Determining the mechanism by which the male sex hormone, testosterone, acts to decrease fat mass.

Project Details

Obesity has been deemed a pandemic by the World Health Organisation, with a staggering 63% of Australian adults being overweight or obese. With current forms of treatment being manifestly inadequate, novel approaches to effective therapy are urgently required.
It is well established that testosterone negatively regulates fat mass. The problem, however, is that we still lack a basic understanding of the mechanism by which this hormone exerts its fat-reducing effects; and due to its masculinising side effects, testosterone itself cannot be used as a treatment for obesity.


We and others have shown that deleting the androgen receptor (AR; target for testosterone action), results in a phenotype that closely mimics the three key clinical aspects of hypogonadism in human males; increased fat mass, decreased bone mass and decreased muscle mass. We have recently published compelling new data showing that subsequently replacing the AR only in bone marrow progenitor cells (PCs) of these mice – whilst it remains absent in all other tissues – dramatically attenuates fat accumulation and improves metabolic function in these PC-AR Gene Replacement mice.

What is responsible for mediating this striking effect on fat mass? We hypothesise that testosterone acts via the AR in bone marrow PCs to regulate the secretion of bone-derived factors, which are released into the circulation to negatively regulate fat mass. We aim to use our novel PC-AR Gene Replacement mouse model and an innovative combination of informed gene, protein and metabolic profiling approaches to identify the circulating factor/s responsible for the decreased fat mass in these mice. Identifying the molecular mechanism by which testosterone decreases fat mass will enable the design of new therapeutic agents for the treatment of obesity that target the specific actions of testosterone to decrease fat – but without the negative side-effects.

Researchers

Collaborators

Funding

  • Sir Edward Dunlop Medical Research Foundation
  • Ian Potter Foundation

Research Outcomes

Research Publications

  • Russell PK, Mangiafico S, Fam BC, Clarke MV, Marin ES, Andrikopoulos S, Wiren KM, Zajac JD, Davey RA. The androgen receptor in bone marrow progenitor cells negatively regulates fat mass. Journal of Endocrinology, 2018, 237(1):15-27.

Research Group

Molecular Endocrinology and Musculoskeletal Research Group


School Research Themes

Musculoskeletal



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Medicine and Radiology

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