Raptin, a novel brain hormone links sleep health to body weight gain

Accumulating evidence suggests that poor sleep health is associated with an increased risk to develop obesity. Recently, Xie and colleagues have identified a novel hormone, raptin, which is secreted from the brain during sleep to decrease body weight gain by regulating food intake.

Recent real-world sleep pattern data have further established an association of poor sleep quality with higher body weight and obesity development.¹ These latest longitudinal assessments of sleep patterns with commercial wearable devices particularly pinpointed a link of shorter sleep duration (< 6 h) and sleep irregularities to increased odds of incident obesity. Understanding the precise mechanisms underlying these observations is of utmost societal importance, as poor sleep health and obesity are increasingly affecting the global population, and are linked to numerous prevalent metabolic diseases. Because of its fundamental role in controlling homeostatic processes, including sleep and food intake,^2,3 the observed dysregulation of these processes may originate in the hypothalamus. This integral part of the brain contains the central circadian pacemaker, the suprachiasmatic nucleus (SCN), whose cellular activity is entrained by light-dark periods, and which in turn times synchronization of various physiological functions, including the sleep-wake cycle.⁴ In addition, the hypothalamus contains key neuron types that control the homeostasis of feeding, body weight, and neuroendocrine systems. One prominent hypothalamic nucleus, that comprises neuronal populations necessary for food intake and the prevention of obesity, is the paraventricular hypothalamus (PVH).⁵ However, despite the established importance of the SCN and PVH in circadian rhythm and feeding, respectively, it remains unclear whether their cohesive deregulation is linked to obesity development in response to sleep irregularities.

In a new study published in Cell Research, Xie et al.⁶ used a sleep fragmentation paradigm to determine differentially regulated proteins in hypothalami of mice. They identified that sleep-deprived mice showed a downregulation of reticulocalbin-2 (RCN2). This endoplasmic reticulum-localized calcium-binding protein was primarily expressed in neurons of the PVH, and exhibited a circadian rhythm with higher expression levels during the sleep period. Because the PVH contains neurons that direct the secretion of hormones into the bloodstream, the authors measured cleaved products of RCN2 and identified a novel short fragment — raptin. Intriguingly, peak of plasma levels of this newly-identified protein also occurred during the sleep period, in both mice and humans, indicating that raptin is a conserved, sleep-inducible hormone released from the hypothalamus. Using viral mapping techniques in mice, the authors found that SCN neurons act as upstream regulators of the PVH neurons that express RCN2 to drive raptin release (Fig. 1).

Fig. 1: Schematic representation of raptin action.

In individuals with balanced sleep (green, left), raptin levels peak during the sleep phase. SCN neuron projections regulate raptin secretion from PVH neurons that express RCN2. Raptin acts locally on PVH neurons and is secreted into the bloodstream to decrease food intake and body weight gain. In individuals with sleep disruption (red, right), raptin secretion is reduced, particularly during the sleep phase. Reduced raptin levels contribute to increased food intake and weight gain in response to sleep irregularities. Created with BioRender.com.

To assess the contribution of raptin in body weight regulation, the authors administered the hormone into the brains of sleep fragmented mice, which showed lower raptin levels. This alleviated body weight gain by decreasing food intake. Consistent with an appetite-suppressing action of raptin, overexpression of RCN2 in the PVH diminished feeding and weight gain in sleep fragmented mice, whereas site-specific genetic knockout increased food intake and body weight. Mechanistically, the authors found that raptin reduces feeding by targeting the metabotropic glutamate receptor GRM3 to activate neurons in the PVH and in the stomach. Thus, raptin appears to exert its body weight-lowering effects by acting centrally as well as peripherally. Finally, to validate the translational relevance, the authors examined the role of raptin in humans. Consistent with the lowered raptin levels seen in sleep fragmented mice with elevated body weight, raptin levels were lower in humans with obesity, particularly in those with low sleep efficiency. Further, patients with obesity and insomnia, who underwent a sleep intervention therapy, displayed increased raptin levels, decreased food intake, and reduced body weight. Moreover, through genetic screening, the authors identified three patients with obesity, carrying a loss-of-function variant of the RCN2 gene, who suffered from night-eating syndrome, characterized by recurrent episodes of food consumption at night after awakening from sleep.

The identification of raptin has several critical implications, including for clinical interventions. First, the strong correlation between low raptin levels and body weight gain suggests a potential approach for unveiling sleep irregularities in patients with obesity. Identifying at-risk individuals early and encouraging participation in sleep intervention programs could help mitigate the long-term detrimental comorbidities associated with obesity. This begs the question whether circulating raptin level assessments hold potential in general clinical settings, and outperform currently available assessments of sleep irregularities? Second, as determined in mice, raptin acts centrally and peripherally by activating neuronal cell types through GRM3. Since raptin treatment ameliorated feeding and weight gain in sleep fragmented mice, this G-protein-coupled signaling pathway may provide new rationales for developing obesity therapeutics. However, given that GRM3 is widely expressed in the brain and in peripheral organs, including adipose tissue, further studies will be required to detail the specificity and safety of targeting the raptin-GRM3 pathway, particularly in the context of previous genetic studies, which revealed associations between the GRM3 gene and schizophrenia-related phenotypes.⁷ Lastly, the study makes the important observations that SCN neurons communicate with PVH neurons, and that stimulation of this circuit increased plasma levels of raptin. Somewhat surprisingly, the authors found that constant darkness had no effect on the rhythmicity of raptin secretion. Future manipulation studies should resolve how light entrainment of SCN activity bypasses raptin secretion, and whether there is a link between irregular light inputs and circadian disruption of feeding behavior. Regardless, as obesity poses a healthcare challenge due to an array of metabolic comorbidities, identification of raptin will support the development of new strategies to help individuals with poor sleep health to maintain a healthy body weight.