We previously identified a novel cell signalling paradigm in which testosterone acts via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to markedly reduce fat mass and increase insulin sensitivity. This was achieved using our PC-AR Gene Replacement mouse model in which the AR gene is only expressed in BM-PCs and deleted in all other tissues (1). A loss of androgen signalling (i.e. in hypogonadal men) results in lipid metabolism disorders, but the role of AR signalling in BMPCs to regulate the lipidome is unknown. To characterise the lipid changes underlying the markedly reduced fat mass in the PC-AR Gene Replacement mice we used untargeted lipidomic analyses.
Lipids from the subcutaneous fat pads of 8-week-old male PC-AR Gene Replacements, wildtype (WT) and Global-AR knockout (Global-ARKOs) controls (n=4-5/group) were extracted, and samples were analysed using UHPLC-MS/MS. Lipid species were identified and quantified using MS-Dial.
Deletion of the AR in Global-ARKOs resulted in a shift in the lipidome compared to WT mice, which was partially restored by replacement of the AR in BMPCs of PC-AR Gene Replacement mice. This was characterised by the normalisation of several lipid classes, including ceramides and hex-ceramides, together with an increase in the total abundance of long-chain phosphatidylcholines and phosphatidylethanolamines which have been shown to profoundly affect the pathophysiology of metabolic diseases including type-2 diabetes and obesity (2).
In conclusion, these data demonstrate that testosterone negatively regulates fat mass via the AR in BMPCs at least in part by modifying both the total abundance of lipids as well as their chain lengths. Ongoing, in-depth analysis of the lipid profiles in PC-AR Gene Replacement mice has the potential to uncover the pathways involved in metabolic diseases in humans, offering a promising avenue to explore novel therapeutic targets for future development.