The CNS Receptor For Asprosin

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PROJECT SUMMARY Asprosin is a recently discovered, fasting-induced hormone that stimulates hepatic glucose production and appetite. Plasma asprosin crosses the blood-brain-barrier and directly activates orexigenic AgRP neurons, resulting in downstream anorexigenic POMC neuron inhibition, in a GABA-dependent manner. This asprosin- mediated chain of events leads to appetite stimulation and a drive to accumulate adiposity and body weight. Genetic deficiency of asprosin in humans results in Neonatal Progeroid Syndrome (NPS), characterized by low appetite and extreme leanness, a result mimicked by mice carrying similar mutations. Obese humans and mice display pathologically elevated circulating asprosin levels, and depletion of plasma asprosin using monoclonal antibodies reduces appetite and body weight in such mice, in addition to improving their glycemic profile. Thus, asprosin, in addition to performing a glucogenic function, is an orexigenic hormone, and anti-asprosin antibodies show therapeutic potential as anti-obesity agents. A central question the above observations have led to is – what is the identity of the asprosin cell-surface receptor? Recently, through unbiased mass spectrometry on the mouse brain we identified a candidate asprosin receptor (AR) as a putative brain receptor for asprosin. AR is robustly expressed in AgRP neurons but not expressed in the liver. Conversely, the recently discovered liver receptor for asprosin (OLF734), while being highly expressed in the liver, is not expressed in AgRP neurons and Olfr734-/- mice do not display leanness or reduced appetite. Thus, Olfr734 cannot account for asprosin’s stimulatory effect on AgRP neurons and appetite. Besides confirming AR as a binding partner for asprosin, we present preliminary studies demonstrating the necessity of AR for asprosin mediated AgRP neuron activation, appetite stimulation and body weight maintenance. This proposal seeks to build on these preliminary results to determine the contribution of AR as an asprosin receptor in the brain. We seek to do so within the following 3 aims: 1) Determine the necessity of AR for asprosin’s orexigenic effects 2) Validate the AR soluble ligand binding domain for efficacy against metabolic syndrome 3) Determine the molecular mechanisms by which asprosin neuralization reduces appetite and body weight and interplay with leptin signaling. At the completion of these aims we expect to definitively validate AR as the brain receptor for asprosin through an exploration of necessity, druggability, function and in vivo mechanism.