OR35-04 Genetic Circuitry of LHCGR: a Modulator of Body Composition and Metabolic Traits in Humans

Disclosure: H. Kannangara: None. O. Moldavski: None. A. Gumerova: None. U. Cheliadinova: None. G. Pevnev: None. P. Surabhi: None. D. Vasilyeva: None. L. Igel: None. O. Barak: None. S. Haider: None. T. Yuen: None. M. Zaidi: None. D. Lizneva: None. Anterior and posterior pituitary hormones regulate multiple physiological systems beyond their classical targets. Expanding this paradigm, we identify a previously unrecognized role for the luteinizing hormone (LH)-LH/choriogonadotropin receptor (LHCGR) axis in human body composition and metabolic regulation. We identified abundant LHCGR expression in human and mouse subcutaneous (SAT) and visceral adipose tissue (VAT). RNAscope and immunohistochemistry confirmed its adipocyte-specific localization, while single-cell RNA sequencing demonstrated LHCGR expression in 10-30% of mature human adipocytes. Among the seven validated sub-clusters (hAd1-hAd7) in the single-cell dataset, LHCGR expression was enriched in hAd1 and hAd4, with hAd4 negatively correlating with BMI. The regulatory variant rs17326656 in the LHCGR locus was associated with reduced LHCGR expression in SAT (P = 2.8 × 10⁻¹⁴) and VAT (P = 4.5 × 10⁻¹⁹). eQTL data (GTEx v8) confirmed these effects were specific to adipose tissue, with no eQTLs detected in gonadal or metabolic tissues. Colocalization analysis confirmed that the SAT eQTL for rs17326656 is strongly associated with unfavorable metabolic traits in GWAS, including increased waist-to-hip ratio (WHR), WHR adjusted for BMI, elevated triglycerides, and reduced HDL levels (posterior probability = 1). The epigenetic findings (ENCODE) reveal that SNP rs17326656 resides in a region marked by chromatin accessibility (ATAC-seq, DNase peaks) and histone modifications (H3K4me1, H3K4me3), primarily in adipose tissue. These features suggest its role as an enhancer regulating LHCGR expression, implicating it in adipose-specific gene regulation. Mouse data were consistent with our findings, and heterozygous Lhcgr⁺/⁻ mice exhibited increased adiposity, independent of sex steroids, confirming Lhcgr’s role in energy balance. Lhcgr activation via LH, hCG, or Org 43553, a synthetic LHCGR agonist, prevented diet-induced obesity by reducing fat mass, adipocyte size, and mVAT/SAT ratio while increasing energy expenditure—independent of testosterone or food intake. Functional studies show that LHCGR acts via PLC-Ca²⁺-pERK signaling. Mechanistically, Lhcgr activation by Org 43553 induced mitochondrial biogenesis and energy expenditure through Atf3 and Pgc1α in vivo and in mouse 3T3-L1 adipocytes, driving UCP1-independent thermogenesis. In silico molecular dynamics simulations revealed that Org 43553 stabilizes LHCGR's active state in mouse and human. These findings establish LHCGR as a genetic contributor to human metabolic traits and a pharmacologic target for body composition. The identified SNP serves as a natural model of reduced LH-LHCGR signaling in adipose tissue, linking genetic variation to established metabolic biomarkers (WHR, triglycerides, HDL) and supporting the clinical translation of LHCGR modulation for obesity. Presentation: Monday, July 14, 2025