Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia; Department of Physiology, Monash University, Clayton 3800, VIC, Australia.
Université of Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionelle et Adaptative, CNRS UMR 8251, 75205 Paris, France.
Cell Rep. 2018 Feb 13;22(7):1745-1759. doi: 10.1016/j.celrep.2018.01.067.
AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver. Crat deletion in AgRP neurons increased peripheral fatty acid substrate utilization and attenuated the switch to glucose utilization after refeeding, indicating altered nutrient partitioning. Proteomic analysis in AgRP neurons shows that Crat regulates protein acetylation and metabolic processing. Collectively, our studies highlight that AgRP neurons require Crat to provide the metabolic flexibility to optimize nutrient partitioning and regulate peripheral substrate utilization, particularly during fasting and refeeding.
AgRP 神经元在能量亏空和营养补充条件下控制外周底物利用和营养分配，但其分子机制尚不清楚。我们研究了 AgRP 神经元中的肉毒碱乙酰转移酶 (Crat) 是否影响外周营养分配。AgRP 神经元中的 Crat 缺失减少了食物摄入和摄食行为，并在禁食期间增加了甘油向肝脏的供应，作为糖异生底物，这是通过改变交感神经输出和肝脏外周脂肪酸代谢来介导的。AgRP 神经元中的 Crat 缺失增加了外周脂肪酸底物的利用，并减弱了再喂养后葡萄糖利用的转变，表明营养分配发生了改变。AgRP 神经元中的蛋白质组学分析表明，Crat 调节蛋白质乙酰化和代谢加工。总的来说，我们的研究强调，AgRP 神经元需要 Crat 提供代谢灵活性，以优化营养分配和调节外周底物利用，特别是在禁食和再喂养期间。
