Body composition changes and inhibition of fat development in vivo implicates androgen in regulation of stem cell lineage allocation

Abstract

Androgens regulate body composition in youth and declining testosterone that occurs with aging is associated with muscle wasting, increased fat mass and osteopenia. Transgenic mice with targeted androgen receptor (AR) overexpression in mesenchymal stem cells (MSC) were generated to explore the role of androgen signaling in the regulation of body composition. Transgenic males, but not females, were shorter and have reduced body weight and visceral fat accumulation. Dual energy x-ray absorptiometry (DXA) revealed significant reductions in fat mass with a reciprocal increase in lean mass, yet no difference in food consumption or locomotor activity was observed. Adipose tissue weight was normal in brown fat but reduced in both gonadal and perirenal depots, and reduced hyperplasia was observed with smaller adipocyte size in visceral and subcutaneous white adipose tissue. Although serum leptin, adiponectin, triglyceride, and insulin levels were no different between the genotypes, intraperitoneal glucose tolerance testing showed improved glucose clearance in transgenic males. High levels of the AR transgene are detected in MSCs but not in mature fat tissue. Reduced fibroblast colony forming units indicate fewer progenitor cells resident in the marrow in vivo. Precocious expression of GLUT4, PPARγ and C/EBPα was observed in proliferating precursor cultures from transgenic mice compared to controls. In more mature cultures, there was little difference between the genotypes. We propose a mechanism where enhanced androgen sensitivity can alter lineage commitment in vivo to reduce progenitor number and fat development, while increasing the expression of key factors to promote smaller adipocytes with improved glucose clearance.

Adipogenesis

“…It was proposed that the two potent androgens, testosterone and dihydrotestosterone, decrease C/EBPa and PPARg2 expression to inhibit differentiation of 3T3-L1 cells (Singh et al 2006). Additionally, transgenic mice with targeted AR overexpression in mesenchymal stem cells have substantial reductions in both WAT and BAT depots (Semirale et al 2011). In summary, the majority of studies on androgens and adipocyte development suggest that these steroid hormones have inhibitory effects.…”

The Aging Overactive Bladder: a Review of Aging-Related Changes from the Brain to the Bladder

“…The age-related increased in MCP-1 is likely linked to other age-related changes in body composition by which a portion of detrusor myocytes are gradually replaced by adipocytes. 43 This also explains the tendency for older bladders to become stiffer and trabeculated, which unresolved, can progress from overactive bladder to DHIC.…”

Adipocytes in Skin Health and Disease

“…Mice that express enhanced levels of the androgen receptor (AR) show decreased fat mass and adipocyte size (Blouin et al 2009;Semirale et al 2011) by preventing the commitment of preadipocytes (Chazenbalk et al 2013), promoting lipolysis (Blouin et al 2009) and blocking preadipocyte proliferation (Fujioka et al 2012). Androgens induce epidermal hyperplasia and affect the skin's barrier function (Kao et al 2001).…”