Obesity-Associated Family with Sequence Similarity 13 Member A Gene Regulates Adipocyte Differentiation

Obesity and its associated morbidities represent the major and most rapidly expanding health epidemic in the world. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphism (SNP) variants in Family with Sequence Similarity 13, Member A (FAM13A) gene to be highly associated with waist-hip ratio (WHR) with adjustment for body mass index (BMI) (WHRadjBMI). However, the exact function of this gene in adipose tissue development and obesity remains largely uncharacterized. We for the first time identified Fam13A as an adipose tissue abundant gene whose expression was highly regulated by fasting/refeed and dramatically reduced in epididymal and subcutaneous fat depots in murine models of genetic obesity and diet-induced obesity (DIO). Its expression was enriched in mature adipocytes and significantly upregulated during murine and human adipogenesis potentially through a PPARγ-dependent mechanism. However, FAM13A-/- mice only exhibited a tendency of higher adiposity and maintained normal glucose clearance and insulin resistance. They are also not protected from high fat diet-induced obesity and metabolic perturbation. The dispensable role of FAM13A was further supported by normal adipogenesis in FAM13A-/- Stromal vascular cells (SVCs). Interestingly, overexpression of FAM13A in 3T3-L1 preadipocytes downregulated beta-catenin expression, impaired preadipocyte survival and enhanced its susceptibility to serum starvation-induced apoptosis. Furthermore, FAM13A-overexpressing preadipocytes failed to differentiate into mature adipocytes through interfering early-stage C/EBPα/PPARγ-mediated adipogenesis. These data for the first time reveal new details of an obesity-associated FAM13A gene in mediating beta-catenin action and adipocyte differentiation, providing novel insight into a relationship between FAM13a and adipose biology.