Changes in neurotensin signalling drive hedonic devaluation in obesity

Calorie-rich foods, particularly those 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). While 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 regular diet mice, neurons in the lateral nucleus accumbens projecting to the ventral tegmental area (NAcLat→VTA) encoded hedonic feeding behaviors. In HFD mice, this behavior was reduced and uncoupled from neural activity. Optogenetic stimulation of the NAcLat→VTA pathway increased hedonic feeding in regular diet mice but not in HFD mice, though this behavior 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 optogenetic-induced hedonic feeding behavior. Enhancing neurotensin signaling via overexpression normalized aspects of diet-induced obesity, including weight gain and hedonic feeding. Altogether, our findings identify a neural circuit mechanism linking the devaluation of hedonic foods with obesity. Neurons from the nucleus accumbens projecting to the VTA were collected from control mice (NORM) and mice on high fat diet (HFD)