Many overweight people report that they have lost the desire to eat rich foods – a phenomenon that has also been observed in overweight mice. Scientists have now discovered the reason for this. A long-term high-fat diet lowers neurotensin levels in the brain, disrupts the dopamine reward network and reduces the craving for high-fat food. Increasing neurotensin levels in mice restores desire and supports weight loss. Restoring cravings could help people break the habit of overeating.
Scientists Discover Why Obesity Takes the Pleasure Out of Eating
The pleasure we get from eating junk food – the dopamine rush that occurs when we enjoy salty, greasy fries and a juicy burger – is often blamed as the cause of overeating and the rising obesity rates in our society. However, a new study by scientists at the University of California, Berkeley, suggests that the pleasure of eating, even eating junk food, is key to maintaining a healthy weight in a society where cheap, high-fat foods are plentiful.
Paradoxically, anecdotal evidence suggests that people with obesity derive less pleasure from food than people of normal weight. Brain scans of obese individuals show reduced activity in brain regions associated with pleasure when presented with food. This pattern has also been observed in animal studies. UC Berkeley researchers have identified a possible cause for this phenomenon – a decrease in neurotensin, a brain peptide that interacts with the dopamine network – and a potential strategy to restore pleasure in eating, thus reducing overall consumption. The study uncovers an unexpected brain mechanism that explains why a chronic high-fat diet can reduce cravings for high-fat, high-sugar foods, even when these foods remain easily accessible. The researchers hypothesize that this lack of craving in overweight individuals is due to a loss of pleasure in eating caused by long-term consumption of high-calorie foods. The loss of this pleasure may actually contribute to the progression of obesity.
“A natural inclination toward junk food is not inherently bad – but the loss of this inclination could further exacerbate obesity,” said Stephan Lammel, a professor in the Department of Neuroscience at UC Berkeley and a member of the Helen Wills Neuroscience Institute. The researchers found that this effect is caused by a reduction in neurotensin levels in a specific brain region associated with the dopamine network. Importantly, they show that restoring neurotensin levels – either through dietary changes or genetic manipulations that increase neurotensin production – can restore pleasure in eating and promote weight loss. Although the results in mice do not always translate directly to humans, this discovery could open up new ways to fight obesity by bringing back the pleasure of eating and breaking unhealthy eating habits. Gazit Shimoni and former UC Berkeley doctoral student Amanda Tose are co-first authors and Lammel is lead author of the study, which was published in the journal Nature.
Restoring Neurotensin Reverses Obesity-Induced Changes in the Brain
For decades, doctors and researchers have struggled to understand and treat obesity, as countless fad diets and diet plans have failed to produce long-term results. The recent success of GLP-1 agonists such as Ozempic, which curb appetite by increasing satiety, stands out among many failed approaches. Lammel is studying the brain’s circuits, particularly the dopamine network, which plays a crucial role in reward and motivation. Dopamine is often associated with pleasure and increases our desire to seek out rewarding experiences, such as eating high-calorie foods. While Gazit Shimoni was raising mice on a high-fat diet, he noticed a striking paradox: in their cages, these mice preferred high-fat food containing 60% fat over normal food with only 4% fat, which led to excessive weight gain. However, when they were taken out of their cages and given free access to high-calorie treats such as butter, peanut butter, jam or chocolate, they showed much less desire to indulge than mice on a normal diet, which immediately ate everything they were offered. The researchers found that this effect had already been reported in previous studies, but no one had followed up on why this was so and how the effect related to the obesity phenotype observed in these mice. “If you give a normal mouse with a normal diet the chance, it eats these foods immediately,” said Gazit Shimoni. “We only see this paradoxical attenuation of feeding motivation in mice fed a high-fat diet.”
To study this phenomenon, Lammel and his team used optogenetics, a technique that allows scientists to control brain circuitry with light. They found that in mice on a normal diet, stimulating a brain circuit linked to the dopamine network increased their craving for high-calorie foods, but in obese mice the same stimulation had no effect, suggesting that something must have changed. The reason for this, they found, was that neurotensin was so severely reduced in obese mice that it prevented dopamine from triggering the usual pleasure response to high-calorie foods. “Neurotensin is this missing link,” said Lammel. Normally, it increases dopamine activity to promote reward and motivation. But in mice on a high-fat diet, neurotensin is downregulated, and they lose the strong desire to consume high-calorie foods – even when they are readily available.
The researchers then tested ways to restore neurotensin levels. When overweight mice were switched back to a normal diet for two weeks, their neurotensin levels returned to normal, dopamine function was restored and they regained interest in high-calorie foods. When neurotensin levels were artificially restored using a genetic approach, the mice not only lost weight, but also showed less anxiety and improved mobility. Their feeding behavior also normalized, with increased motivation for high-calorie foods and a simultaneous decrease in total food consumption in their home cages. The restoration of neurotensin appears to be very, very important in preventing the loss of cravings for high-calorie foods. According to the researchers, it does not make the animals immune to renewed obesity, but it would help to control and normalize eating behavior.
More Precise Treatment Methods for Obesity
Although direct administration of neurotensin could theoretically restore eating motivation in obese individuals, neurotensin affects many areas of the brain and increases the risk of unwanted side effects. To address this problem, the researchers used gene sequencing, a technique that allowed them to identify specific genes and molecular signaling pathways that regulate neurotensin function in obese mice. This discovery provides crucial molecular targets for future obesity treatments and paves the way for more precise therapies that could selectively improve neurotensin function without having broad systemic effects.
“We now have the full genetic profile of these neurons and know how they change in response to a high-fat diet,” explained Lammel. The next step is to explore the pathways upstream and downstream of neurotensin to find precise therapeutic targets. Lammel and Gazit Shimoni plan to expand their research to explore the role of neurotensin beyond obesity and investigate its involvement in diabetes and eating disorders. The bigger question is whether these systems interact across different diseases. How does hunger affect dopamine circuitry? What happens in eating disorders? These are the questions the researchers will address next.