Sex steroid hormones related protection against metabolic dysfunction through beiging adaptation
Résumé
Background and aims : The impact of sex steroids on brown adipose tissue (BAT) and “beiging” function is of paramount importance since the tremen- dous capacity of BAT and “beige’ adipocytes for combusting not only lipids but also carbohydrates is actually seen as a promising therapeutic way to clear excess glucose and triglycerides from blood of patients in pathologic situations such as type 2 diabetes and obesity. Yet, paradoxically, despite the key roles of sexual hormones in maintaining energy homeostasis, the molecular mechanisms and their precise modes of action in the metabolic tissues remain largely unexplained, especially along “beiging” adaptation. We hypothesize that transcriptional coactivators might play a pivotal role in mediating the metabolic effects of sex steroids and their impact on beiging processes. Materials and methods : Subcutaneous white adipose tissue (WAT) biopsies and mature isolated adipocytes from premenopausal women were screened by large unbiased transcriptomic analysis to determine gene expression levels of important transcriptional coregulators. Specifically, the cell-autonomous im- pact of the nuclear receptor coactivator SRC-1 in the browning process of WATwas then addressed using primary fat cells initially collected from SRC-1 KO and WT mice and subjected to differentiation into either brown or white adipocyte. In vivo investigation of SRC-1 role on beiging was further per- formed using β3 adrenergic receptor agonist. Finally, a phenotypic evaluation of SRC-1 KO has been realized using a metabolic phenotyping pipeline. Results: We found in subcutaneous WAT biopsies isolated from women, that, among all key transcriptional coregulators with established roles in subcutaneous WAT function, SRC-1 displayed the highest levels of gene expression. SRC-1 was consistently found highly expressed in mature adipocytes isolated from subcutaneous WAT from an independent cohort of premenopausal female patients. In a white-to-brown differentiation model of primary adipocytes isolated from female mice SRC-1 KO and their WT littermates, we found that the total genetic invalidation of SRC- 1 strongly decreased UCP-1 gene activation during “beiging” adaptation. Following the injection of β3 adrenergic receptor agonist (CL316,243) to SRC-1 WT and KO mice, a strong decrease in UCP-1 gene induction was seen in SRC-1 KO compared to WT, in both sexes. Finally, female mice, between 8 to 10 months of age, gained significantly more body weight than sex-matched WT littermates. Consistently, SRC-1 KO female mice displayed glucose intolerance, hyperleptinemia, hyperinsulinemia and liver steatosis as compared to WT littermates, with no difference in males. Conclusion : Our findings unveil the central role of SRC-1 in mediating fuel utilization and protecting against deleterious metabolic effects ob- served in sexual hormones deprivation situations during aging. Therefore, this potential key impact of SRC-1 on “sex energy homeostasis” represents great therapeutic potential in the fight against obesity-related disorders such as type 2 diabetes and cardiovascular diseases.
