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Serotonin (5-HT) is a monoamine neurotransmitter in the central nervous system that is widely used inthe treatment of diseases such as obesity and depression.
Current studies have shown that 5-HT has at least 14 different receptors, which regulate weight and mood through different signaling pathways, and the complexity of this receptor has brought uncertainty
about the role of many drugs.
Second-generation antipsychotics (clozapine and olanzapine) improve different psychiatric symptoms by binding to different 5-HT receptors, but cause adverse effects
such as hunger and weight gain in up to 60% of patients.
Animal experiments have shown that lowering 5-HT in the brain causes excessive food intake and leads to obesity; Promoting 5-HT content inhibits eating
.
The appetite-suppressing effect of 5-HT is mainly mediated by the 5-HT 2C receptor (5-HT2CR) expressed on hypothalamic melanogen (POMC) neurons
.
On December 15, 2022, Professor Yong Xu of Baylor College of Medicine published an article in the journal Nature Medicine to reveal the presence of 5-HT 2C receptor mutations in severely obese patients, which can cause maladaptive behavior
in the body.
Figure 1: Obese people develop mutations in the 5-HT 2C receptor
The researchers performed exome sequencing on 2548 obese people and 1117 healthy adults (normal weight) and found that 13 rare mutations in the gene encoding the 5-HT 2C receptor in 19 obese patients, and these obese patients with mutated genes had a historyof excessive diet and weight gain.
Furthermore, ex vivo experiments found that among these gene mutants of 5-HT 2C receptors, F327L mutants could significantly cause 5-HT 2C receptor dysfunction, and localization experiments found that F327L mutants were located in the endoplasmic reticulum
.
Figure 2: F327L mutant mice promote obesity in mice
After further knocking the 5-HT2CR-F327L mutant into mice (referred to as F327L mutant mice) through CRISPR-Cas9 technology, even after the ordinary diet, excessive feeding, weight gain, fat and fat increase.
Obesity in mice can be accelerated after a high-fat diet
.
The 5-HT2CR agonist suppressed appetite in mice, but this inhibitory effect was attenuated in F327L mutant mice, suggesting that the 5-HT2CR-F327L mutant gained body weight
by promoting food intake.
Immunofluorescence experiments found that 5-HT2CR agonists can activate hypothalamic POMC neurons, but this activation is inhibited in F327L mutant mice, and electrophysiological experiments have further found that the firing frequency of POMC neurons in F327L mutant mice is reduced, and the depolarization of POMC neurons caused by 5-HT2CR agonists is weakened in F327L mutant mice, which indicates F327L Mutant mice respond weakly
to 5-HT2CR agonists.
Studies have shown that 5-HT signaling is involved in the defensive response
caused by threats.
Through the interloper experiment, it was found that the F327L mutant mice had enhanced their defensive behavior after facing unfamiliar invading mice
.
In the three-box social experiment, the social interaction behavior of F327L mutant mice with other mice was significantly reduced
.
In elevated experiments, F327L mutant mice took more time to enter the open arm and exhibited an anxiolytic state
.
In this paper, multiple mutations in the gene encoding 5-HT2CR were found through the genetic data of obese patients, among which the F327L mutant affected the function of 5-HT2CR the most obviously, and further knocked the F327L mutant into mice and found that this mutation could cause obesity and social behavior disorders
.
and further revealed that melanocortisol receptor agonists may be effective in treating severely obese patients
carrying the HTR2C variant.
【References】
https://doi.
org/10.
1038/s41591-022-02106-5
The images in the article are from references
