加州大学Stephan Lammel团队的最新研究报道了神经紧张素信号的改变导致肥胖患者的享乐贬值。相关论文发表在2025年3月26日出版的《自然》杂志上。

在这里，该团队研究了慢性高脂肪饮食（HFD）小鼠的这种现象。尽管这些老鼠在家里的笼子里更喜欢高脂肪的食物，而不是普通的食物，但在不费力的环境中，它们对高热量食物的兴趣降低了。这种享乐性进食的矛盾减少已经被报道过，但其神经生物学基础尚不清楚。该研究组发现，在正常饮食的小鼠中，向腹侧被盖区（VTA）投射的外侧伏隔核（NAcLat）神经元编码了享乐性进食行为。在HFD小鼠中，这种行为减少并且与神经活动分离。光基因刺激NAcLat→VTA通路增加了正常饮食小鼠的享乐性摄食，但在HFD小鼠中没有，尽管当HFD小鼠恢复正常饮食时，这种行为得以恢复。HFD小鼠在NAcLat→VTA通路中神经紧张素的表达和释放降低。

此外，NAcLat中的神经紧张素敲除和VTA中的神经紧张素受体阻断均可消除光遗传诱导的享乐性摄食行为。增强神经紧张素信号通过过度表达正常化方面的饮食引起的肥胖，包括体重增加和享乐喂养。总之，他们的发现确定了一种神经回路机制，将享乐性食物的贬值与肥胖联系起来。

研究人员表示，高热量的食物，特别是那些高脂肪和高糖的食物，能引起人类和动物的愉悦感。然而，长时间食用这些食物可能会降低它们的享乐价值，潜在地导致肥胖。

附：英文原文

Title: Changes in neurotensin signalling drive hedonic devaluation in obesity

Author: Gazit Shimoni, Neta, Tose, Amanda J., Seng, Charlotte, Jin, Yihan, Lukacsovich, Tams, Yang, Hongbin, Verharen, Jeroen P. H., Liu, Christine, Tanios, Michael, Hu, Eric, Read, Jonathan, Tang, Lilly W., Lim, Byung Kook, Tian, Lin, Fldy, Csaba, Lammel, Stephan

Issue&Volume: 2025-03-26

Abstract: Calorie-rich foods, particularly those that are high in fat and sugar, evoke pleasure in both humans and animals1. However, prolonged consumption of such foods may reduce their hedonic value, potentially contributing to obesity2,3,4. Here we investigated this phenomenon in mice on a chronic high-fat diet (HFD). Although these mice preferred high-fat food over regular chow in their home cages, they showed reduced interest in calorie-rich foods in a no-effort setting. This paradoxical decrease in hedonic feeding has been reported previously3,4,5,6,7, but its neurobiological basis remains unclear. We found that in mice on regular diet, neurons in the lateral nucleus accumbens (NAcLat) projecting to the ventral tegmental area (VTA) encoded hedonic feeding behaviours. In HFD mice, this behaviour was reduced and uncoupled from neural activity. Optogenetic stimulation of the NAcLat→VTA pathway increased hedonic feeding in mice on regular diet but not in HFD mice, though this behaviour was restored when HFD mice returned to a regular diet. HFD mice exhibited reduced neurotensin expression and release in the NAcLat→VTA pathway. Furthermore, neurotensin knockout in the NAcLat and neurotensin receptor blockade in the VTA each abolished optogenetically induced hedonic feeding behaviour. Enhancing neurotensin signalling via overexpression normalized aspects of diet-induced obesity, including weight gain and hedonic feeding. Together, our findings identify a neural circuit mechanism that links the devaluation of hedonic foods with obesity.

DOI: 10.1038/s41586-025-08748-y

Source: https://www.nature.com/articles/s41586-025-08748-y