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New Sleep-Linked Hormone Raptin May Help Fight Obesity

A recent study published in Cell Research identified a new hypothalamic hormone named Raptin. This hormone is closely linked to sleep and has powerful appetite-suppressing and anti-obesity effects. The discovery sheds new light on the connection between sleep and obesity, and may open new avenues for obesity treatment.

Why Does Sleep Deprivation Lead to Weight Gain?

In modern society, staying up late has become the norm. But what many don't realize is that those late nights might be quietly making you gain weight. Research shows that sleep deprivation alters hormone levels. It increases ghrelin and decreases satiety hormones like leptin, PYY, and GLP-1. This imbalance leads to increased energy intake, which outweighs any increase in energy expenditure—ultimately resulting in weight gain.

Figure 1. Energy intake under different sleep durations[1].
Figure 2. Potential pathways by which less than 6 hours of sleep affects body weight regulation[2].
Raptin: A Sleep-Induced Hormone with Satiety-Promoting Effects

In this study, scientists discovered a new hormone called Raptin, a protein hormone secreted by the hypothalamus. It is cleaved from reticulocalbin-2 (RCN2). Using a sleep fragmentation (SF) mouse model, researchers performed proteomic analysis of the hypothalamus. They found altered protein expression in SF mice, including significant changes in RCN2, which is highly expressed in the suprachiasmatic nucleus (SCN) and paraventricular nucleus (PVN).

Further experiments showed that RCN2 is cleaved into a shorter fragment in hypothalamic GT1-7 neurons, which is then secreted. Mass spectrometry identified this fragment as spanning amino acids 28-249 of RCN2. The researchers named this fragment Raptin.

Figure 3. Schematic of RCN2 cleavage into Raptin[3].

Raptin secretion follows a circadian rhythm, peaking during sleep and dropping during wakefulness. Sleep deprivation disrupts this rhythm and reduces Raptin levels—potentially leading to increased appetite and obesity.

Figure 4. Plasma Raptin levels in mice and humans at different time points (purple area indicates sleep phase)[3].

Using patch-clamp electrophysiology, researchers found that Raptin activates GRM3-positive neurons in the PVN. Chemogenetic manipulation of these neurons showed that their activation suppresses appetite without affecting gastric emptying, suggesting the PVN pathway does not directly communicate with the stomach. In contrast, activation of GRM3+ neurons in the stomach suppresses both appetite and gastric emptying.

To explore the mechanism, researchers performed phosphoproteomic analysis of hypothalamic neurons. They found that Raptin significantly affects the PI3K-AKT signaling pathway. Raptin increases the colocalization of kinesin heavy chain (KHC) with mitochondria. KHC is a key motor protein for mitochondrial transport in axons, and its mitochondrial localization reflects mitochondrial mobility.

Treatment with PI3K inhibitors (Wortmannin and LY294002) abolished the Raptin-induced increase in KHC-mitochondria binding and the rise in mitochondrial ATP levels—highlighting the critical role of the PI3K-AKT pathway.

Compared to glutamate, which inhibits the cAMP pathway, Raptin activates the AKT pathway—and the two do not interfere with each other. Knocking down KHC in the PVN weakened Raptin's ability to activate neurons and suppress appetite—confirming that KHC is essential for Raptin-GRM3 signaling in neuronal activation and appetite control.

Figure 5. Raptin binding sites with GRM3 in the PVN and stomach[3].
The Neural Circuit of Raptin: A Bridge from Sleep to Appetite

Further investigation revealed that Raptin secretion is regulated by AVP neurons in the SCN. These neurons connect to Raptin-secreting neurons in the PVN, forming a neural circuit that controls Raptin release.

Using optogenetics and chemogenetics, researchers activated or inhibited SCN AVP neurons and observed corresponding changes in Raptin secretion and appetite. These results confirm that the SCN-AVP to PVN-Raptin circuit is key in regulating appetite and body weight.

Raptin and Obesity: Clinical Evidence and Genetic Mutations

To validate Raptin's role in obesity, researchers overexpressed Raptin in the PVN of SF mice. Compared to controls, these mice showed reduced food intake and weight gain, as well as improved glucose tolerance and insulin sensitivity. This suggests that Raptin not only regulates appetite and weight but also benefits metabolic health—making it a promising therapeutic target.

Figure 6. Body weight and food intake in SF mice after 4-week ICV infusion of Raptin or PBS[3].

In human studies, researchers found that obese individuals often have poor sleep quality and lower Raptin levels. After sleep restriction therapy (SRT), Raptin levels increased, and both body weight and energy intake decreased.

Figure 7. Sleep efficiency and plasma Raptin levels in obese vs. non-obese individuals[3].

Moreover, a mutation in the RCN2 gene was identified that prevents normal Raptin secretion. Individuals with this mutation are more prone to obesity and exhibit night eating syndrome (NES)—waking up at night to eat uncontrollably.

Figure 8. Plasma Raptin levels during the night phase in NES patients vs. controls[3].
Figure 9. Cumulative energy intake during day and night in NES patients vs. matched obese controls[3].
Raptin: A New Hope for Future Obesity Treatment

This study not only reveals Raptin's key role in appetite and weight regulation but also opens new doors for obesity treatment. Scientists believe that targeting the Raptin-GRM3 signaling pathway could lead to the development of new weight-loss drugs. Additionally, improving sleep quality may become an effective strategy for weight control.

In short, the discovery of Raptin deepens our understanding of the link between sleep and obesity. Perhaps one day, we really can sleep our way to a better figure. But until then, maintaining good sleep habits remains one of the best ways to manage weight.

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