Raptin, a Sleep-Induced Hypothalamic Hormone, Suppresses Appetite and Obesity
In modern society, sleep deficiency has become one of the major causes of metabolic diseases. Studies have shown that insufficient sleep increases energy intake, but its effects on energy expenditure remain unclear. Although some clinical research indicates that sleep-deprived populations exhibit greater energy intake, energy expenditure does not change significantly. Therefore, the mechanisms by which sleep deficiency contributes to obesity require further investigation. Sleep, as a circadian behavior, is closely related to hormonal homeostasis. Sleep deficiency disrupts circadian rhythms, thereby affecting the levels of appetite hormones (such as ghrelin, leptin, orexin, etc.). The hypothalamus, a critical brain region for hormone secretion, is also affected by disruptions in the sleep-wake cycle. Thus, identifying hypothalamic hormones influenced by circadian rhythms, including sleep, may provide new insights into the treatment of obesity.
Source of the Paper
This paper was co-authored by Ling-qi Xie, Biao Hu, Ren-bin Lu, and others, affiliated with the Endocrinology Research Center at Xiangya Hospital of Central South University, the Department of Endocrinology at the First People’s Hospital of Xiangtan City, and other institutions. The paper was published in 2025 in the journal Cell Research, titled “Raptin, a sleep-induced hypothalamic hormone, suppresses appetite and obesity.”
Research Process and Results
1. Discovery and Identification of Raptin
The research team first used a sleep fragmentation (SF) mouse model and found that long-term sleep disturbances led to increased body weight and food intake, but no significant change in energy expenditure. Through mass spectrometry (MS) analysis comparing the hypothalamic proteomes of SF mice and control mice, the researchers identified nine differentially expressed proteins, among which Reticulocalbin-2 (RCN2) was highly expressed in the hypothalamus. Further experiments confirmed that RCN2 is expressed in the paraventricular nucleus (PVN) of the hypothalamus in both mice and humans, with its expression significantly increased during the sleep phase. The researchers discovered that RCN2 is cleaved into a shorter fragment, named Raptin. Raptin secretion peaks during sleep, and sleep deficiency inhibits its release.
2. Mechanism of Raptin Secretion Regulation
The study found that Raptin secretion is regulated by vasopressin (AVP) neurons in the suprachiasmatic nucleus (SCN) through the SCN-PVN neural circuit. Using chemogenetic and optogenetic techniques, the researchers confirmed that activation of SCN-AVP neurons promotes the activity of PVN-RCN2 neurons, thereby increasing Raptin secretion. Conversely, inhibition of SCN-AVP neurons reduces Raptin secretion and increases food intake.
3. Functional Validation of Raptin
By overexpressing RCN2 in the PVN of mice, the research team observed a significant increase in Raptin levels, which effectively alleviated SF-induced weight gain and increased food intake. Additionally, intracerebroventricular (ICV) injection of recombinant Raptin protein confirmed its ability to suppress appetite and gastric emptying, thereby reducing obesity. In high-fat diet (HFD)-induced obese mice, Raptin treatment also demonstrated significant weight loss effects.
4. Receptor and Signaling Pathway of Raptin
Through MS analysis, the researchers identified glutamate metabotropic receptor 3 (GRM3) as the functional receptor of Raptin. Upon binding to GRM3, Raptin activates the PI3K-AKT signaling pathway, suppressing appetite and gastric emptying. Further experiments showed that Raptin maintains neuronal activity by promoting mitochondrial movement in neurons, thereby exerting its appetite-suppressing effects.
5. Clinical Relevance Studies
The research team conducted a cross-sectional study of 262 participants and found that obese individuals had poorer sleep quality and significantly lower plasma Raptin levels. Furthermore, sleep restriction therapy (SRT) increased Raptin levels in obese patients and reduced body weight and energy intake. Additionally, the researchers identified an RCN2 nonsense variant associated with obesity, which leads to reduced Raptin secretion and is linked to night eating syndrome (NES).
Research Conclusions and Significance
This study is the first to identify a sleep-induced hypothalamic hormone, Raptin, which suppresses appetite and gastric emptying through the GRM3 receptor, thereby preventing obesity. Raptin secretion is regulated by SCN-AVP neurons, and sleep deficiency inhibits its release, leading to increased energy intake and weight gain. This discovery not only reveals the molecular mechanisms linking sleep and obesity but also provides a new potential target for obesity treatment.
Research Highlights
- Discovery of a New Hormone: Raptin is the first identified sleep-induced hypothalamic hormone, with its secretion closely related to sleep quality.
- Neural Circuit Elucidation: The study revealed the neural circuit through which SCN-AVP neurons regulate Raptin secretion via PVN-RCN2 neurons.
- Receptor and Signaling Pathway Identification: GRM3 was identified as the functional receptor of Raptin, which exerts appetite-suppressing effects through the PI3K-AKT signaling pathway.
- Clinical Relevance: The study confirmed the association between sleep quality, Raptin levels, and obesity, providing new insights into obesity treatment.
Other Valuable Information
The research team also found that the RCN2 nonsense variant leads to reduced Raptin secretion and is associated with night eating syndrome. This finding provides new clues for understanding the molecular mechanisms of hereditary obesity. Additionally, the discovery of Raptin offers a potential direction for developing anti-obesity drugs targeting GRM3.
This study not only reveals the complex relationship between sleep and obesity but also provides new molecular targets for obesity treatment, holding significant scientific and practical value.