Department of Pediatrics, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Regul Integr Comp Physiol. 2011 Jul;301(1):R209-17. doi: 10.1152/ajpregu.00092.2011. Epub 2011 Apr 20.
Hypothalamic fatty acid metabolism is involved in central nervous system controls of feeding and energy balance. Malonyl-CoA, an intermediate of fatty acid biosynthesis, is emerging as a significant player in these processes. Notably, hypothalamic malonyl-CoA has been implicated in leptin's feeding effect. Leptin treatment increases malonyl-CoA level in the hypothalamic arcuate nucleus (Arc), and this increase is required for leptin-induced decrease in food intake. However, the intracellular downstream mediators of malonyl-CoA's feeding effect have not been identified. A primary biochemical action of malonyl-CoA is the inhibition of the acyltransferase activity of carnitine palmitoyltransferase-1 (CPT-1). In the hypothalamus, the predominant isoform of CPT-1 that possesses the acyltransferase activity is CPT-1 liver type (CPT-1a). To address the role of CPT-1a in malonyl-CoA's anorectic action, we used a recombinant adenovirus expressing a mutant CPT-1a that is insensitive to malonyl-CoA inhibition. We show that Arc overexpression of the mutant CPT-1a blocked the malonyl-CoA-mediated inhibition of CPT-1 activity. However, the overexpression of this mutant did not affect the anorectic actions of leptin or central cerulenin for which an increase in Arc malonyl-CoA level is also required. Thus, CPT-1a does not appear to be involved in the malonyl-CoA's anorectic actions induced by leptin. Furthermore, long-chain fatty acyl-CoAs, substrates of CPT-1a, dissociate from malonyl-CoA's actions in the Arc under different feeding states. Together, our results suggest that Arc intracellular mechanisms of malonyl-CoA's anorectic actions induced by leptin are independent of CPT-1a. The data suggest that target(s), rather than CPT-1a, mediates malonyl-CoA action on feeding.
下丘脑的脂肪酸代谢参与了中枢神经系统对摄食和能量平衡的控制。丙二酰辅酶 A（malonyl-CoA）是脂肪酸生物合成的中间产物，它作为这些过程中的一个重要参与者而崭露头角。值得注意的是，下丘脑丙二酰辅酶 A 与瘦素的摄食作用有关。瘦素处理会增加下丘脑弓状核（Arc）中的丙二酰辅酶 A 水平，而这种增加是瘦素诱导摄食量减少所必需的。然而，丙二酰辅酶 A 的摄食作用的细胞内下游介质尚未确定。丙二酰辅酶 A 的主要生化作用是抑制肉碱棕榈酰转移酶-1（CPT-1）的酰基转移酶活性。在下丘脑中，具有酰基转移酶活性的 CPT-1 的主要同工型是 CPT-1 肝型（CPT-1a）。为了研究 CPT-1a 在丙二酰辅酶 A 的厌食作用中的作用，我们使用表达对丙二酰辅酶 A 抑制不敏感的突变 CPT-1a 的重组腺病毒。我们发现，Arc 过表达突变的 CPT-1a 阻断了丙二酰辅酶 A 介导的 CPT-1 活性抑制。然而，这种突变体的过表达并不影响瘦素或中枢苍术苷的厌食作用，这两种物质的作用也需要增加 Arc 丙二酰辅酶 A 水平。因此，CPT-1a 似乎不参与瘦素诱导的丙二酰辅酶 A 的厌食作用。此外，长链脂肪酸酰基辅酶 A（CPT-1a 的底物）在下丘脑中与丙二酰辅酶 A 的作用在不同的进食状态下分离。总之，我们的结果表明，Arc 内丙二酰辅酶 A 诱导瘦素的厌食作用的细胞内机制独立于 CPT-1a。数据表明，靶点而不是 CPT-1a 介导丙二酰辅酶 A 对摄食的作用。
