Sex difference in the mouse BAT transcriptome reveals a role of progesterone

Abstract

Brown adipose tissue (BAT) is a metabolically active organ that exhibits sex-differential features, i.e., 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 towards 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 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.

Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

“…However, in vitro studies of the effects of progesterone on murine brown adipocytes have provided contradictory results. While our study and others showed that progesterone reduced basal Ucp1 mRNA expression and inhibited norepinephrine-stimulated Ucp1 mRNA expression and lipolysis in cultured male and female brown adipocytes (43,127), other studies showed that progesterone had a stimulatory effect on these parameters (115,124). In part, these conflicting results can be explained by the difference in progesterone concentrations used, with high concentrations having an inhibitory effect.…”

“…Mechanistically, it remains to be determined how the effects of progesterone on BAT are mediated. Our results suggest that when progesterone concentrations are high, part of the effects may be driven by the GR (43). Progesterone may also signal through to the MR, which was shown to be expressed in BAT (130).…”

“…However, studies in male mice suggest that BAT does not express Cyp19a1 and, in line, has undetectable E2 levels (102)(103)(104). Our RNA-sequencing data suggest that also in female BAT Cyp19a1 expression is absent (43). Whether this is also true for human BAT remains to be determined, as human BAT is more heterogeneous, showing a mix of brown and white-like adipocytes (22,105).…”

“…The effects of progesterone on BAT have limitedly been studied and are, therefore, poorly understood. Our recent study suggests that progesterone might be involved in sex differences in BAT function (43). Analysis of the murine interscapular BAT transcriptome by RNA-sequencing identified 295 genes showing ≥2-fold sex-differential expression pattern.…”

“…For instance, random X-inactivation in female cells and genomic imprinting of autosomes have been shown to contribute to sex-specific gene expression (175). Indeed, cultured primary brown adipocytes, isolated and differentiated from BAT of male and female mice, maintained a sex-differential expression profile even though they were cultured and differentiated under the same standard culture conditions (43). In addition, human adipocytes differentiated from pre-adipocytes isolated from female perirenal fat had a higher UCP1 mRNA expression level than those isolated from male perirenal fat despite similar culture conditions (176).…”