Sci Adv | Wu Qi's team reports a novel dopamine loop that reduces obesity and weight by enhancing satiety

Editor | Enzyme Beauty Just like every good story has a beginning, a climax, and an end, the animal instinctive behavior of foraging consists of a trilogy that includes the beginning, the continuation, and the end.

Animals start to search for food when they are hungry, find a food source and ingest it to replenish nutrition and energy, and then gradually develop a sense of fullness and slow down eating as the food intake increases, until they stop eating completely.

So far, we still lack a full understanding of how the brain regulates the occurrence and enhancement of satiety until the feeding behavior is completely stopped.

The Wu Qi team of Baylor College of Medicine in Houston recently published a paper online in Science Advances: A hindbrain dopaminergic neural circuit prevents weight gain by reinforcing food satiation, reporting a new dopaminergic (DA) neural circuit, which explains how the circuit is Through the dynamic regulation of satiety, the series of processes of feeding termination and weight control are precisely adjusted, and new targeted drugs and related mechanisms of action that are expected to be effective in the treatment of obesity mediated by this loop are revealed.

Although DA neurons located in the ventral tegmental area of ​​the midbrain (Ventral tegmental area, VTA) are recognized to play a vital role in regulating complex physiological functions such as motivation, reward, motor function, and wakefulness, how does the DA nervous system There has been a lack of in-depth research on controlling the entire foraging behavior, and its potential efficacy and neural mechanisms have long been controversial.

The neural circuit newly discovered by Wu Qi's team connects a group of specific dopamine neurons in the midbrain of animals with the parabrachial nucleus (PBN) in the hindbrain, and dynamically regulates the animal's sense of satiety to effectively inhibit food intake.

The parabrachial nucleus plays a key role in regulating taste response and sensitivity, and avoiding bad or toxic foods.

Researchers use a variety of genetics and neurobiology techniques, including specific gene knockout, double retrograde labeling, optical genetics, and in vivo electrophysiological recording, etc.
, and at the same time the group of DA-VTA neurons and DRD1-LPBN neurons In terms of structure and function, the regulation of feeding termination behavior has been studied in depth.

The team observed that the DA-VTA neurons in the experimental mice produced slow and continuous discharge enhancement over time during the feeding behavior, and then produced instantaneous violent activities within a specific time window when the feeding behavior was about to be terminated, followed by the feeding behavior The end was quickly suppressed to a static level.

On the contrary, the researchers can significantly prolong their eating time and food intake by inhibiting the transient firing process of this group of DA neurons in the satiety time window, thus proving that this neural circuit is effective for the feeding termination behavior caused by the satiety response.
Dynamic two-way adjustment.

At the same time, they also found that enhancing the activity of downstream DRD1-LPBN neurons also has the effect of stopping foraging behavior.

Therefore, Wu Qi’s team explained through this series of studies that a group of specific DA-VTA neurons dynamically and continuously stimulate the activities of downstream PBN neurons through the postsynaptic DRD1 receptor, and finally produce instantaneous satiety, and then precisely control the whole The whole process of stopping feeding.

In order to explore the high efficiency of the dopamine neural circuit in the targeted treatment of metabolic diseases, especially obesity, the team successfully screened a targeted specific drug Methylphenidate (MPH) through genetics and pharmacology.
And found that it reduces food intake by specifically activating the dopamine neural circuit to produce an effective weight loss effect.

Methylphenidate is currently the first-line clinical drug approved by the US FDA for the treatment of attention deficit hyperactivity disorder.

This important discovery has laid an important foundation for further exploration of the transformation and clinical medical research of methylphenidate and its related derivatives in the field of weight control and obesity treatment.

Professor Yong Xu, Dr.
Xia Guobin, Dr.
He Yanlin, Dr.
He Yang, and Monica Farias of Baylor College of Medicine are co-signed authors of this article.

Original link: https://advances.
sciencemag.
org/content/7/22/eabf8719 Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.