In addition, even though receptor for asprosin in the liver has been discovered recently (Li et al., 2019), the identity of its receptor in the CNS remains unknown. are included NMDI14 in the manuscript and supporting files. Abstract Background: Recently, we discovered a new glucogenic and centrally acting orexigenic hormone C asprosin. Asprosin is elevated in metabolic syndrome (MS) patients, and its genetic loss results in reduced appetite, leanness, and blood glucose burden, leading to protection from MS. Methods: We generated three impartial monoclonal antibodies (mAbs) that recognize unique asprosin epitopes and investigated their preclinical efficacy and tolerability in the treatment of MS. Results: Anti-asprosin mAbs from three distinct species lowered appetite and body weight, and reduced blood glucose in a dose-dependent and epitope-agnostic fashion in three impartial MS mouse models, with an IC50 of ~1.5 mg/kg. The mAbs displayed a half-life of over 3days in vivo, with equilibrium dissociation-constants in picomolar to low nanomolar range. Conclusions: We demonstrate that anti-asprosin mAbs are dual-effect pharmacologic therapy that targets two key pillars of MS C over-nutrition and hyperglycemia. This evidence paves the way for further development towards an investigational new drug application and subsequent human trials for treatment of MS, a defining physical ailment of our time. Funding: DK118290 and DK125403 (R01; National Institute of Diabetes and Digestive and Kidney Diseases), DK102529 (K08; National Institute of Diabetes and Digestive and Kidney Diseases), Caroline Wiess Legislation Scholarship (Baylor College of Medicine, Harrington Investigatorship Harrington Discovery Institute at University Hospitals, Cleveland); Chao Physician Scientist Award (Baylor College of Medicine); RP150551 and RP190561 (Cancer Prevention and Research Institute of Texas [CPRIT]). Research organism: Mouse Introduction Obesity and its co-morbidities, such as insulin resistance, hypertension, and dyslipidemia, are omnipresent, affecting nearly a quarter of the world populace by some estimates (Saklayen, 2018). These conditions, which feed the spread of type II diabetes, coronary artery disease, stroke, nonalcoholic steatohepatitis, nephropathy, and other diseases, are commonly clustered under the umbrella term metabolic syndrome (MS) or syndrome X (Saklayen, 2018). MS is usually a consequence of chronic over-nutrition, turning the evolutionary drive to gather energy from the environment into a liability. As a whole, Rabbit polyclonal to INPP4A MS currently exists as an untreatable malady despite decades of basic research and drug development (Saklayen, 2018). Through the study of a rare genetic condition in humans, neonatal progeroid syndrome (NPS, also known as marfanoidCprogeroidClipodystrophy syndrome), we recently discovered a fasting-induced, glucogenic, and orexigenic hormone that is the C-terminal cleavage product of profibrillin (encoded by FBN1) and named it asprosin (Romere et al., 2016). Its two major sites of action are the liver and the brain (Romere et al., 2016; Li et al., 2019; Duerrschmid et al., 2017). At the liver, asprosin causes a glucogenic effect through a cAMP-PKA-dependent pathway (Romere et al., 2016). It was found recently to promote hepatic glucose release through the binding of OR4M1, an olfactory G-coupled protein receptor in the rhodopsin family (Li et al., 2019). In addition, asprosin was shown to bind the mouse ortholog, Olfr734 NMDI14 with high affinity, and elimination of the receptor considerably reduced the glucogenic effects of exogenously administered asprosin (Li et al., 2019). There is also evidence, that asprosin crosses the blood brain barrier and exerts effects around the hypothalamus (Duerrschmid et al., 2017). In the arcuate nucleus of the hypothalamus, asprosin directly activates orexigenic AgRP neurons and indirectly inhibits anorexigenic POMC neurons, resulting in appetite stimulation. Patients with NPS, a human genetic model of deficiency NMDI14 in plasma asprosin, present with low appetite associated with extreme leanness and strong insulin sensitivity (Romere et al., 2016; Duerrschmid et al., 2017). NPS mutations in mice (mice are completely immune to diet-induced MS (Duerrschmid et al., 2017). On the opposite end of the energy-balance spectrum, patients and mice with MS exhibit elevated plasma asprosin (Duerrschmid et al., 2017; Wang et al., 2020a; Ugur and Aydin, 2019; Alan et al., 2019; Zhang et al., 2019; Baykus et al., 2019). Based on these observations, we hypothesized that pharmacologic inhibition of asprosin is particularly well suited to the treatment of MS, a condition in need of simultaneous reduction in both appetite and the blood glucose burden. Similar to humans, mice with MS display elevations in plasma asprosin (Li et al., 2019; Duerrschmid et al.,.