New research reveals how fat-rich diets silence the brain’s reward for food—and how a single molecule may reignite the pleasure of eating.
Study: Changes in neurotensin signalling drive hedonic devaluation in obesity. Image Credit: StudioMolekuul / Shutterstock
In a recent study published in the journal Nature, researchers investigated how a chronic high-fat diet (HFD) affects hedonic feeding behaviors in mice, as well as the neural mechanisms underlying these behaviors. Mice on an HFD exhibited a reduced interest in calorie-rich foods in a no-effort setting, linked to uncoupled neural activity in the NAcLat→VTA pathway (lateral nucleus accumbens to ventral tegmental area) of the mesolimbic dopamine system.
Optogenetic stimulation failed to restore this behavior in HFD mice, but recovery occurred when they returned to a regular diet. Neurotensin (NTS) signaling plays a crucial role in regulating hedonic food intake and the associated changes related to obesity.
Background
Obesity is often linked to excessive consumption of high-calorie foods, driven by their pleasurable effects. However, prolonged exposure to an HFD appears to reduce this hedonic value, altering feeding behaviors. The mesolimbic dopamine system, particularly projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), plays a critical role in food reward processing.
The study focused on inhibitory GABAergic projections from the lateral subregion of the NAc (NAcLat) to the VTA, which are distinct from the broader VTA→NAc dopamine pathways. While dopamine-related mechanisms in feeding and obesity have been well-studied, the impact of chronic high-fat diets (HFDs) on inhibitory NAc→VTA projections remains unclear.
About the Study
In this study, researchers investigated the impact of a high-fat diet (HFD) on neural activity in the brain’s reward system, with a particular focus on the connection between the NAcLat and VTA.
Researchers injected retrograde viruses into the brains of C57Bl6 mice to express light-sensitive proteins (ChR2) in NAcLat neurons projecting to the VTA. They implanted optrodes to record brain activity. Mice were divided into two groups: one was fed a regular diet comprising 4% fat (REG), while the other was given free access to both regular and high-fat food, containing 60% fat (HFD). After 30 days, an open-field experiment was conducted where mice were exposed to low-calorie (chow) and palatable, high-calorie jelly, and their behaviors were recorded and analyzed.
Researchers measured neuron firing rates in the mice before, during, and after different behaviors, classifying responses as increased (IR), decreased (DR), or unchanged. In another experiment, mice were genetically modified to activate NAcLat→VTA neurons using laser light. They were tested with and without optogenetic stimulation to assess changes in food consumption.
RNA sequencing was employed to identify changes in gene expression in NAcLat→VTA neurons. A fluorescent sensor (ntsLight1.1) measured NTS release. A second, more sensitive sensor (ntsLight2.0) was later used to confirm reduced NTS release in vivo. These methods helped determine how chronic HFD alters brain activity and reduces the release of NTS, a neuropeptide linked to feeding behavior.
Findings
In REG individuals, NAcLat→VTA neurons exhibited high firing rates when eating palatable, high-calorie jelly, but firing decreased during other behaviors. In contrast, HFD mice had uncoupled neural activity (no firing increase during jelly consumption), indicating disrupted hedonic (pleasure-driven) feeding. Activating NAcLat→VTA neurons in REG mice increased consumption of high-calorie foods but did not affect low-calorie foods or water intake.
Silencing this pathway reduced hedonic feeding. However, in HFD mice, optogenetic activation failed to increase food intake, suggesting the pathway's function was impaired. Notably, HFD mice still preferred high-fat chow in home-cage settings, highlighting a paradoxical context-dependent shift in feeding behavior.
When HFD mice returned to a regular diet for two weeks, their hedonic feeding behavior gradually normalized, and their neural responses to food recovered. RNA sequencing revealed that HFD reduced the expression of NTS in NAcLat→VTA neurons.
Using fluorescent sensors, researchers confirmed that HFD mice released less NTS in response to neuronal stimulation. The ntsLight2.0 sensor showed reduced NTS release in HFD mice, confirming diet-induced suppression of this key neuropeptide.
Conclusions
The study reveals that chronic high-fat diet (HFD) exposure alters hedonic feeding by disrupting activity in the NAcLat→VTA pathway. Typically, this pathway is engaged during pleasurable feeding experiences; however, in mice given high-fat diets (HFD), the coupling between neural activity and feeding behavior was lost.
Optogenetic stimulation, which increased hedonic feeding behavior in regular-diet mice, did not affect the HFD mice, suggesting an underlying neural dysfunction. Further analysis identified NTS as a key modulator of this pathway. HFD mice also showed reduced NTS release and expression, impairing hedonic feeding.
Experimental manipulation confirmed its role: knocking out NTS in the NAcLat or blocking NTSR1 receptors in the VTA abolished hedonic feeding responses. NTS acts through two mechanisms: disinhibiting dopamine neurons by suppressing GABAergic interneurons and directly exciting them via NTSR1. Conversely, restoring NTS signaling helped normalize not only feeding motivation and weight gain but also locomotor activity and anxiety-like behaviors induced by diet.
These findings suggest that obesity is associated with a neurobiological shift in reward processing, resulting in a decreased enjoyment of calorie-rich foods in specific contexts. This may contribute to compensatory overeating behaviors in certain environments, as individuals seek greater stimulation to compensate for the reduced pleasure associated with food.
By identifying NTS as a key factor, the study provides potential therapeutic targets for addressing obesity-related reward deficits. Future research should investigate whether similar mechanisms exist in humans and explore how NTS modulation could be leveraged for obesity treatment.
Journal reference:
- Changes in neurotensin signalling drive hedonic devaluation in obesity. Shimoni, NG., Tose, A.J., Seng, C., Jin, Y., Lukacsovich, T., Yang, H., Verharen, J.P.H., Liu, C., Tanios, M., Hu, E., Read, J., Tang, L.W., Lim, B.K., Tian, L., Földy, C., Lammel, S. Nature (2025). DOI: 10.1038/s41586-025-08748-y, https://www.nature.com/articles/s41586