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Retroviral Transduction of Bone Marrow Progenitor Cells to Generate T-cell Receptor Retrogenic Mice
Published on: July 11, 2016
The androgen receptor in bone marrow progenitor cells negatively regulates fat mass
Patricia K Russell1, Salvatore Mangiafico1, Barbara C Fam1
1Department of MedicineAustin Health, University of Melbourne, Heidelberg, Victoria, Australia.
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.
Insights
Testosterone
Area of Science:
- Endocrinology
- Metabolism
- Molecular Biology
Background:
- Testosterone's role in regulating fat mass is known, but the precise mechanism remains unclear.
- Androgen receptor (AR) deletion in mice leads to increased fat and decreased bone/muscle mass, mimicking human hypogonadism.
- Mesenchymal progenitor cells (PCs) are crucial for bone marrow function and potentially involved in metabolic regulation.
Purpose of the Study:
- To investigate the specific role of the androgen receptor (AR) in mesenchymal progenitor cells (PCs) of bone marrow in regulating fat mass and metabolic function.
- To determine if targeted AR replacement in bone marrow PCs can reverse the effects of global AR deletion.
- To elucidate the mechanism by which androgens influence adipose tissue and insulin sensitivity.
Main Methods:
- Generation of mice with AR specifically deleted in all tissues except bone marrow mesenchymal progenitor cells (Global-ARKO mice).
- Selective reintroduction of the AR gene into bone marrow mesenchymal progenitor cells (PC-AR Gene Replacements) in Global-ARKO mice.
- Analysis of fat mass (subcutaneous and visceral), adipocyte size, serum metabolic markers (leptin, adiponectin), and insulin sensitivity (euglycaemic/hyperinsulinaemic clamp studies).
Main Results:
- PC-AR Gene Replacement mice exhibited significantly reduced subcutaneous and visceral fat mass (50-90% lower than controls).
- These mice displayed smaller adipocytes and an improved metabolic profile, with normal leptin and elevated adiponectin levels.
- Enhanced whole-body insulin sensitivity and increased glucose uptake in adipose tissue were observed in PC-AR Gene Replacement mice compared to wild-type.
Conclusions:
- Androgens act via the AR in bone marrow mesenchymal progenitor cells to negatively regulate fat mass.
- Targeting AR in these specific cells improves metabolic function and insulin sensitivity.
- These findings identify a novel mechanism for androgen action in metabolic homeostasis.
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