ADCY3 Ser107Pro links difficulty awakening in the morning to adiposity through circadian regulation of adipose thermogenesis

Abstract

Modern lifestyles often disturb circadian rhythms, yet the genetic circuits that convert this stress into metabolic dysfunction remain poorly defined. Here, we identify a missense variant in ADCY3 (rs11676272; Ser107Pro) as a pleiotropic regulator of circadian preference and adiposity. Using genome-wide pleiotropy analysis in [~]480,000 UK Biobank participants, we show that the G risk allele (Pro107) increases morningness, BMI, and fat mass in European (N=451,324) and African (N=8,738) ancestry groups, with behavioral amplification by morning difficulty awakening observed in Europeans, power limited interaction modeling in other populations. Structural modeling and transcriptomic analysis suggest this allele destabilizes ADCY3 and alters adipose-specific splicing and expression. In mice, Adcy3 is rhythmically expressed in adipose tissue, with the conserved Pro107 site showing BMAL1 binding and cold-inducible activation. Human adipose ADCY3 expression also increases after weight loss. Together, these findings reveal a genotype-dependent, behaviorally modifiable axis linking difficulty awakening to adipose thermogenesis and obesity risk.