Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse

Purpose: Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences - hepatic steatosis and atherosclerosis. The testicular feminised (tfm) mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet whereas androgen replete XY littermate controls do not. Testosterone replacement ameliorates these effects, although the underlying mechanisms remain unknown. Methods: We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous (SAT) and visceral adipose tissue (VAT). Results: Tfm mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and SAT but not VAT. Lipoprotein lipase required for fatty acid uptake was only reduced in SAT, enzymes of fatty acid synthesis were increased. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in VAT and cholesterol efflux components (ABCA1, apoE) were decreased. Master regulator nuclear receptors involved in metabolism:- Liver X receptor expression was suppressed in all tissues except VAT whereas PPARγ was lower in SAT and VAT and PPARα only in SAT. Testosterone replacement improved the expression (androgen receptor independent) of some targets but not all. Conclusion: These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in SAT and muscle and fatty acids in SAT. This would lead to an overspill and uptake of excess glucose and triglycerides into VAT, liver and arterial walls.