A brand new candidate for weight-loss treatment is on the table, with scientists uncovering for the first time how a hormone produced by the hypothalamus during sleep has a direct impact on appetite regulation and metabolism. This opens the door to developing a novel class of medication that could tackle obesity like GLP-1 agonists.
"Sleep deficiency is associated with obesity, but the mechanisms underlying this connection remain unclear," the Chinese scientists noted in the study. "Here, we identify a sleep-inducible hypothalamic protein hormone in humans and mice that suppresses obesity. This hormone is cleaved from reticulocalbin-2 (RCN2), and we name it raptin."
Researchers from the Xiangya Hospital of Central South University have become the first to identify and understand how this sleep-induced hypothalamic hormone signals satiety to the gut, curbing food intake. What's more, poor or inadequate sleep greatly reduces raptin levels, which blocks appetite control. And raptin levels were much lower in those with obesity.
"Raptin binds to glutamate metabotropic receptor 3 (GRM3) in neurons of the hypothalamus and stomach to inhibit appetite and gastric emptying, respectively," the researchers wrote.
Raptin is a 'cleaved fragment' of the reticulocalbin-2 (RCN2) protein – which is known to play a role in bone formation and cancer, but has never been linked to appetite control or other metabolic functions before.
In the study, the team identified and confirmed raptin's role in metabolic processes through a combination of proteomics to understand the structure and biology of the RCN2 protein, as well as molecular biology, neuroscience, and human clinical data. Raptin's role was also shown to be consistent in both mice and humans.
Essentially, raptin is closely tied to circadian rhythm cycles, and while the scientists did not state during which specific sleep stage the hormone is produced and released, its levels peak during night shut-eye – most likely during the non-rapid-eye-movement (NREM) phase. The hormone gradually depletes during the day, before being replenished once again during the next sleep cycle. (Further studies will, however, need to confirm if sleep stages play a specific role here.)
Poor or inadequate sleep has, of course, been implicated in hormone-related weight gain. One such study from 2022 found that a lack of sleep ramps up the production of ghrelin, which results in increased appetite, and limits the secretion of leptin, which then interferes with the gut's satiety signals. Other research has tied poor sleep to increased levels of stress hormones and their impact on metabolic regulation.
In humans, the researchers assessed raptin levels, 'sleep efficiency' and other metabolic measures in 262 participants, with 127 of those considered clinically obese. Then, they conducted a trial with 30 individuals, 15 in the control and 15 who underwent Sleep Restriction Therapy (SRT) for three months. At the end of the trial, data was collected to assess changes in raptin levels and body weight, as well as sleep quality and energy intake.
"Participants suffering from sleep deficiency exhibited lower raptin levels and aggravated obesity, whereas patients with obesity that underwent SRT had higher raptin levels and alleviated obese phenotypes," the researchers wrote. "These findings further emphasize the importance of sleep quality on metabolic homeostasis."
What's more, a further genetic study of 2,000 obese individuals led to the discovery of an RCN2 variant, which was present in the biological code of a group of family members who all suffered from Night Eating Syndrome (NES). NES is currently hard to treat – it's generally approached as a psychological disorder – and is often misdiagnosed, so these findings could have a huge impact on those who suffer from these nocturnal binges. The variant blocked the production of raptin, and all individuals with it were also obese.
"Individuals with RCN2 nonsense variant suffered from obesity," the team said. "Our study confirmed that the protein encoded by RCN2 nonsense variant could not be secreted, and thus could not bind to GRM3 to exert the downstream effects."
The team also noted a connection between high-fat diets and poor sleep, and more research is needed to see how this may further impact raptin production and its ability to regulate appetite. Overall, though, these findings lay the groundwork for developing novel therapeutics for weight loss and obesity.
"Here, we showed that the circadian release of hypothalamic raptin decreases 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 cooperates with GRM3 to suppress appetite and obesity, thus providing a potential new avenue to treat obesity."
The study was published in the journal Cell Research.
Source: Xiangya Hospital of Central South University via Nature