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

Patricia K. Russell, Salvatore Mangiafico, Barbara C. Fam, Michele V. Clarke, Evelyn S. Marin, Sofianos Andrikopoulos, Kristine Wiren, Jeffrey D. Zajac, Rachel A. Davey

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 Ar 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.

Original languageEnglish (US)
Pages (from-to)15-27
Number of pages13
JournalJournal of Endocrinology
Volume237
Issue number1
DOIs
StatePublished - Apr 1 2018

Fingerprint

Androgen Receptors
Bone Marrow Cells
Intra-Abdominal Fat
Stem Cells
Fats
Genes
Subcutaneous Fat
Testosterone
Glucose
White Adipose Tissue
Glucose Clamp Technique
Hypogonadism
Metabolome
Groin
Adiponectin
Leptin
Serum
Mesenchymal Stromal Cells
Adipocytes
Androgens

Keywords

  • Adipose tissue
  • Androgen
  • Androgen receptor
  • Glucose metabolism
  • Testosterone

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Russell, P. K., Mangiafico, S., Fam, B. C., Clarke, M. V., Marin, E. S., Andrikopoulos, S., ... Davey, R. A. (2018). The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. Journal of Endocrinology, 237(1), 15-27. https://doi.org/10.1530/JOE-17-0656

The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. / Russell, Patricia K.; Mangiafico, Salvatore; Fam, Barbara C.; Clarke, Michele V.; Marin, Evelyn S.; Andrikopoulos, Sofianos; Wiren, Kristine; Zajac, Jeffrey D.; Davey, Rachel A.

In: Journal of Endocrinology, Vol. 237, No. 1, 01.04.2018, p. 15-27.

Research output: Contribution to journalArticle

Russell, PK, Mangiafico, S, Fam, BC, Clarke, MV, Marin, ES, Andrikopoulos, S, Wiren, K, Zajac, JD & Davey, RA 2018, 'The androgen receptor in bone marrow progenitor cells negatively regulates fat mass', Journal of Endocrinology, vol. 237, no. 1, pp. 15-27. https://doi.org/10.1530/JOE-17-0656
Russell PK, Mangiafico S, Fam BC, Clarke MV, Marin ES, Andrikopoulos S et al. The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. Journal of Endocrinology. 2018 Apr 1;237(1):15-27. https://doi.org/10.1530/JOE-17-0656
Russell, Patricia K. ; Mangiafico, Salvatore ; Fam, Barbara C. ; Clarke, Michele V. ; Marin, Evelyn S. ; Andrikopoulos, Sofianos ; Wiren, Kristine ; Zajac, Jeffrey D. ; Davey, Rachel A. / The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. In: Journal of Endocrinology. 2018 ; Vol. 237, No. 1. pp. 15-27.
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