Many people who have dieted are familiar with what’s known as the yo-yo effect, when they experience the kilos creeping back on after dieting. Researchers at the Max Planck Institute for Metabolism Research and at Harvard Medical School have now shown in mice that dieting affects communication between brain cells, and in particular signaling to AgRP neurons in a region of the brain called the arcuate nucleus of the hypothalamus (ARC), which promote hunger.
The studies showed that in mice, the nerve cells that mediate the feeling of hunger receive stronger signals after fasting, so that the animals then eat significantly more after the diet and gain weight more quickly. Blocking this dieting-related increase in signaling then held back the weight gain. The researchers, headed by Henning Fenselau, PhD, a researcher at the Max Planck Institute for Metabolism Research, suggest that their finding could help in the future development of drugs that hold back this signal amplification and help to maintain a reduced body weight after dieting.
Reporting on their findings in Cell Metabolism (“A synaptic amplifier of hunger for regaining body weight in the hypothalamus”) Fenselau and colleagues wrote, “Viewed in the context of the emerging obesity epidemic, our results provide new rationales for developing therapeutic strategies to support long-term maintenance of reduced body weight after dieting.”
Dieting is the most widely used approach to losing body weight, but the vast majority of individuals who initially succeed in reducing their weight will “fail in long-term adherence to a caloric deficit and eventually regain lost weight,” the authors wrote, “which poses a major public health issue in humans.”
The ARC is thought to present an essential part of the neurocircuitry that drives weight regain, and ARC neurons have been shown to integrate central and circulating signals of energy availability. Moreover, the team continued, “… distinct ARC neurons are both necessary and sufficient for driving feeding behavior, and their genetic manipulations result in profound body weight alterations, underscoring a key role for the ARC in long-term control of body weight.” Interestingly, there is a large body of literature demonstrating that synaptic inputs to key ARC neurons that control body weight do undergo changes in response to calorie restriction. “ … structural and functional synaptic changes in ARC neuron inputs suggest that weight loss fundamentally alters how their activity is coordinated by afferent brain regions.”
However, the researchers acknowledged, scientists still have only a basic understanding of how weight loss-induced changes in the neurocircuits in the ARC might be involved in counterregulatory processes, such as increasing hunger, which could explain why most diets fail in the longer term. “People have looked mainly at the short-term effects after dieting. We wanted to see what changes in the brain in the long term,” explained Fenselau.
AgRP neurons are the population of ARC neurons that are most strongly associated with driving hunger. Restricted calorie intake—for example, during fasting—activates these AgRP neurons, leading to increased feeding and weight gain, the scientists continued. “Conversely, AgRP neuron inhibition reduces food intake in energy-deprived states, and their ablation leads to starvation and weight loss.”
For their newly reported study, the researchers put mice on a calorie-restricted diet, and used a combination of circuit-specific electrophysiological, optogenetic, and chemogenetic approaches to assess which circuits in the brain changed, focusing on the hypothalamic AgRP neurons. They demonstrated that the neuronal pathways that stimulate AgRP neurons sent increased signals when the mice were on a diet.
The results showed that weight loss resulting from caloric restriction activates a population of cells called paraventricular hypothalamus thyrotropin-releasing (PVHTRH) neurons, which then increase the number of active PVHTRH → AgRP neuron synapses. Importantly, this “profound” change in the brain could be detected for a long time after the diet, the scientists noted. “A key finding of our study is that the reported amplification of transmission across PVHTRH → AgRP synapses is long-lasting in nature, as it persists during states of energy deficit, namely days after food access and on a caloric restricted diet following fasting,” the authors pointed out. In these conditions, mice exhibited increased feeding and gained body weight.
Conversely, selectively inhibiting the neural pathways that activated AgRP neurons led to significantly less weight gain after the diet. “Silencing PVHTRH neurons inhibits the potentiation of excitatory input to AgRP neurons and diminishes concomitant regain of lost weight,” they continued. “Our results provide a circuit-level understanding of synaptic plasticity in AgRP neurons in response to weight loss and, more specifically, how plastic changes of a defined circuit serve as a control point for the long-term maintenance of body weight.”
“This work increases understanding of how neural wiring diagrams control hunger,” added co-author Bradford Lowell, PhD, at Harvard Medical School. “We had previously uncovered a key set of upstream neurons that physically synapse onto and excite AgRP hunger neurons. 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.”
The findings, Fenselau suggested, “… could give us the opportunity to diminish the yo-yo effect. In the long term, our goal is to find therapies for humans that could 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.”
This long-term plasticity, the authors commented, “may underlie the long-lasting facilitation of the hunger drive during the weight maintenance phase after dieting and the consequent increased motivation for food consumption and regain of lost body weight in the long-term, which is observed in most human dieters.”
