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

Study protocol to investigate the effects of testosterone therapy as an adjunct to exercise rehabilitation in hypogonadal males with chronic heart failure

BACKGROUND: Testosterone deficiency is a common occurrence in men with chronic heart failure (CHF) and may underpin features of advanced disease, including reduced skeletal muscle mass and fatigue. It is positively correlated with cardiac output and exercise capacity in patients with CHF, whereas a significant improvement in both these parameters has been observed following testosterone replacement therapy. Testosterone therapy has also been shown to reduce circulating levels of inflammatory markers, (TNF-α, sICAM-1 and sVCAM-1) in patients with established coronary artery disease and testosterone deficiency. This pilot study will assess the feasibility of a combined exercise rehabilitation and adjunctive testosterone therapy intervention for evoking improvements in exercise capacity, circulating inflammatory markers, cardiac and skeletal muscle function, indices of psychological health status and quality of life in hypogonadal males with chronic heart failure. METHODS/DESIGN: Following ethical approval, 36 patients will be randomly allocated to one of two groups: testosterone or placebo therapy during exercise rehabilitation. A combined programme of moderate intensity aerobic exercise and resistance (strength) training will be used. The primary outcome measure is exercise capacity, assessed using an incremental shuttle walk test. Secondary outcome measures include measures of peak oxygen uptake, cardiac function, lower-limb skeletal muscle contractile function and oxygenation during exercise, circulating inflammatory markers, psychological health status and quality of life. DISCUSSION: Exercise rehabilitation can safely increase exercise capacity in stable CHF patients but there is a need for studies which are aimed at evaluating the long-term effects of physical training on functional status, morbidity and mortality. This pilot study will provide valuable preliminary data on the efficacy of testosterone therapy as an adjunct to exercise rehabilitation on a range of functional, physiological and health-related outcomes in this patient population. Preliminary data will be used in the design of a large-scale randomised controlled trial, aimed at informing clinical practice with respect to optimisation of exercise rehabilitation in this patient group