AgRP neurons may not be as indispensable to body weight maintenance as previously thought

Researchers from the University of Texas Health Science Center at Houston and the University of Science and Technology of China (USTC) explored the role of AgRP neurons in the hypothalamus in maintaining a healthy body weight. While past research had suggested that these neurons played a crucial role in regulating feeding behavior and body weight, the new findings published in Cell Reports suggest they may not be as essential as previously believed.

Feeding is vital for acquiring energy and nutrients, and its impact on overall health, including body weight, metabolism, and immune function, cannot be underestimated. Understanding the neural processes involved in excessive eating and obesity could have significant implications for global health and targeted treatments promoting healthy food intake.

Previous studies had shown that activating AgRP neurons in mice’s brains led to binge eating behaviors and extreme obesity, implying their sufficiency in promoting feeding and weight gain. In contrast, in 2005, researchers selectively killed AgRP neurons in adult mice using diphtheria toxin, causing the mice to stop feeding, lose weight rapidly, and even starve to death.

Dr. Cheng Zhan, one of the researchers involved in the recent study, explained that their work aimed to shed light on the mechanisms underlying weight maintenance and feeding regulation. The brain plays a crucial role in regulating feeding and metabolism, as demonstrated in both humans and animals. The hypothalamus, a small region at the brain’s center, is of particular interest due to its connection to AgRP neurons and their impact on food intake behavior in adult mice.

“These findings have been widely cited and reiterated and have found their way into textbooks. For a long time, it has thus been widely believed that AgRP neurons in the hypothalamus are crucial and indispensable for feeding behavior and regulation. Our present study challenges the longstanding dogma that AgRP neurons are required for normal feeding and body weight regulation.”

This recent study was carried out in two different labs, one in the United States and the other in China. The first series of experiments was conducted by Dr. Tong’s Lab at University of Texas Health Science Center of Houston.

In these experiments, the researchers selectively expressed the human diphtheria toxin receptor on AgRP neurons in the brain of adult mice and injected low doses of diphtheria into their brain ventricles. Diphtheria is a toxic substance secreted by certain bacteria that inhibits the synthesis of proteins and can kill cells.

“Selectively expressing and injecting diphtheria was sufficient to kill AgRP neurons, but it did not affect the weight and basal feeding levels of the mice,” Dr. Zhan said. “However, injecting high doses of diphtheria toxin not only caused weight and feeding reduction in diphtheria toxin receptor mice, but also in wild-type mice, and could even lead to death. These results suggest that the feeding and weight reduction observed in previous studies that killed AgRP neurons may be attributed to the non-specific toxicity of diphtheria toxin.”

In a separate set of experiments carried out by Dr. Zhan’s Lab at USTC in China, the researchers tried to kill AgRP neurons using a different method, to assess the impact of this on the mice’s feeding behavior. Specifically, they selectively expressed the Caspase-3 gene, inducing the apoptosis (i.e., programmed death) of AgRP,

“We found that killing AgRP neurons using this method did not decrease the weight and feeding of adult mice,” Dr. Zhan said. “Interestingly, although killing AgRP neurons did not affect basal feeding and weight, it had some impact on refeeding after fasting, indicating that AgRP neurons may play a role in responding to environmental stress. Using two different methods to kill AgRP neurons, our study concluded that AgRP neurons are not essential for maintaining basal feeding and weight under laboratory conditions but may be more important for feeding and weight regulation under conditions of food scarcity.”

The recent findings gathered by Dr. Zhan, Dr. Tong and their colleagues challenge the common understanding of AgRP neurons as indispensable for feeding behavior and body weight maintenance. In addition, their work suggests that feeding behavior is regulated by complex neural mechanisms involving multiple brain nuclei and neuronal subgroups. In the future, this study could pave the way for further research exploring the role of AgRP neurons and other neuron populations in regulating feeding behavior.

“In recent years, research has discovered several brain regions that possess feeding-promoting functions,” Dr. Zhan added. “As a next step, we will focus on studying the robustness of feeding behavior and the redundancy in its regulatory mechanisms. This includes investigating the interconnections between different orexigenic neurons and exploring new targets for feeding regulation.

“Further research will provide a comprehensive understanding of the neural mechanisms underlying feeding regulation and offer new targets and insights for controlling diet and treating eating disorders.”

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