Ready access to and excessive consumption of high-calorie foods are widely held to be key contributing factors in the development and progression of obesity. The link has been observed in people, but also tested repeatedly in animals.

This research has confirmed that chronic exposure to a high-fat diet “profoundly influences eating behaviors,” particularly those driven by the pleasurable (sometimes called “hedonic”) properties of food. So note a team of researchers led by two BBRF grantees who have published in the journal Nature results of new research on the relationship between the functioning of the brain’s reward system and obesity.

It was their aim to investigate how a chronic high-fat diet affects eating behaviors, one aspect of which seems to defy common sense. It has been observed in mice and people that after a period of time, individuals who have become accustomed to eating a high-fat diet begin to exhibit a reduced desire to consume or actively seek high-calorie or high-fat food. Just as curious, this observed tendency actually seems to contribute to the progression of obesity. How to explain this?

Seeking in mouse models to answer “the critical question of how continuous access to calorie-rich foods affects neural circuits involved in feeding and motivation,” the team was led by Stephan Lammel, Ph.D., a 2015 BBRF Young Investigator. Neta Gazit Shimoni, Ph.D., whose 2021 BBRF Young Investigator grant was devoted to studying the regulation of hedonic, or pleasure-driven feeding, and its relation to obesity, and Amanda J. Tose, Ph.D., were co-first authors. All are at the University of California, Berkeley.

“The paradox is that we normally think that people with obesity tend to seek out foods that induce pleasure,” Dr. Lammel explains. “However, our research suggests that these people actually may experience less pleasure from eating palatable foods. They do not eat less, but the way they eat has changed. They are not eating for pleasure anymore.”

In both people and mice, dopamine-producing neurons in the brain’s ventral tegmental areas (VTA) that connect to cells in the brain’s nucleus accumbens (NAc) have been implicated in the motivational aspects of feeding behavior. Activation of dopamine neurons in the VTA that are connected with the NAc has been pinpointed as centrally associated with the reward that is involved in seeking and consuming food. Even the mere anticipation of reward has the effect of enhancing dopamine-cell firing, which in turn promotes behaviors in which both animals and people seek food rewards.

Conversely, however, past research in mice and people has indicated the paradox: that chronic exposure to a high-fat diet reduces dopamine activity in this circuit, potentially impairing reward-related processes, but, as noted, actually contributing to obesity. Drs. Lammel, Shimoni and colleagues in past work have shown that by artificially stimulating the pathway connecting the lateral NAc and the VTA, mice could be driven to display robust reward-related behaviors. In the current research, they sought to learn about whether increased activity in the lateral NAc-VTA pathway is associated with hedonic feeding behaviors, and how these may be affected by diet-induced obesity.

The newly reported research demonstrates that chronic consumption by mice of a high-fat diet alters hedonic feeding behaviors and disrupts signaling in the pathway connecting the lateral NAc and the VTA. The signaling disrupted specifically involves neurotensin, a neuropeptide, or signaling protein, found in the brain and central nervous system. The change in neurotensin signaling was observed to have an impact on the progression of obesity.

The team’s finding that neurotensin release from neurons in the lateral NAc decreases after mice have grown accustomed to a high-fat diet, in the team’s view, “provides a circuit-level explanation for the link between dopamine activity and weight gain, altered feeding behavior, and obesity progression.”

As they explain, neurotensin acts through the neurotensin-1 receptor on dopamine neurons to enhance their activity, leading to an increase in dopamine release in the NAc. Dopamine, importantly, is a key regulator of reward learning and motivated behavior. Thus, they say, a reduction in neurotensin release in the lateral NAc induced by a high-fat diet “is likely to diminish” excitation of dopamine neurons, which in turn “reduces the desire to consume high-calorie foods.”

The new research may help explain the paradox in which such alterations actually contribute to obesity. “It may be challenging to comprehend,” the team notes, why mice (or people) acclimated to rich food begin to devalue acquiring it—yet continue to eat it and become obese.

The answer is not yet clear, but may have to do at least in part with habit. “Obesity is often associated with reduced behavioral sensitivity to changes in the motivational value of hedonic food rewards, including habit-like behavioral control that encourages overconsumption of food,” the team wrote. Other possibilities are that when the reward initially attached to rich food is diminished or devalued, this alters an individual’s feeding habits and circadian rhythm. Also, it may involve changes in locomotion or reduced “exploration behavior,” which may indirectly promote weight gain.

The newly reported research suggests that in mice, at least, restoring neurotensin levels in the lateral NAc-VTA pathway can mitigate high-fat diet-induced changes in hedonic feeding, anxiety, mobility, and food consumption. Each of these factors appears to have a role in obesity progression, the researchers said. “Reduced anxiety, in particular may not only improve food consumption behaviors but also enhance overall mental health, which is highly relevant for treating obesity and its comorbidities.”

“A high-fat diet changes the brain, leading to lower neurotensin levels, which in turn alters how we eat and respond to these foods,” Dr. Lammel said. “We found a way to restore the desire for high-calorie foods, which may actually help with weight management.” If this approach can be translated into humans, it could open new avenues for addressing obesity by restoring food-related pleasure in those who lose it, possibly altering unhealthy eating patterns. Such research is already under way in the Lammel lab.

Given the role of high-calorie foods “in driving the obesity epidemic,” the team says “targeting neurotensin signaling in the NAc-VTA pathway may offer a promising strategy” to regulate food intake and support healthy weight maintenance—perhaps “without disrupting other essential functions” that are mediated by neurotensin, which in addition to feeding behaviors include the regulation of pain and body temperature.

The team also included Byung Kook Lim, Ph.D., a 2015 BBRF Young Investigator.