The central melanocortin system directly controls peripheral lipid metabolism
The central melanocortin system directly controls peripheral lipid metabolism
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DOI：
10.1172/jci31743
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Tschoep, Matthias H.
中科院分区：
文献类型：
--
作者：
Nogueiras, Ruben;Wiedmer, Petra;Tschoep, Matthias H.
黑皮质素信号系统的破坏与肥胖有关。我们研究了中枢神经黑皮质素系统（CNS-Mcr）在控制肥胖中的可能作用，通过影响营养分配和细胞脂质代谢，而不依赖于营养摄入。我们报告说，大鼠黑皮质素受体（Mcr）的药理学抑制和小鼠Mc 4 r的遗传破坏直接和有效地促进脂质摄取，甘油三酯合成和脂肪蓄积在白色脂肪组织（WAT），而增加CNS-Mcr信号引发脂质动员。这些影响与食物摄入无关，并且先于肥胖的变化。此外，降低CNS-Mcr信号促进WAT中胰岛素敏感性和葡萄糖摄取增加，同时降低肌肉和棕色脂肪组织中的葡萄糖利用。这种中枢神经系统对外周营养分配的控制依赖于交感神经系统功能，并通过对肝脏甘油三酯合成的协同作用而增强。我们的研究结果提供了一个解释，增加肥胖导致黑皮质素信号减少，即使在没有摄食过多，并与喂养无关的底物利用率的变化，反映了呼吸商，这是增加与慢性Mcr阻滞在啮齿动物和人类MC 4 R功能丧失突变。我们还揭示了CNS-Mcr直接控制脂质代谢的分子基础。这些结果提示了设计更有效的控制肥胖的药理学方法的方法。
Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.