The AR in bone marrow progenitor cells protects against short-term high caloric diet induced weight gain in male mice.

2022-05-10

Venkatesh, Varun S

Russell, Patricia K

Fam White, Barbara

Clarke, Michele V

Golub, Suzanne

Mangiofico, Salvatore

Haralambous, Christian

Lokan, Julie

Andrikopoulos, Sofianos

Zajac, Jeffrey D

Davey, Rachel A

Journal Article

0000-0002-1295-0033

0000-0003-4351-3271

0000-0002-0249-0483

0000-0001-7731-1649

0000-0002-1333-4734

0000-0002-8932-8592

0000-0003-3933-5708

0000-0001-5121-0209

10.1530/JME-22-0038

We previously identified a novel pathway of testosterone action via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to negatively regulate fat mass and improve metabolic function in male mice. This was achieved using our PC-AR Gene Replacement mouse model in which the AR is only expressed in BM-PCs and deleted in all other tissues. We hypothesise that the markedly reduced fat mass and increased insulin sensitivity of PC-AR Gene Replacements will confer protection from diet-induced overweight and obesity. To test this, 6-week-old male PC-AR Gene Replacements and controls (wild-type (WT), Global-AR knockouts (KOs)) were fed a chow or high caloric diet (HCD) for 8 or 18 weeks. Following 8 weeks (short-term) of HCD, WT and Global-ARKOs had markedly increased subcutaneous white adipose tissue (WAT) and retroperitoneal visceral adipose tissue (VAT) mass compared to chow-fed controls. In contrast, PC-AR Gene Replacements were resistant to WAT and VAT accumulation following short-term HCD feeding accompanied by fewer large adipocytes and upregulation of expression of the metabolic genes Acaca and Pnlpa2. Following long-term HCD feeding for 18 weeks, the PC-AR Gene Replacements were no longer resistant to increased WAT and VAT adiposity; however, maintained their improved whole-body insulin sensitivity with an increased rate of glucose disappearance and increased glucose uptake into subcutaneous WAT. In conclusion, testosterone action via the AR in BM-PCs to negatively regulate fat mass and improve metabolism, confers resistance from short-term diet induced weight gain and partial protection from long-term diet induced obesity in male mice.

link

Journal of Molecular Endocrinology 2022;69(1):269-283

Journal of molecular endocrinology