Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
FEBS J. 2011 Feb;278(4):552-8. doi: 10.1111/j.1742-4658.2010.07978.x. Epub 2010 Dec 30.
Metabolic integration of nutrient sensing in the central nervous system has been shown to be an important regulator of adiposity by affecting food intake and peripheral energy expenditure. Modulation of de novo fatty acid synthetic flux by cytokines and nutrient availability plays an important role in this process. Inhibition of hypothalamic fatty acid synthase by pharmacologic or genetic means leads to an increased malonyl-CoA level and suppression of food intake and adiposity. Conversely, the ectopic expression of malonyl-CoA decarboxylase in the hypothalamus is sufficient to promote feeding and adiposity. Based on these and other findings, metabolic intermediates in fatty acid biogenesis, including malonyl-CoA and long-chain acyl-CoAs, have been implicated as signaling mediators in the central control of body weight. Malonyl-CoA has been hypothesized to mediate its effects in part through an allosteric interaction with an atypical and brain-specific carnitine palmitoyltransferase-1 (CPT1c). CPT1c is expressed in neurons and binds malonyl-CoA, however, it does not perform the same biochemical function as the prototypical CPT1 enzymes. Mouse knockout models of CPT1c exhibit suppressed food intake and smaller body weight, but are highly susceptible to weight gain when fed a high-fat diet. Thus, the brain can directly sense and respond to changes in nutrient availability and composition to affect body weight and adiposity.
营养感应在中枢神经系统中的代谢整合已被证明是影响食物摄入和外周能量消耗的肥胖重要调节剂。细胞因子和营养可用性对从头脂肪酸合成通量的调节在此过程中起着重要作用。通过药理学或遗传学手段抑制脂肪酸合酶会导致丙二酰辅酶 A 水平升高，并抑制食物摄入和肥胖。相反，在脑下丘脑中异位表达丙二酰辅酶 A 脱羧酶足以促进进食和肥胖。基于这些和其他发现，脂肪酸生物合成中的代谢中间产物，包括丙二酰辅酶 A 和长链酰基辅酶 A，已被认为是体重中枢控制的信号介质。丙二酰辅酶 A 被假设通过与非典型和脑特异性肉毒碱棕榈酰基转移酶-1（CPT1c）的变构相互作用部分介导其作用。CPT1c 在神经元中表达并结合丙二酰辅酶 A，但它不执行与典型 CPT1 酶相同的生化功能。CPT1c 的小鼠敲除模型表现出食物摄入减少和体重减轻，但在喂食高脂肪饮食时极易增重。因此，大脑可以直接感知和响应营养可用性和组成的变化，从而影响体重和肥胖。
