Academic Latitude Academic Latitude 2024-06-29 08:05 Beijing
Since semaglutide was launched, a new weight loss boom has been quickly sparked. Compared with the previous weight loss drugs that can only lose 5% of their body weight, the weight loss effect of semaglutide is particularly impressive, and obese patients who take semaglutide on time and in the right amount can lose an average of 15% of their body weight.
As a glucagon-like peptide-1 receptor agonist (GLP-1RA), semaglutide mimics the functions of GLP-1 in the body, including suppressing appetite and causing feelings of fullness, thereby reducing feeding behavior. It is believed that people who have used this type of drug have experienced a great loss of interest in food, especially when the food is already in front of them but do not want to eat it.
Image source: 123RF
Hyung Jin Choi, a neuroscientist from Seoul National University, tried liraglutide, another GLP-1RA drug, and he was also impressed by it, because whenever he saw or smelled food, he immediately felt full, which is a typical preingestive satiation. In the latest Science paper, Professor Choi and his colleagues found that neurons in the dorsomedial nucleus (DMH) of the hypothalamus are responsible for encoding pre-digested satiety information, and direct activation of these neurons can cause satiety without the use of GLP-1RA, which also indicates that a new neural target for weight loss has been found.
In the human trial, they recruited a group of volunteers to participate in the GLP-1RA test, and they assessed the level of satiety in all people in three stages: baseline state (no food), pre-digestion stage (having food but not having eaten it), and digestion stage. They found that the control group felt less satiety as they transitioned from baseline to pre-digestive. However, in those treated with GLP-1RA, satiety continues to increase, especially during the pre-digestion phase.
▲The study found a class of GLP-1RA-targeted neurons in the hypothalamus (Image source: Reference [1])
With the help of a special mouse model, the authors found that GLP-1RA entering the body specifically activated a small subset of neurons in DMH, which were completely independent of the neurons expressing leptin receptors in DMH. They called this type of neuron, DMHGLP-1RA, and if DMHGLP-1RA was selectively inhibited, mice significantly increased the duration of their meals and the amount of food they ate. Conversely, if DMHGLP-1RA is activated, then the mice immediately stop eating. Experiments in mice have also shown that after artificially removing the GLP-1 receptor of DMHGLP-1RA neurons, even drugs such as semaglutide cannot suppress the desire to eat, and the effect of the "miracle drug" disappears.
In addition, the authors found that DMHGLP-1RA continued to divide into two subpopulations, some of which remained active until the mice began to look for food, and others that remained active after eating. Although they both cause feelings of fullness, the former tells you "don't eat" and the latter tells you "eat enough".
Researchers in related fields pointed out that this finding also has important implications for GLP-1 research, for example, some studies have found that after manipulating GLP-1 receptors in certain brain regions, the expected feeding behavior changes are not observed, so it is likely that the correct neuronal population has not been found. These new discoveries are expected to further promote the research progress of GLP-1, and it is believed that more and more effective weight loss therapies will emerge in the future.
Resources:
[1] GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans. Science (2024). DOI: 10.1126/science.adj2537
[2] How blockbuster obesity drugs create a full feeling — even before one bite of food. Retrieved June 28, 2024 from https://www.nature.com/articles/d41586-024-02106-0