Université de Paris, BFA, UMR 8251, CNRS, F-75014 Paris, France; Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Neuherberg, Germany.
Université de Paris, BFA, UMR 8251, CNRS, F-75014 Paris, France.
Cell Metab. 2020 Apr 7;31(4):773-790.e11. doi: 10.1016/j.cmet.2020.02.010. Epub 2020 Mar 5.
Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, post-prandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TGs directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior.
能量密集型食物会改变中脑边缘多巴胺（DA）系统的传递，从而促进奖励功能障碍、强迫性进食和体重增加。然而，营养物质影响 MCL 电路的机制仍不清楚。在这里，我们表明，营养三酸甘油脂（TGs）是哺乳动物中一种保守的餐后代谢特征，可以在 MCL 系统内被代谢，并通过一种涉及脂蛋白脂肪酶（LPL）作用的机制，调节多巴胺受体亚型 2（DRD2）表达神经元的活性，从而调节与 DA 相关的行为。此外，我们表明，在人类中，餐后 TG 波动会调节携带 DRD2 信号降低遗传风险的个体对食物线索的大脑反应。总的来说，这些发现揭示了一种新的机制，即膳食 TGs 可以直接改变奖励回路中的信号，从而调节行为，为富含能量的饮食如何导致（异常）适应 DA 信号提供了新的机制基础，而 DA 信号是奖励缺陷和强迫行为的基础。
