The prevalence of obesity and overweight is increasing year by year worldwide, and patients can be complicated by hypertension, diabetes, and cardiovascular and cerebrovascular diseases, resulting in reduced life expectancy and increased mortality. Although the weight loss drugs that have been marketed have good efficacy, the frequent gastrointestinal side effects and injection administration often make patients unbearable, so diet drugs with few side effects and free injection are the current research hotspot. Small peptide drugs have been widely used in the prevention and treatment of various diseases due to their high safety and low side effects. More and more studies have shown that small peptides can effectively affect the body's metabolism and regulate the structure of intestinal flora, but there is still a lack of oral peptides that can reduce weight.
Zhao Fangqing's team from the Beijing Institute of Biological Sciences, Chinese Academy of Sciences, and Wei Hong's team from Army Medical University published a research paper in the journal Gut entitled A novel peptide protects against diet-induced obesity by suppressing appetite and modulating the gut microbiota.
Using a variety of animal models of dietary obesity such as mice, rats and macaques, the study studied and confirmed that the oral small peptide D3, independently developed by the team, has a significant weight loss effect.
By targeting the "microbiota-gut-brain axis", this small peptide stimulates intestinal epithelial cells to produce more anorexial hormones (urinosylene, UGN), and promotes the enhancement of POMC neuronal activity with food suppressive effects in the hypothalamus, reducing animal food intake; In addition, the small peptide can significantly improve the balance of intestinal flora and increase the abundance of the mucinophilin Akkermansia muciniphila.
First, the team screened a small peptide that could improve metabolic function from the end product of human humoral defensin digested by intestinal enzymes, and then modified it based on intelligent design to obtain small peptide D3 with high cellular affinity. Compared with other derivatives of the same series, D3 reduced the body weight of mice, rats and macaques on a high-fat diet by about 12.06% (8 weeks), 8.89% (10 weeks) and 7.71% (6 weeks), respectively. In addition, D3 had the same weight loss effect in obese mice and reduced hyperglycemia caused by a high-fat diet and improved insulin resistance.
Through the study of the mechanism of action of D3, it was found that after oral administration, D3 was mainly absorbed by intestinal epithelial cells in the small intestine, which significantly promoted the expression of the anorexia hormone UGN, while the activity and expression of POMC expression neurons with antiphasitic effect in the hypothalamus were enhanced and increased, and the food intake of mice was finally reduced. D3 has limited effects on indirect energy metabolism in mice.
The researchers further found that after D3 treatment, the intestinal microbiota structure of mice underwent significant changes, which were manifested by a decrease in the Firmicutes/Bacteroides phylum ratio, a significant decrease in the genera such as Oscillospira and Desulfovibrio, and a significant enrichment in Bacteroides and Akkermansia and the quantitative results showed that the abundance of Akkermansia increased by about 100 times. Transplantation of the microbiota or single bacterium Akkermansia from D3-treated mice to obese mice also had weight loss effects.
This study is the first to develop a small molecule peptide with high safety and oral weight loss, and systematically elaborates the target site of D3 and its dual mechanism of action against host and intestinal bacteria, respectively, suggesting that D3 has a good safety profile and the potential of drug candidates to resist dietary obesity.
This study provides new ideas for expanding in vivo and in vivo screening methods for orally available small molecule drugs, and provides new targets for the development of anti-obesity drugs around the "bacteria-intestine (UGN)-brain (GUCY2G) axis".
Overview of D3 mechanisms of action
Article from: Biological World