FAM13A affects body fat distribution and adipocyte function

Mohsen Fathzadeh,Allan Attie,Thomas Quertermous,Jiehan Li,Naomi L Cook ,Iván Cárcamo-Orive ,Stephen B Montgomery,Aldons J Lusis,Cliona Molony ,Dermot F Reilly ,Myung K Shin ,Abhiram Rao,Tracey Mclaughlin,Yuko Tada,Gerald M Reaven ,Xiang Zhou,Jing Yang,Indumathi Chennamsetty,Erik Ingelsson,Michael J Gloudemans,Panjamaporn Sangwung,Martin Wabitsch,Mark P Keller ,Marcus M Seldin ,Joshua Knowles

doi:10.1038/s41467-020-15291-z

Abstract

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.

Highlights

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS)
By using refined measures of body composition and fat distribution, follow-up analysis shows that the lower Body mass index (BMI)-associated variants are associated with a higher waist-to-hip ratio (WHR) and visceral-to-subcutaneous adipose tissue ratio (VAT/SAT), which is driven by a fat deposition shift from subcutaneous depots around the hip to visceral depots around the waist[5]
Variants in the FAM13A locus, including rs3822072, rs1377290, and rs9991328, have been reported as lead variants within the locus across GWAS studies of insulin resistance (IR)-related traits such as body fat percentage, WHRadjBMI, fasting insulin levels. These variants were associated with FAM13A expression in subcutaneous adipose tissue (SAT), but not in visceral adipose tissue (VAT; Fig. 1) in data from the Genotype-Tissue Expression project (GTEx v7)

Summary

Introduction

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). By using refined measures of body composition and fat distribution, follow-up analysis shows that the lower BMI-associated variants are associated with a higher waist-to-hip ratio (WHR) and visceral-to-subcutaneous adipose tissue ratio (VAT/SAT), which is driven by a fat deposition shift from subcutaneous depots around the hip to visceral depots around the waist[5]. Among these unfavorable fat distribution risk loci are variants located in or near FAM13A (Family With Sequence Similarity 13 Member A)[4,5]. Our in vitro and in vivo experimental studies show that FAM13A plays a role in adipocyte differentiation and function

Methods

Results

Conclusion