Gazit Shimoni Neta, Tose Amanda J, Seng Charlotte, Jin Yihan, Lukacsovich Tamás, Yang Hongbin, Verharen Jeroen P H, Liu Christine, Tanios Michael, Hu Eric, Read Jonathan, Tang Lilly W, Lim Byung Kook, Tian Lin, Földy Csaba, Lammel Stephan
Department of Neuroscience and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
Brain Research Institute, Faculties of Medicine and Science, University of Zurich, Zürich, Switzerland.
Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08748-y.
Calorie-rich foods, particularly those that are high in fat and sugar, evoke pleasure in both humans and animals. However, prolonged consumption of such foods may reduce their hedonic value, potentially contributing to obesity. 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 previously, 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.
富含卡路里的食物，尤其是那些高脂肪和高糖的食物，会在人类和动物身上引发愉悦感。然而，长期食用这类食物可能会降低它们的享乐价值，这可能会导致肥胖。在这里，我们在长期高脂饮食（HFD）的小鼠中研究了这一现象。尽管这些小鼠在其饲养笼中更喜欢高脂肪食物而非常规食物，但在无需费力获取食物的环境中，它们对富含卡路里食物的兴趣降低。这种享乐性进食的矛盾性降低此前已有报道，但其神经生物学基础仍不清楚。我们发现，在正常饮食的小鼠中，伏隔核外侧核（NAcLat）中投射到腹侧被盖区（VTA）的神经元编码享乐性进食行为。在高脂饮食小鼠中，这种行为减少，并且与神经活动解耦。对NAcLat→VTA通路进行光遗传学刺激可增加正常饮食小鼠的享乐性进食，但对高脂饮食小鼠无效，不过当高脂饮食小鼠恢复正常饮食时，这种行为得以恢复。高脂饮食小鼠在NAcLat→VTA通路中神经降压素的表达和释放减少。此外，NAcLat中的神经降压素基因敲除和VTA中的神经降压素受体阻断均消除了光遗传学诱导的享乐性进食行为。通过过表达增强神经降压素信号传导可使饮食诱导的肥胖的各个方面正常化，包括体重增加和享乐性进食。总之，我们的研究结果确定了一种将享乐性食物贬值与肥胖联系起来的神经回路机制。
