Changes in neurotensin signalling drive hedonic devaluation in obesity

GazitShimoni N; Tose AJ; Seng C; Jin Y; Lukacsovich T; Yang H; Verharen JPH; Liu C; Tanios M; Hu E; Read J; Tang LW; Lim BK; Tian L; Foldy C; Lammel S

doi:10.1530/ey.22.15.12

15.12

Prev Next

Section Contents Cite

ESPE Yearbook of Paediatric Endocrinology (2025) 22 15.12 | DOI: 10.1530/ey.22.15.12

ESPEYB25 15. Editors' Choice Obesity (3 abstracts)

15.12. Changes in neurotensin signalling drive hedonic devaluation in obesity

GazitShimoni N , Tose AJ , Seng C , Jin Y , Lukacsovich T , Yang H , Verharen JPH , Liu C , Tanios M , Hu E , Read J , Tang LW , Lim BK , Tian L , Foldy C & Lammel S

Nature 2025; 641:1238-1247. PMID: 40140571 doi: 10.1038/s41586-025-08748-y

In Brief: This experimental study explored why mice show descreasing interest in a chronic high-fat diet (HFD), over time. They identified a neural circuit mechanism that activates hedonic eating behaviour: neurotensin expression and release in the lateral nucleus accumbens (NAcLat) projecting to the ventral tegmental area (VTA).

Comment: As well eating to satisfy our appetites and induce satiety (‘fullness’), we eat many types of food for pleasure. This is one of the reasons why foods that are high in sugars, fat and calories increase risks of overweight and obesity. While the leptin-melanocortin pathway that regulates appetite and satiety is well characterised, the pathway responsible for ‘hedonic eating’ has been less understood.

The authors provide several lines of evidence for the NAcLat→VTA pathway. Artificial optogenetic stimulation of this pathway increased hedonic feeding in mice on regular diet. By contrast, mice fed on a chronic HFD diet were insensitive to the same stimulation, consistent with their reduced interest in that diet, but this process could be restored by returning them to a regular diet. Optogenetically induced hedonic feeding could also be blocked by neurotensin knockout in the NAcLator neurotensin receptor blockade in the VTA. Conversely, neurotensin overexpression also restored weight gain and hedonic feeding in HFD mice.

Drug targeting of neurotensin signalling specifically in the NAcLat→VTA pathway may be a potential strategy to regulate food intake and support healthy body weights.