FAM13A affects body fat distribution and adipocyte function

Mohsen Fathzadeh; Jiehan Li; Abhiram Rao; Naomi Cook; Indumathi Chennamsetty; Marcus Seldin; Xiang Zhou; Panjamaporn Sangwung; Michael J Gloudemans; Mark Keller; Allan Attie; Jing Yang; Martin Wabitsch; Ivan Carcamo-Orive; Yuko Tada; Aldons J Lusis; Myung Kyun Shin; Cliona M Molony; Tracey McLaughlin; Gerald Reaven; Stephen B Montgomery; Dermot Reilly; Thomas Quertermous; Erik Ingelsson; Joshua W Knowles

doi:10.1038/s41467-020-15291-z

FAM13A affects body fat distribution and adipocyte function

Nat Commun. 2020 Mar 19;11(1):1465. doi: 10.1038/s41467-020-15291-z.

Authors

Mohsen Fathzadeh^#^{1

2

3}, Jiehan Li^#^{1

2

3}, Abhiram Rao^#^{1

4}, Naomi Cook⁵, Indumathi Chennamsetty^{1

2}, Marcus Seldin⁶, Xiang Zhou^{1

2}, Panjamaporn Sangwung^{1

2

3}, Michael J Gloudemans⁷, Mark Keller⁸, Allan Attie⁸, Jing Yang⁹, Martin Wabitsch¹⁰, Ivan Carcamo-Orive^{1

2

3}, Yuko Tada^{1

2}, Aldons J Lusis⁶, Myung Kyun Shin¹¹, Cliona M Molony¹¹, Tracey McLaughlin^{3

12}, Gerald Reaven^{1

2

3}, Stephen B Montgomery^{3

7

12

13}, Dermot Reilly¹¹, Thomas Quertermous^{1

2

3}, Erik Ingelsson^{14

15

16}, Joshua W Knowles^{17

18

19}

Affiliations

¹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
² Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
³ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁴ Bioengineering Department, School of Engineering and Medicine, Stanford, CA, USA.
⁵ Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.
⁶ Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
⁷ Department of Genetics, Stanford University, California, CA, USA.
⁸ Department of Biochemistry, University of Wisconsin, Madison, WI, USA.
⁹ Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
¹⁰ Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany.
¹¹ Genetics and Pharmacogenomics, Merck & Co., Inc., Kenilworth, NJ, USA.
¹² Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Department of Pathology, Stanford University, California, CA, USA.
¹⁴ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. eriking@stanford.edu.
¹⁵ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. eriking@stanford.edu.
¹⁶ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. eriking@stanford.edu.
¹⁷ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. knowlej@stanford.edu.
¹⁸ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. knowlej@stanford.edu.
¹⁹ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. knowlej@stanford.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / metabolism*
Adipogenesis / genetics
Animals
Body Fat Distribution*
Cell Differentiation / genetics
GTPase-Activating Proteins / genetics*
GTPase-Activating Proteins / metabolism
Gene Knockdown Techniques
Genetic Loci
Genome-Wide Association Study
HEK293 Cells
Humans
Insulin Resistance / genetics
Intra-Abdominal Fat / metabolism
Male
Metabolomics
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Polymorphism, Single Nucleotide / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
Subcutaneous Fat / metabolism

Substances

FAM13A protein, human
Fam13a protein, mouse
GTPase-Activating Proteins
RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding