Genetics of sexually dimorphic adipose distribution in humans

Grace T. Hansen; Débora R. Sobreira; Zachary T. Weber; Alexis G. Thornburg; Ivy Aneas; Li Zhang; Noboru J. Sakabe; Amelia C. Joslin; Gabriela A. Haddad; Sophie M. Strobel; Samantha Laber; Farhath Sultana; Faezeh Sahebdel; Kohinoor Khan; Yang I. Li; Melina Claussnitzer; Liang Ye; Ricardo A. Battaglino; Marcelo A. Nóbrega

doi:10.1038/s41588-023-01306-0

Genetics of sexually dimorphic adipose distribution in humans

Grace T. Hansen, Débora R. Sobreira, Zachary T. Weber, Alexis G. Thornburg, Ivy Aneas, Li Zhang, Noboru J. Sakabe, Amelia C. Joslin, Gabriela A. Haddad, Sophie M. Strobel, Samantha Laber, Farhath Sultana, Faezeh Sahebdel, Kohinoor Khan, Yang I. Li, Melina Claussnitzer, Liang Ye, Ricardo A. Battaglino, Marcelo A. Nóbrega

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Abstract

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.

Original language	English (US)
Pages (from-to)	461-470
Number of pages	10
Journal	Nature Genetics
Volume	55
Issue number	3
DOIs	https://doi.org/10.1038/s41588-023-01306-0
State	Published - Mar 2023

Bibliographical note

Funding Information:
This work was supported by the Novo Nordisk Foundation (challenge grant NNF18OC0033754 to M.A.N.), Novo Nordisk Foundation grant NNF21SA0072102 to M.C., the National Institutes of Health (grants R01HL128075, P30DK020595 and R01HL119577 to M.A.N., grant R01AR064793 to R.A.B., grant UM1126185 to M.C. and training grant T32HL007381 to A.C.J) and the American Heart Association (grant 20PRE35210899 to G.T.H.). We thank A. Candles for support with the paper.

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© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

PubMed: MeSH publication types

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

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Hansen, G. T., Sobreira, D. R., Weber, Z. T., Thornburg, A. G., Aneas, I., Zhang, L., Sakabe, N. J., Joslin, A. C., Haddad, G. A., Strobel, S. M., Laber, S., Sultana, F., Sahebdel, F., Khan, K., Li, Y. I., Claussnitzer, M., Ye, L., Battaglino, R. A., & Nóbrega, M. A. (2023). Genetics of sexually dimorphic adipose distribution in humans. Nature Genetics, 55(3), 461-470. https://doi.org/10.1038/s41588-023-01306-0

Hansen, GT, Sobreira, DR, Weber, ZT, Thornburg, AG, Aneas, I, Zhang, L, Sakabe, NJ, Joslin, AC, Haddad, GA, Strobel, SM, Laber, S, Sultana, F, Sahebdel, F, Khan, K, Li, YI, Claussnitzer, M, Ye, L , Battaglino, RA & Nóbrega, MA 2023, 'Genetics of sexually dimorphic adipose distribution in humans', Nature Genetics, vol. 55, no. 3, pp. 461-470. https://doi.org/10.1038/s41588-023-01306-0

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title = "Genetics of sexually dimorphic adipose distribution in humans",

abstract = "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.",

author = "Hansen, {Grace T.} and Sobreira, {D{\'e}bora R.} and Weber, {Zachary T.} and Thornburg, {Alexis G.} and Ivy Aneas and Li Zhang and Sakabe, {Noboru J.} and Joslin, {Amelia C.} and Haddad, {Gabriela A.} and Strobel, {Sophie M.} and Samantha Laber and Farhath Sultana and Faezeh Sahebdel and Kohinoor Khan and Li, {Yang I.} and Melina Claussnitzer and Liang Ye and Battaglino, {Ricardo A.} and N{\'o}brega, {Marcelo A.}",

note = "Funding Information: This work was supported by the Novo Nordisk Foundation (challenge grant NNF18OC0033754 to M.A.N.), Novo Nordisk Foundation grant NNF21SA0072102 to M.C., the National Institutes of Health (grants R01HL128075, P30DK020595 and R01HL119577 to M.A.N., grant R01AR064793 to R.A.B., grant UM1126185 to M.C. and training grant T32HL007381 to A.C.J) and the American Heart Association (grant 20PRE35210899 to G.T.H.). We thank A. Candles for support with the paper. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Hansen, Grace T.

AU - Sobreira, Débora R.

AU - Weber, Zachary T.

AU - Thornburg, Alexis G.

AU - Aneas, Ivy

AU - Zhang, Li

AU - Sakabe, Noboru J.

AU - Joslin, Amelia C.

AU - Haddad, Gabriela A.

AU - Strobel, Sophie M.

AU - Laber, Samantha

AU - Sultana, Farhath

AU - Sahebdel, Faezeh

AU - Khan, Kohinoor

AU - Li, Yang I.

AU - Claussnitzer, Melina

AU - Ye, Liang

AU - Battaglino, Ricardo A.

AU - Nóbrega, Marcelo A.

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PY - 2023/3

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N2 - 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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Genetics of sexually dimorphic adipose distribution in humans

Abstract

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UN SDGs

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