Abstract
Brown adipose tissue (BAT) is a metabolically active organ that exhibits sex-differential features, that is, being generally more abundant and active in females than in males. Although sex steroids, particularly estrogens, have been shown to regulate BAT thermogenic function, the underlying molecular mechanisms contributing to sexual dimorphism in basal BAT activity have not been elucidated. Therefore, we assessed the transcriptome of interscapular BAT of male and female C57BL/6J mice by RNA sequencing and identified 295 genes showing ≥2-fold differential expression (adjusted P < 0.05). In silico functional annotation clustering suggested an enrichment of genes encoding proteins involved in cell-cell contact, interaction, and adhesion. Ovariectomy reduced the expression of these genes in female BAT toward a male pattern whereas orchiectomy had marginal effects on the transcriptional pattern, indicating a prominent role of female gonadal hormones in this sex-differential expression pattern. Progesterone was identified as a possible upstream regulator of the sex-differentially expressed genes. Studying the direct effects of progesterone in vitro in primary adipocytes showed that progesterone significantly altered the transcription of several of the identified genes, possibly via the glucocorticoid receptor. In conclusion, this study reveals a sexually dimorphic transcription profile in murine BAT at general housing conditions and demonstrates a role for progesterone in the regulation of the interscapular BAT transcriptome.
Highlights
A growing number of studies suggest that the prevalence of obesity and obesity-related diseases differs between women and men
Functional annotation and clustering showed enrichment of genes encoding proteins involved in cellular structure, cell–cell contact, and cell adhesion
We confirmed our previous findings by this approach, showing that Bmp8b is sex-differentially expressed in brown adipose tissue (BAT) (Grefhorst et al 2015)
Summary
A growing number of studies suggest that the prevalence of obesity and obesity-related diseases differs between women and men. The global prevalence of obesity is higher in women than in men (GBD Obesity Collaborators et al 2017), obese men are more prone to develop obesity-related conditions, such as type 2 diabetes mellitus, than obese women (Logue et al 2011). This sex difference diminishes when women enter menopause, suggesting a prominent role for sex steroids in controlling adipose tissue function, since disturbances in adipose tissue function lead to obesity and associated metabolic diseases (Palmer & Clegg 2015, Longo et al 2019). Upon confirmation of active BAT being present in adults, BAT has been studied extensively because BAT activation is considered a potential therapeutic option for obesity and metabolic syndrome (Moonen et al 2019)
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