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. 2022 Jul 4;11(13):3878.
doi: 10.3390/jcm11133878.

The Effect of Sex and Obesity on the Gene Expression of Lipid Flippases in Adipose Tissue

Hanieh Motahari-Rad  1   2 , Alba Subiri  2   3 , Rocio Soler  4 , Luis Ocaña  4 , Juan Alcaide  2   3 , Jorge Rodríguez-Capitan  5   6 , Veronica Buil  6 , Hamid El Azzouzi  7 , Almudena Ortega-Gomez  2   3 , Rosa Bernal-Lopez  3   8 , Maria Insenser  9 , Francisco J Tinahones  2   3   6 , Mora Murri  2   3
Affiliations

The Effect of Sex and Obesity on the Gene Expression of Lipid Flippases in Adipose Tissue

Hanieh Motahari-Rad et al. J Clin Med. .

Abstract

Molecular mechanisms behind obesity and sex-related effects in adipose tissue remain elusive. During adipocyte expansion, adipocytes undergo drastic remodelling of lipid membrane compositions. Lipid flippases catalyse phospholipid translocation from exoplasmic to the cytoplasmic leaflet of membranes. The present study aimed to analyse the effect of sex, obesity, and their interactions on the gene expression of two lipid flippases-ATP8A1 and ATP8B1-and their possible microRNA (miR) modulators in visceral adipose tissue (VAT). In total, 12 normal-weight subjects (5 premenopausal women and 7 men) and 13 morbidly obese patients (7 premenopausal women and 6 men) were submitted to surgery, and VAT samples were obtained. Gene expression levels of ATP8A1, ATP8B1, miR-548b-5p, and miR-4643 were measured in VAT. Our results showed a marked influence of obesity on VAT ATP8A1 and ATP8B1, although the effects of obesity were stronger in men for ATP8A1. Both genes positively correlated with obesity and metabolic markers. Furthermore, ATP8B1 was positively associated with miR-548b-5p and negatively associated with miR-4643. Both miRs were also affected by sex. Thus, lipid flippases are altered by obesity in VAT in a sex-specific manner. Our study provides a better understanding of the sex-specific molecular mechanisms underlying obesity, which may contribute to the development of sex-based precision medicine.

Keywords: P4-ATPases; adipose tissue; flippases; miRs; obesity; sex; sex dimorphism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Visceral adipose tissue expression levels of ATP8A1 and ATP8B1 in women and men as a function of obesity. Data are expressed as means ± SEM and were submitted to multivariate and univariate general linear models introducing groups of subjects and obesity as independent variables. * p < 0.05 for the significant difference between normal-weight and obese subjects. ‡ p < 0.05 for the difference between the interaction of obesity and sex.
Figure 2
Figure 2
Spearman correlation analysis: (a) correlations between clinical/metabolic parameters and P4-ATPase gene expression levels; (b) correlations between clinical/metabolic parameters and miR expression levels. Spearman correlation analysis was performed. * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Visceral adipose tissue expression levels of microRNAs in women and men as a function of obesity. Data are expressed as means ± SEM and were submitted to multivariate and univariate general linear models introducing groups of subjects and obesity as independent variables. * p < 0.05 for the significant difference between normal-weight and obese subjects. † p < 0.05 for the difference between women’s and men’s cases. ‡ p < 0.05 for the difference between the interaction of obesity and sex.
Figure 4
Figure 4
Illustration of the pathways proposed in the present study through which obesity and sex influence ATP8A1, ATP8B1, miR-548b-5p, and miR-4643 gene expressions, and the ATP8B1 modulation by miRs. The black colour of the human figures represents all patients, the pink colour represents obese women, and the blue colour represents obese men. In summary, obesity increased the levels of ATP8A1 and ATP8B1 gene expression, although the effects of obesity were stronger in men than in women, especially for ATP8A1. On the other hand, sex influenced ATP8A1-modulator miRs, miR-548b-5p, and miR-4643—namely, their levels were increased in women. Moreover, there was an interaction between sex and obesity, according to which obesity increased the levels of miR-4643 in men and, conversely, tended to decrease their levels in women.
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