Changes in neurotensin signalling drive hedonic devaluation in obesity

Area of Science:

• Neuroscience
• Obesity Research
• Behavioral Biology

Background:

• Calorie-rich foods (high fat/sugar) are pleasurable but prolonged consumption can decrease hedonic value, potentially leading to obesity.
• The neurobiological basis for this reduced hedonic feeding in obesity remains unclear.

Purpose of the Study:

• To investigate the neurobiological mechanisms underlying the reduced hedonic value of calorie-rich foods in mice on a chronic high-fat diet (HFD).
• To identify the neural circuits and molecular pathways involved in diet-induced changes in food preference and hedonic feeding.

Main Methods:

• Utilized a mouse model with chronic high-fat diet (HFD) exposure.
• Investigated neural activity in the nucleus accumbens lateral (NAcLat) to ventral tegmental area (VTA) pathway.
• Employed optogenetics to stimulate the NAcLat→VTA pathway.
• Assessed neurotensin expression and release.
• Used neurotensin knockout and receptor blockade models.
• Examined effects of neurotensin signaling enhancement on weight gain and hedonic feeding.

Main Results:

• HFD mice showed reduced interest in calorie-rich foods despite preferring them in home cages.
• The NAcLat→VTA pathway, encoding hedonic feeding in regular diet mice, was uncoupled from behavior in HFD mice.
• Optogenetic stimulation of NAcLat→VTA increased hedonic feeding in regular diet mice but not HFD mice (restored upon return to regular diet).
• HFD mice exhibited reduced neurotensin expression/release in the NAcLat→VTA pathway.
• Neurotensin manipulation (knockout/blockade) abolished optogenetically induced hedonic feeding.
• Enhanced neurotensin signaling normalized weight gain and hedonic feeding in HFD mice.

Conclusions:

• Identified a neural circuit mechanism (NAcLat→VTA pathway) linking devaluation of hedonic foods to obesity.
• Reduced neurotensin signaling in this pathway is a key factor in diet-induced obesity and hedonic feeding deficits.
• Restoring neurotensin signaling offers a potential therapeutic strategy for obesity.