The androgen receptor in bone marrow progenitor cells negatively regulates fat mass

Abstract

It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50-80% lower than wild-type (WT) and 75-90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT 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 and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function.

Effects of testosterone and 17β-estradiol on osteogenic and adipogenic differentiation capacity of human bone-derived mesenchymal stromal cells of postmenopausal women

“…In accordance with our observation, testosterone was shown to inhibit adipogenic differentiation of a 3T3-L1 cell line (Singh et al, 2006), and to reduce proliferation of adipocytes (Ray et al, 2008). Moreover, dihydrotestosterone (DHT) inhibited adipogenesis of human MSCs (Gupta et al, 2008; Russell et al, 2018). Considering the relationship between AR receptor expression and adipogenesis, it has been reported that the AR is downregulated in human MSCs by DHT under adipogenic culture conditions (Gupta et al, 2008).…”

“…Testosterone reduces proliferation capacity of adipocytes (Ray et al, 2008), and inhibits adipogenic differentiation of the 3T3-L1 cell line (Singh et al, 2006). However, 5α-dihydrotestosterone (DHT), a considerably more potent agonist of the androgen receptor than testosterone (Jakob et al, 2010), is able to inhibit adipogenic differentiation of human MSCs (Gupta et al, 2008; Russell et al, 2018). In mouse bone marrow MSCs the effects of testosterone have been shown to be mediated by the androgen receptor (AR) (Russell et al, 2018) that is expressed in an age- and sex-independent manner in almost all tissues, including bone and bone marrow.…”

“…However, 5α-dihydrotestosterone (DHT), a considerably more potent agonist of the androgen receptor than testosterone (Jakob et al, 2010), is able to inhibit adipogenic differentiation of human MSCs (Gupta et al, 2008; Russell et al, 2018). In mouse bone marrow MSCs the effects of testosterone have been shown to be mediated by the androgen receptor (AR) (Russell et al, 2018) that is expressed in an age- and sex-independent manner in almost all tissues, including bone and bone marrow. Deletion of the AR in male mice (global-ARKO mice) results in increased fat mass whereas bone and muscle mass were decreased (Russell et al, 2018).…”

“…In mouse bone marrow MSCs the effects of testosterone have been shown to be mediated by the androgen receptor (AR) (Russell et al, 2018) that is expressed in an age- and sex-independent manner in almost all tissues, including bone and bone marrow. Deletion of the AR in male mice (global-ARKO mice) results in increased fat mass whereas bone and muscle mass were decreased (Russell et al, 2018).…”

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

“…Indeed, a crucial issue that is often overlooked is the role of sudden hormonal changes in facilitating the metastasis of CRPC cells, primarily to the bone marrow and brain [167,168] . Since androgen signaling plays an important role in normal physiology and cellular functions [169][170][171][172] , whole body hormone deprivation may result in systemic oxidative stress, especially in the bone marrow and brain, where the CRPC cells with an acquired redox-signaling network can find new sanctuaries and form metastatic foci, resulting in increased mortality associated with mCRPCs. Hence, potent compounds that may restore the antioxidant homeostasis in PCa patients following hormone deprivation, may not only suppress the selection of CRPC cells but may also decrease progression to metastatic CRPCs.…”