A Loss Of Pleasure From High-fat Food That Paradoxically Supports Obesity Is Traced To A Brain Signaling Pathway Involving Neurotensin | Brain & Behavior Research Foundation

Ready entree to and excessive depletion of high-calorie foods are wide held to beryllium cardinal contributing factors successful nan improvement and progression of obesity. The nexus has been observed successful people, but besides tested many times successful animals.

This investigation has confirmed that chronic vulnerability to a high-fat fare “profoundly influences eating behaviors,” peculiarly those driven by nan pleasurable (sometimes called “hedonic”) properties of food. So statement a squad of researchers led by 2 BBRF grantees who person published successful nan diary Nature results of caller investigation connected nan narration betwixt nan functioning of nan brain’s reward strategy and obesity.

It was their purpose to analyse really a chronic high-fat fare affects eating behaviors, 1 facet of which seems to defy communal sense. It has been observed successful mice and group that aft a play of time, individuals who person go accustomed to eating a high-fat fare statesman to grounds a reduced desire to devour aliases actively activity high-calorie aliases high-fat food. Just arsenic curious, this observed inclination really seems to lend to nan progression of obesity. How to explicate this?

Seeking successful rodent models to reply “the captious mobility of really continuous entree to calorie-rich foods affects neural circuits progressive successful feeding and motivation,” nan squad was led by Stephan Lammel, Ph.D., a 2015 BBRF Young Investigator. Neta Gazit Shimoni, Ph.D., whose 2021 BBRF Young Investigator assistance was devoted to studying nan regularisation of hedonic, aliases pleasure-driven feeding, and its narration to obesity, and Amanda J. Tose, Ph.D., were co-first authors. All are astatine nan University of California, Berkeley.

“The paradox is that we usually deliberation that group pinch obesity thin to activity retired foods that induce pleasure,” Dr. Lammel explains. “However, our investigation suggests that these group really whitethorn acquisition little pleasance from eating palatable foods. They do not eat less, but nan measurement they eat has changed. They are not eating for pleasance anymore.”

In some group and mice, dopamine-producing neurons successful nan brain’s ventral tegmental areas (VTA) that link to cells successful nan brain’s nucleus accumbens (NAc) person been implicated successful nan motivational aspects of feeding behavior. Activation of dopamine neurons successful nan VTA that are connected pinch nan NAc has been pinpointed arsenic centrally associated pinch nan reward that is progressive successful seeking and consuming food. Even nan specified anticipation of reward has nan effect of enhancing dopamine-cell firing, which successful move promotes behaviors successful which some animals and group activity nutrient rewards.

Conversely, however, past investigation successful mice and group has indicated nan paradox: that chronic vulnerability to a high-fat fare reduces dopamine activity successful this circuit, perchance impairing reward-related processes, but, arsenic noted, really contributing to obesity. Drs. Lammel, Shimoni and colleagues successful past activity person shown that by artificially stimulating nan pathway connecting nan lateral NAc and nan VTA, mice could beryllium driven to show robust reward-related behaviors. In nan existent research, they sought to study astir whether accrued activity successful nan lateral NAc-VTA pathway is associated pinch hedonic feeding behaviors, and really these whitethorn beryllium affected by diet-induced obesity.

The recently reported investigation demonstrates that chronic depletion by mice of a high-fat fare alters hedonic feeding behaviors and disrupts signaling successful nan pathway connecting nan lateral NAc and nan VTA. The signaling disrupted specifically involves neurotensin, a neuropeptide, aliases signaling protein, recovered successful nan encephalon and cardinal tense system. The alteration successful neurotensin signaling was observed to person an effect connected nan progression of obesity.

The team’s uncovering that neurotensin merchandise from neurons successful nan lateral NAc decreases aft mice person grown accustomed to a high-fat diet, successful nan team’s view, “provides a circuit-level mentation for nan nexus betwixt dopamine activity and weight gain, altered feeding behavior, and obesity progression.”

As they explain, neurotensin acts done nan neurotensin-1 receptor connected dopamine neurons to heighten their activity, starring to an summation successful dopamine merchandise successful nan NAc. Dopamine, importantly, is simply a cardinal regulator of reward learning and motivated behavior. Thus, they say, a simplification successful neurotensin merchandise successful nan lateral NAc induced by a high-fat fare “is apt to diminish” excitation of dopamine neurons, which successful move “reduces nan desire to devour high-calorie foods.”

The caller investigation whitethorn thief explicate nan paradox successful which specified alterations really lend to obesity. “It whitethorn beryllium challenging to comprehend,” nan squad notes, why mice (or people) acclimated to rich | nutrient statesman to devalue acquiring it—yet proceed to eat it and go obese.

The reply is not yet clear, but whitethorn person to do astatine slightest successful portion pinch habit. “Obesity is often associated pinch reduced behavioral sensitivity to changes successful nan motivational worth of hedonic nutrient rewards, including habit-like behavioral power that encourages overconsumption of food,” nan squad wrote. Other possibilities are that erstwhile nan reward initially attached to rich | nutrient is diminished aliases devalued, this alters an individual’s feeding habits and circadian rhythm. Also, it whitethorn impact changes successful locomotion aliases reduced “exploration behavior,” which whitethorn indirectly beforehand weight gain.

The recently reported investigation suggests that successful mice, astatine least, restoring neurotensin levels successful nan lateral NAc-VTA pathway tin mitigate high-fat diet-induced changes successful hedonic feeding, anxiety, mobility, and nutrient consumption. Each of these factors appears to person a domiciled successful obesity progression, nan researchers said. “Reduced anxiety, successful peculiar whitethorn not only amended nutrient depletion behaviors but besides heighten wide intelligence health, which is highly applicable for treating obesity and its comorbidities.”

“A high-fat fare changes nan brain, starring to little neurotensin levels, which successful move alters really we eat and respond to these foods,” Dr. Lammel said. “We recovered a measurement to reconstruct nan desire for high-calorie foods, which whitethorn really thief pinch weight management.” If this attack tin beryllium translated into humans, it could unfastened caller avenues for addressing obesity by restoring food-related pleasance successful those who suffer it, perchance altering unhealthy eating patterns. Such investigation is already nether measurement successful nan Lammel lab.

Given nan domiciled of high-calorie foods “in driving nan obesity epidemic,” nan squad says “targeting neurotensin signaling successful nan NAc-VTA pathway whitethorn connection a promising strategy” to modulate nutrient intake and support patient weight maintenance—perhaps “without disrupting different basal functions” that are mediated by neurotensin, which successful summation to feeding behaviors see nan regularisation of symptom and assemblage temperature.

The squad besides included Byung Kook Lim, Ph.D., a 2015 BBRF Young Investigator.