Unlocking the “yo-yo effect”: Brain amplifies hunger signals in synapses when dieting, study flags

28 Mar 2023 --- Nerve cells that mediate the feeling of hunger receive stronger signals after dieting which may cause people to eat significantly more and to gain weight more quickly, according to a mouse-model study. This could explain dietary fluctuations, where people rapidly put back on the weight that has been lost.

The researchers put mice on a diet and assessed how Agouti-related protein (AgRP) expressing neurons in the hypothalamus – known to control the feeling of hunger – sent increased signals when mice were on a diet. Moreover, these changes in the brain could be detected for a long time after the diet had ended. 

“This could allow us to diminish the yo-yo effect,” notes lead author Henning Fenselau, a researcher at the Max Planck Institute for Metabolism Research. 

“In the long term, we aim to find therapies for humans to help maintain body weight loss after dieting. To achieve this, we continue to explore how we could block the mechanisms that mediate the strengthening of the neural pathways in humans as well.”

AgRP neurons in the hypothalamus are known to control the feeling of hunger.Hunger-stimulating neurons 
According to the research, hypothalamic circuits that control the drive for hunger significantly impact body weight. 

The authors identified the effect of synaptic plasticity – the change that occurs at synapses – the junctions between neurons that allow them to communicate – on stimulating hunger-promoting AgRP neurons. These are potent and long-lasting appetite stimulators. 

“In our present study, we find that the physical neurotransmitter connection between these two neurons, in a process called synaptic plasticity, greatly increases with dieting and weight loss and this leads to long-lasting excessive hunger,” explains co-author Bradford Lowell from Harvard Medical School.

In energy-deprived states, AgRP neurons are inhibited to help reduce food intake, if the neurons do not function, this leads to people losing weight or even starving. 

The study published in Cell Metabolism demonstrated that weight loss after caloric deprivation activates paraventricular hypothalamus thyrotropin-releasing (PVH TRH) neurons, which increase the number of active PVH TRH and AgRP neuron synapses. 

As a result, AgRP neurons have an elevated activity, leading to increased hunger and weight gain until the lost weight has been regained. 

Long-term effects of neuron connection
A brief stimulation of the connection between the two neurons triggered a persisting body weight gain. 

The researchers found that the physical neurotransmitter connection between two neurons leads to long-lasting excessive hunger.The researchers note that the effect on nerve cells is long-lasting. It continues during energy deficit states, days after food access and on a restricted caloric diet following fasting. The effect did not stop until the energy deficit during weight loss was fully restored. 

“People have looked mainly at the short-term effects of dieting. We wanted to see what changes in the brain in the long term,” explains Fenselau.

“This work increases understanding of how neural wiring diagrams control hunger. We had previously uncovered a key set of upstream neurons that physically synapse onto and excite AgRP hunger neurons,” adds Lowell. 

At the same time, silencing the PVH TRH neurons inhibited their activation of AgRP neurons, diminishing the accompanying weight gain. 

51% of the world overweight by 2035
The World Obesity Federation has predicted that 51% of the world’s population will be overweight or obese by 2035 if current patterns are unchanged. 

Another study on mice found that high-protein diets and specific antibiotics can prevent weight gain after dieting. 

Prescription weight loss drugs are becoming more available worldwide, such as semaglutide, which is used to tackle obesity. However, 90% of people regain weight after finishing the treatment. 

Alex Miras, a professor of endocrinology at Ulster University, Northern Ireland, previously told NutritionInsight on semaglutide: “All studies have shown that the patients’ cardiometabolic benefits from the drug almost completely disappear when the medication is stopped.” 

According to Innova Market Insights, weight management claims in supplements are decreasing, globally shrinking by 24% annually since the end of 2020. Weight loss was the top subcategory, mostly paired with digestive and liver health, energy, stamina and immune health. 

By Jolanda van Hal