The effect of testosterone on factors associated with diabetes, atherosclerosis and obesity.

Obesity has recently become a major global health problem. Epidemiologic studies indicate that obesity is an important risk factor for type 2 diabetes (T2DM), atherosclerosis and low testosterone in men. Importantly, testosterone replacement treatment (TRT) can improve the condition of these diseases. According to human and animal studies testosterone can act as an anti-inflammatory and anti- atherogenic factor leading to inhibition of the risk factors and consequence of T2DM and atherosclerosis. Consequences of these diseases include dysregulation in atherogenic factors such as apolipoproteins or pro-inflammatory mediators such as cytokines and chemokines and their receptors. The effect of testosterone on these factors remains unclear. The objective of the present study was to demonstrate whether testosterone has antiinflammatory and anti-atherogenic action and by which mechanisms. This was achieved by using in vivo human and mice studies as well as in vitro models. The in vivo human study was conducted on short and long term studies, to determine the effect of TRT on anti and pro-inflammatory cytokines, HDL fractions and apolipoproteins in diabetic hypogonadal patients. Samples of liver tissue from testicular feminization mice (Tfm) were studied to investigate the effect of testosterone therapy on mRNA expression of adiponectin, PP ARb/o, PAI-1, apolipoproteins and pro-inflammatory chemokines with their receptors. Additionally, models of cell culture were studied including human macrophage THP-1 cells and mouse 3T3L1 cells to study the effect of testosterone with or without blocked androgen receptor (AR) on CX3CR1 and CCR2 and pro-inflammatory cytokines in macrophage cells and on adiponectin, PP ARB/o, PAI-1, leptin and chemokines in adipocyte cells, respectively.In the clinical studies, a reduction in adiponectin levels after 3 months was seen in the short-term study and an increase in HDL2 and HDL2/HDL3 ratio in the long-term study. No significant effect of testosterone was observed on body composition and atherogenic factors in either the short or long-term studies. In the animal study, testosterone increased hepatic expression of mRNA adiponectin, PP ARB/o and PAI-1 mRNA expression in Tfm. In the cell culture studies, testosterone treatment increased CCR2 mRNA expression and decreased secretion of IL-8 and TNF level in the supernatant of THP-1 macrophages. Testosterone decreased secretion of CCL2 and CX3CL1 from 3T3L1 adipocytes while increasing PAI-1 mRNA expression in these cells. The action of testosterone was based on the type of cells and time, route and dose size of treatment. In conclusion, although testosterone therapy showed a positive effect on some risk factors of obesity and its associated conditions, negative effects were also seen. However the exact mechanism of action of testosterone that influences risk factors of obesity and its associated conditions in men with low testosterone remain unclear, therefore further studies are needed to fully elucidate the above finding.