LAUSR

Dear Editor, Organisms need to maintain the balance between energy intake and expenditure for healthy survival. For mammals, eating is the most common process to fuel the body, and ingestive behaviors are well controlled by the neural system in response to peripheral signals, such as nutrients and hormones. In the arcuate nucleus (ARC) of the hypothalamus, Agouti-related peptide-expressing (AgRP) neurons are activated by energy deficit to promote appetitive behaviors. By contrast, proopiomelanocortin (POMC) neurons sense when energy levels are sufficient and inhibit food intake. Hormones, such as neuropeptide Y (NPY), ghrelin, leptin and glucagon-like peptide-1 (GLP-1), and circulating nutrients deliver signals to these neurons. Olfaction also plays an important role in regulating appetitive behavior. The hypothalamus can receive olfactory inputs from olfactory sensory neurons and the olfactory bulb (OB) to coordinate food appreciation and selection. Asprosin, which is cleaved from fibrillin 1, is a fastinginduced hormone secreted by adipose tissue. Circulating Asprosin binds to the olfactory receptor OLFR734 in the liver to promote hepatic gluconeogenesis via the cAMPPKA-signaling pathway. It is also reported that Asprosin can cross the blood–brain barrier to activate AgRP neurons to stimulate appetite. However, it is still unknown whether OLRF734, as an olfactory receptor and a receptor of Asprosin, mediates appetitive behaviors. To determine whether OLFR734 regulates appetitive behaviors, we compared the food intake between wildtype (WT) mice and Olfr734 mice. OLFR734 deficiency significantly decreased the food intake in overnight-fasted mice compared with WT mice (Fig. 1a), especially in the first hour after fasting and at night (dark phase). As a result, the accumulated amount of food intake of Olfr734 mice is much less than WT mice (Fig. 1b). Under ad lib-feeding conditions, the accumulated food intake is comparable between fed WT and Olfr734 mice, although Olfr734 mice ate slightly less at the very beginning of the test than WT mice (Supplementary Fig. S1a, b). In addition, the body weights of WT and Olfr734 mice are similar under fed or fasted conditions (Supplementary Fig. S1c). Together, these results indicate that OLFR734 promotes fasting-induced food intake in mice. AgRP neurons in the ARC of the hypothalamus are activated by energy deficit to promote feeding behaviors. To investigate whether OLFR734 can mediate the activation of AgRP neurons, we first identified the expression of Olfr734 in AgRP neurons. Olfr734 is expressed in AgRP neurons, as evaluated by fluorescence in situ hybridization (Fig. 1c). The expression of Fos in the AgRP neurons and the proportion of cells positive for Fos (a marker of neuronal activation) are much lower in Olfr734 mice than in WT mice (Fig. 1d, e). In addition, Asprosin administration enhanced Fos staining in AgRP neurons from WT mice but not Olfr734 mice (Fig. 1d, e). Together, these results show that OLFR734, as a receptor of Asprosin, promotes AgRP neuronal activity. Since olfaction also plays an important role in regulating appetitive behavior, we investigated whether the Asprosin–OLFR734 module affects olfactory performance. Olfactory performance is enhanced by fasting and reduced by feeding in rodents and humans. Since Asprosin is enhanced during fasting and OLFR734 is also highly expressed in olfactory epithelium and OB, we used a buried food test to investigate whether Asprosin affects mouse olfaction via OLFR734. Plasma Asprosin was enhanced to a similar extent in WT and Olfr734 mice after fasting, while OLFR734 expression was not