Scientists have for the first time identified a new hormone produced by the hypothalamus during sleep, which plays a key role in the regulation of appetite and metabolism. This discovery paves the way for the creation of a fundamentally new class of drugs that can effectively fight obesity similar to GLP-1 agonists.
"Sleep deficiency has long been associated with excess weight gain, but the biological mechanisms of this relationship have remained a mystery until now," the Chinese researchers note. In their work, they present a sensational discovery: a protein hormone of the hypothalamus, activated during sleep in humans and mice, suppresses the development of obesity. This hormone, formed as a result of the cleavage of reticulocalbin-2 (RCN2), was named raptin.
Researchers at Xiangya Hospital of Central South University were the first to reveal the mechanism of action of raptin: it transmits signals to the gastrointestinal tract about satiety, thereby limiting food intake.
Moreover, lack of sleep dramatically reduces the concentration of raptin, which weakens appetite control. The study also showed that the level of this hormone is noticeably lower in obese people.
"Raptin binds to glutamate metabotropic receptor 3 (GRM3) in hypothalamic and gastric neurons, resulting in suppression of hunger sensation and delayed gastric emptying," the authors of the paper explain.
Interestingly, reticulocalbin-2 has previously been linked to bone formation and oncogenesis, but its effects on appetite and metabolism remained unknown until now. The team of scientists confirmed the role of raptin in the regulation of metabolic processes by applying proteomic analysis, molecular biology, neuroscience and clinical data. The effects of raptin were found to be universal in both humans and rodents.
This hormone is closely linked to circadian rhythms. Although the exact phase of
sleep in which it peaks has yet to be determined, studies indicate its maximum concentration during the night - probably in the slow-wave sleep (NREM) stage. During the day, raptin levels gradually decrease and then replenish again with the onset of the next sleep cycle. However, further research should clarify what role the different phases of sleep play in this process.
Sleep deprivation has previously been shown to induce hormonal changes that contribute to weight gain. For example, a 2022 study showed that sleep deprivation increases the synthesis of ghrelin, a hormone that stimulates appetite, while decreasing the production of leptin, which is responsible for feelings of satiety.
Now scientists are closer to understanding another important biological mechanism driving the link between sleep quality and weight control. Other studies have linked poor sleep to elevated levels of
stress hormones and their effect on metabolic regulation.
The researchers assessed raptin levels, "sleep efficiency" and other metabolic indicators in 262 participants, 127 of whom were considered clinically obese. They then conducted a study involving 30 people, 15 of whom were in the control group and 15 of whom were undergoing sleep restriction therapy (SRT) for three months. At the end of the study, data were collected to assess changes in raptin levels and body weight, as well as sleep quality and energy intake.
"Sleep-deficient participants exhibited lower raptin levels and worsened obesity, whereas obese patients who underwent SRT had higher raptin levels and alleviated the obesity phenotype," the researchers wrote. "These data further emphasize the importance of sleep quality for metabolic homeostasis."
Moreover, further genetic study of 2,000 obese people led to the discovery of an RCN2 variant that was present in the biological code of a group of family members who suffered from nocturnal overeating syndrome (NES).
NES is currently difficult to treat - it is usually seen as a psychological disorder - and is often misdiagnosed, so these findings could have a huge impact on those who suffer from nocturnal attacks. The variant blocked the production of raptin, and all people with it were also obese.
"People with the nonsense variant of RCN2 suffered from obesity," the team stated. "Our study confirmed that the protein encoded by the RCN2 nonsense variant cannot be secreted and therefore cannot bind to GRM3 to exert downstream effects."
The team also noted a link between high-fat diets and poor sleep, and more research is needed to understand how this may affect the production of raptin and its ability to regulate appetite. Overall, however, these findings lay the groundwork for the development of new therapeutics for weight loss and the treatment of obesity.
"We have shown that circadian release of hypothalamic raptin reduces appetite but does not affect other important circadian behaviors, including the sleep cycle itself or physical activity," the researchers concluded. "Our study identifies raptin as a unique hypothalamic hormone that interacts with GRM3 to suppress appetite and obesity, thereby opening a potentially new avenue for the treatment of obesity."
The study was published in the journal Cell Research.