Could this specific protein change how we treat obesity?

After five years of research, Alexandre Fisette’s team has pinpointed a protein, called Cited1, which establishes a molecular bridge between a metabolic hormone (leptin) and a sex hormone (estradiol) in the neurons of the brain. In doing so, it triggers a mechanism that helps control the energy balance and subsequently body weight. “It is believed that Cited1 has a therapeutic potential to fight against obesity and this is what we are now seeking to verify,” says Fisette, professor in the department of medical biology at the University of Quebec at Trois-Rivières. “Our preliminary results are very promising.” Read: Powerful new obesity drug poised to upend weight loss care Leptin, commonly known as the "satiety hormone," is secreted into the bloodstream by fat. The more fat cells there are, the more leptin there is in circulation. “For the brain, it is the gauge of the amount of energy stored in the body. Leptin triggers the appropriate response by reducing appetite and promoting energy expenditure,” explains Fisette. In obese people, however, there is a resistance to leptin which no longer manages to play its role of satiety controller. From there, the scientific community has been looking for a way to "re-sensitize" the brain to leptin in order to treat obesity. One of the avenues explored led to sex hormones. “During their reproductive life, women are protected against metabolic disorders, such as diabetes and obesity, but they become susceptible to them after menopause,” Fisette says. In studying estradiol, an estrogen necessary for the maintenance of fertility and secondary sexual characteristics, the research shows that it succeeds in reactivating the sensitivity to leptin by activating in the same area of the brain. The catch: due to its carcinogenic potential and harmful side effects on fertility, estradiol cannot be used in therapy in humans. Read: WeightWatchers is getting into the prescription weight loss business "We therefore sought to understand the molecular path that allows estradiol to re-sensitize to leptin, saying to ourselves that if we found this path, we could probably do without estradiol," says Fisette. In trying to find this path, he and his team used different open databases, and in particular genetic databases, which they crossed with each other. “We identified that Cited1 could be a good candidate. It is a transmission cofactor protein that can stick to other proteins to modify their action,” he says. Evidence on mice To validate their intuition, the researchers took a preclinical approach by performing tests on mice. Some were genetically modified by removing Cited1 from their genome, others were not, and all followed an obese diet. As a result, the male mice all became obese, while those female mice lacking Cited1 became twice as obese. In order to verify whether this difference depended on estradiol, the research team simulated menopause in “normal” female mice deprived of Cited1 by having them undergo an ovariectomy. “After the same obese diet, there was no longer any difference between the mice without Cited1 and the others,” says Fisette. Conversely, male mice were treated with estradiol and those deprived of Cited1 grew while the others were protected against becoming overweight, he added. This circumstantial evidence of the role of Cited1 was then corroborated by more pointed molecular studies leading to research published in Cell Metabolism. The article caught the attention of the editors of Nature Reviews Endocrinology. "We demonstrate how Cited1 generates a molecular cascade that allows the meeting between leptin and estradiol to induce the mechanism of satiety,” says Fisette. In the near future, this discovery could eventually lead to treatments for obesity. “Can we boost Cited1 to re-sensitize the brain to leptin without resorting to estradiol? This is the subject of our research in order to verify whether there is a therapeutic interest in this avenue,” says Fisette, who thinks that this approach could also be useful for the treatment of gestational diabetes or infertility. This article has been translated from its original French and first appeared on our sister site Profession Santé.

Could this specific protein change how we treat obesity?

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