Changes in neurotensin signalling drive hedonic devaluation in obesity

Neta Gazit Shimoni, Amanda J. Tose, Charlotte Seng, Yihan Jin, Tamás Lukacsovich, Hongbin Yang, Jeroen P. H. Verharen, Christine Liu, Michael Tanios, Eric Hu, Jonathan Read, Lilly W. Tang, Byung Kook Lim, Lin Tian, Csaba Földy and Stephan Lammel ()
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Neta Gazit Shimoni: University of California Berkeley
Amanda J. Tose: University of California Berkeley
Charlotte Seng: University of Zurich
Yihan Jin: University of California Davis
Tamás Lukacsovich: University of Zurich
Hongbin Yang: Zhejiang University
Jeroen P. H. Verharen: University of California Berkeley
Christine Liu: University of California Berkeley
Michael Tanios: University of California Berkeley
Eric Hu: University of California Berkeley
Jonathan Read: University of California Berkeley
Lilly W. Tang: University of California Berkeley
Byung Kook Lim: University of California San Diego
Lin Tian: University of California Davis
Csaba Földy: University of Zurich
Stephan Lammel: University of California Berkeley

Nature, 2025, vol. 641, issue 8065, 1238-1247

Abstract: 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 obesity2–4. 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 previously3–7, 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.

Date: 2025
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DOI: 10.1038/s41586-025-08748-y

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