice, however, showed no defect in the glucose- or refeeding-induced rise in hypothalamic malonyl-CoA after food deprivation, demonstrating that leptin was not required for this effect. These studies show that hypothalamic malonyl-CoA responds to the level of circulating glucose and leptin, both of which affect energy homeostasis.
原始出处：
Michael J. Wolfgang, Seung Hun Cha, Aniket Sidhaye, Shigeru Chohnan, Gary Cline, Gerald I. Shulman, and M. Daniel Lane . Regulation of hypothalamic malonyl-CoA by central glucose and leptin
PNAS published November 21, 2007, 10.1073/pnas.0709778104 ( Biochemistry )
