The fun we get from eating junk food – dopamine falls from salty, greasy fries and sweet burgers – is often blamed for the reasons for overeating and rising obesity rates in our society.
But a new study conducted by UC Berkeley scientists suggests that in the diet, even the pleasure of eating junk food, is crucial to maintaining a healthy weight in a society full of cheap, high-fat foods.
Paradoxically, anecdotal evidence suggests that obese patients may feel less dietary pleasure than those with normal weight. Brain scans in obese individuals showed reduced activity in brain regions associated with pleasure when food was found, and this pattern was also observed in animal studies.
Now, UC Berkeley researchers have identified a possible root cause of this phenomenon—the decline of neuropine, a brain peptide that interacts with the dopamine network, and a potential strategy to restore the pleasure of diet in a way that reduces overall consumption.
The study reveals a non-causing brain mechanism that explains why a chronic high-fat diet can reduce cravings for high-fat, sugary foods, even if these foods are still easily accessible. Researchers suggest that obese individuals lack desire is due to dietary loss caused by long-term consumption of high-calorie foods. Losing this happiness may actually contribute to the development of obesity.
“The natural tendency to junk food is not inherently bad, but losing it may further exacerbate obesity,” said Stephan Lammel, a professor at the Department of Neuroscience at the University of California, Berkeley and a member of the Helen Wells Institute for Neuroscience.
The researchers found that this effect was driven by a decrease in neuronin in specific brain regions connected to the dopamine network. Importantly, they show that restoring neuron levels through dietary changes or genetic manipulation can enhance neuron production – which can restore diet and promote the pleasure of weight loss.
“A high-fat diet changes the brain, which leads to lower neuron levels, which changes our diet and response to these foods,” Lammel said. “We found a way to restore cravings for high-calorie foods, which may actually help weight management.”
While the findings in mice do not always translate directly into humans, this discovery can open up new avenues to address obesity by restoring food-related pleasures and disrupting unhealthy diets.
“Imagine having an amazing dessert at a great restaurant in Paris – you’ll experience an outbreak of dopamine and happiness,” said Neta Gazit Shimoni, a postdoctoral fellow at UC Berkeley. “We found that in a normal diet, mice also experience this feeling, but lack it in a high-fat diet. They may be constantly out of habit or boredom rather than real enjoyment.”
Gazit Shimoni and former UC Berkeley graduate student Amanda Tose are co-first authors and Lammel is senior author of the study, which will be published in the Journal on March 26 nature.
Solve long-term problems in obesity research
For decades, doctors and researchers have struggled to understand and treat obesity as countless fashionable diets and dietary regimens fail to produce long-term results. The latest success of GLP-1 agonists such as Ozempic, which curbs appetite by increasing the feeling of fulfillment, stands out among many failed approaches.
Lammel studies brain circuitry, especially dopamine networks, plays a crucial role in rewards and motivation. Dopamine is often associated with pleasure, enhancing our desire to seek meaningful experiences, such as eating high-calorie foods.
Gazit Shimoni noticed a stunning paradox when raising mice on a high-fat diet: In their homes, the high-fat foods that these mice strongly preferred contain 60% fat, rather than normal fat, with only 4% fat, causing them to produce too much weight. But when they are taken out of their cage and get free high-calorie snacks like butter, peanut butter, jelly or chocolate, they have much less desire for addiction than regular mice, and the craving of regular dogs instantly eats everything they have to offer.
“If you give regular regular mice a chance, they will eat these foods immediately,” Gazit Shimoni said. “We only see the paradoxical decay of feeding motivations that occur in mice on this high-fat diet.”
She found that this effect has been reported in past studies, but no one followed up to find out why and how the impact is associated with the obesity phenotype observed in these mice.
Restoring neurinin reversal of obesity-related brain changes
To study this phenomenon, Lammel and his team used optogenetics, a technology that allows scientists to control brain circuits with light. They found that in ordinary mice, stimulating brain circuits connected to the dopamine network increased their desire to eat high-calorie foods, but in obese mice, the same stimulation had no effect, indicating that something had to change.
They found that the reason was that neuron was so reduced in obese mice that it prevented dopamine from triggering a usual pleasant response to high-calorie foods.
“Neurin is the link to this deletion,” Lammel said. “Generally, it can enhance dopamine activity to drive rewards and motivation. However, in mice with high-fat diets, neuronin is downregulated and even if it is easy to use, they lose the strong desire to consume high-calorie foods.”
The researchers then tested ways to restore neuron levels. When obese mice switched back to their normal diet for two weeks, their neuron levels returned to normal, dopamine function returned, and interest in high-calorie foods was restored.
When genetic methods were used to artificially restore neuron levels, the mice not only lost weight, but also showed reduced and improved mobility in anxiety disorders. Their feeding behavior also normalizes it, increasing motivation for high-calorie foods and simultaneously reducing their total food consumption at home.
“Bringing back neuron seems very, very important to prevent the loss of the desire to lose the desire to eat high-calorie food,” Lammel said. “This doesn’t make you obese again, but it will help control your dietary behavior and get it back to normal.”
Take a more accurate treatment for obesity
Although the direct administration of neuron can theoretically restore feeding motivation in obese individuals, neuron acts on many brain regions, increasing the risk of unnecessary side effects. To overcome this, the researchers used gene sequencing, a technology that allowed them to identify specific genes and molecular pathways that regulate neurotin function in obese mice.
This discovery provides a vital molecular target for future obesity treatments, paving the way for more precise therapies that can selectively enhance the function of neuron without extensive systemic effects.
“We now have the complete genetic characteristics of these neurons and how they change through a high-fat diet,” Lammel said. “The next step is to explore pathways upstream and downstream of neuron proteins to find precise therapeutic targets.”
Lammel and Gazit Shimoni plan to expand their research to explore the role of neurons, rather than obesity, investigate their involvement in diabetes and eating disorders.
“The bigger question is whether these systems interact under different conditions,” Gazit Shimoni said. “How does hunger affect the dopamine circuit? What happens with eating disorders? These questions are the questions we’re going to look at next.”
Other co-authors are Charlotte Seng, Tamás Lukacsovich and Csaba Földy of the University of Zurich, Switzerland; Yihan Jin and Lin Tian of the University of California, Davis; Hong Binyang of Zheng University in Hangzhou, China; Jeroen Verharen, Christine Liu, Michael Tanios, Eric Hu, Jonathan Read and Lilly Tang of UC Berkeley; and Byung Kook Lim of San Diego.
This work was obtained by the McKnight Foundation, Mind Foundation, Weill Neurohub, Rita Allen Foundation, Wayne and Wayne and Gladys Valley Foundation and the National Institutes of Health (R01DA042889, U01NS12089, U01NS10820, U01NS113295, R01NS113295, R01NS1NS1231, R01231, R01DA01DA049777777). Shimoni is supported by the National Alliance for Schizophrenia and Depression Research Young Investigators Award.
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