Despite extensive studies demonstrating an action of testosterone to negatively regulate fat mass in humans and mice, the mechanism by which testosterone exerts these effects is poorly understood. We, and others have shown in mice that deletion of the target for testosterone action, the androgen receptor (AR) in Global ARKOs results in a phenotype that closely mimics the three key clinical aspects of hypogonadism in human males, i.e. increased fat mass, decreased bone and muscle mass.

We have compelling new data showing that replacement of the AR gene specifically in bone marrow progenitor cells (PCs) of Global-ARKOs, in the absence of the AR in all other tissues (PC-AR Gene Replacements), attenuates their fat accumulation. Subcutaneous and peri-renal visceral fat depots in PC-AR Gene Replacement mice are 50-80% lower than wild type (P<0.001) and 75-90% lower than Global-ARKO controls (P<0.001) at 12 weeks of age. The marked decrease in subcutaneous and peri-renal visceral fat mass in PC-AR Gene Replacements is associated with a shift in the distribution of adipocyte cross-sectional area with more, smaller adipocytes than WT and Global-ARKOs (P<0.05). PC-AR Gene Replacement mice also have a healthier metabolic profile compared to controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice (P<0.01 vs WT) and increased glucose uptake into subcutaneous fat (P<0.001).

In conclusion, these data provide the first evidence for an action of androgens via the AR in bone marrow PCs to negatively regulate fat mass. We propose that this action of the AR in bone marrow PCs is mediated via the regulation of bone-derived factors, osteokines, which are then released into the circulation to negatively regulate fat mass.