WDTC1 (WD and tetratricopeptide repeats 1) is an evolutionarily conserved suppressor of lipid accumulation and adipogenesis 1. The protein functions as a substrate receptor for the CRL4-DDB1 E3 ubiquitin ligase complex 1, promoting histone H2AK119 monoubiquitylation to facilitate transcriptional repression during adipogenic differentiation 1. WDTC1 suppresses adipogenesis by promoting degradation of MED20, a Mediator complex subunit that organizes the early adipogenic complex 2. In humans, WDTC1 genetic variation associates with obesity; carriers of the minor allele i22835G exhibit significantly lower BMI and reduced obesity risk, while major allele carriers show elevated BMI 3. Consistent with animal studies, higher WDTC1 expression in human adipose tissue correlates with lower fat mass and enhanced insulin sensitivity 4. Beyond metabolic regulation, WDTC1 is frequently mutated in microsatellite-unstable colorectal cancer, where it functions as an oncogene; silencing WDTC1 suppresses cancer cell proliferation, migration, and invasion 5. These findings establish WDTC1 as a key regulator of fat metabolism and a potential therapeutic target for obesity and metabolic disease, while also identifying its emerging role in cancer biology.