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Genetics of sexually dimorphic adipose distribution in humans. 2023
Grace T Hansen, and
Débora R Sobreira, and
Zachary T Weber, and
Alexis G Thornburg, and
Ivy Aneas, and
Li Zhang, and
Noboru J Sakabe, and
Amelia C Joslin, and
Gabriela A Haddad, and
Sophie M Strobel, and
Samantha Laber, and
Farhath Sultana, and
Faezeh Sahebdel, and
Kohinoor Khan, and
Yang I Li, and
Melina Claussnitzer, and
Liang Ye, and
Ricardo A Battaglino, and
Marcelo A Nóbrega
Department of Human Genetics, University of Chicago, Chicago, IL, USA. gthansen@uchicago.edu.
Obesity-associated morbidity is exacerbated by abdominal obesity, which can be measured as the waist-to-hip ratio adjusted for the body mass index (WHRadjBMI). Here we identify genes associated with obesity and WHRadjBMI and characterize allele-sensitive enhancers that are predicted to regulate WHRadjBMI genes in women. We found that several waist-to-hip ratio-associated variants map within primate-specific Alu retrotransposons harboring a DNA motif associated with adipocyte differentiation. This suggests that a genetic component of adipose distribution in humans may involve co-option of retrotransposons as adipose enhancers. We evaluated the role of the strongest female WHRadjBMI-associated gene, SNX10, in adipose biology. We determined that it is required for human adipocyte differentiation and function and participates in diet-induced adipose expansion in female mice, but not males. Our data identify genes and regulatory mechanisms that underlie female-specific adipose distribution and mediate metabolic dysfunction in women.
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