生物谷報道：肥胖的根源在于能源攝入過多,，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，如果有一天人類能自由控制食欲的話,，也就有可能控制肥胖,。美國Johns Hopkins大學(xué)醫(yī)學(xué)院科學(xué)家發(fā)現(xiàn)控制食欲的根本機制，這一原創(chuàng)性文章將在12月21日出版的PNAS上,。
人類食欲的控制中心在下丘腦,，但是下丘腦是如何控制食欲的仍存在爭議,，先前的研究發(fā)現(xiàn)，許多神經(jīng)肽在其中都發(fā)揮著重要作用,，如NPY,，leptin，但這些因子如何相互作用,，并最終形成控制食欲的網(wǎng)絡(luò)中心,，仍不清楚。先前發(fā)現(xiàn)下丘腦中的malonyl-CoA 可能是所有因子的平衡中心,，在控制能量攝入和代謝中起到核心作用,，但是何種因素調(diào)節(jié)它，缺乏研究（生物谷注：包括NPY,，leptin等被確認與食欲直接相關(guān)的因子的信號通路都未徹底闡明）,。這一研究成果表明中樞神經(jīng)系統(tǒng)中的葡萄糖的水平和leptin的水平共同調(diào)節(jié)了下丘腦malonyl-CoA表達，如果僅其中之一,，并不能良好地發(fā)揮作用,。
生物谷專家認為，肥胖的根本機制還遠比這復(fù)雜,，它是外周與中樞系統(tǒng)共同調(diào)節(jié)的結(jié)果,，是很多信號通路共同綜合的。如外周可以由脂肪細胞釋放TNF,，leptin等因子,，當(dāng)脂肪細胞過多時，釋放這些因子自然上升,，這些因子進一步進入中樞,，促進中樞神經(jīng)系統(tǒng)中某些信號啟動，降低食欲,，從而抑制能量的攝入,，減輕脂肪的含量，這是動態(tài)平衡的結(jié)果,。但是外界環(huán)境因素,，或體內(nèi)穩(wěn)態(tài)被打破了，使這一調(diào)控環(huán)路無法正常運轉(zhuǎn),，自然會導(dǎo)致肥胖的發(fā)生,。肥胖是綜合因素的結(jié)果，而不僅僅是一兩個基因決定的,。
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.
原始出處：
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 )
