Title of project

A human-centric approach to discover non-incretin obesity targets

Abstract

Obesity remains a global health challenge, yet effective, widely accessible treatments are limited. Injectable peptide therapies such as GLP-1 receptor agonists can induce substantial weight loss but are costly, require refrigeration, and are poorly tolerated by 30–50% of patients, highlighting the need for orally available, small-molecule anti-obesity medications (AOMs). Monogenic obesity syndromes are rare but can provide clear mechanistic insight. An example hereof is adenylyl cyclase 3 (Adcy3). Adcy3 encodes a cAMP-generating enzyme localized on primary cilia in hypothalamic neurons known to converge appetite signals. Loss-of-function variants in ADCY3 cause severe obesity in humans, a phenotype recapitulated in mice with hypothalamic Adcy3 deletion.

ADCY3 provides a genetically validated and human-relevant node in appetite regulation and body weight maintenance, and with this project we aim to delineate the molecular and cellular mechanisms underlying the human phenotype of ADCY3 loss-of-function. To improve translational relevance beyond traditional rodent models, we combine human iPSC-derived hypothalamic neurons, humanized mice, and conditional knockout models to map ADCY3-dependent signaling and identify novel anti-obesity targets. We aim to 1) generate ADCY3-deficient iPSCs carrying a fluorescent cAMP reporter, differentiated into neurons from three hypothalamic nuclei (VMH, ARC, PVN). These cultures will be screened with small-molecule and secreted-protein libraries and hits will be deorphanized and prioritized based on GPCR co-localization data. 2) Using an Adcy3 reporter mouse (Adcy3.tdT) we will isolate Adcy3+ hypothalamic neurons and map their receptor repertoire using FACS and custom qPCR arrays, providing insight into ligands that directly regulate these cells. And 3) evaluate Adcy3-activating compounds in Adcy3-WT and Adcy3-KO mice using automated feeding systems; monitoring food intake, body weight, and circulating hormones.

This integrated human- and rodent-centric platform enables the identification of human-relevant pathways, receptors, and chemical activators of ADCY3, bridging molecular mechanisms to translational potential and advancing the development of affordable, scalable AOMs.