Testosterone: a metabolic hormone in health and disease

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   Figure 1

   The hypogonadal–obesity–adipocytokine hypothesis. High aromatase activity in adipocytes converts testosterone to oestradiol (1). Reduced tissue testosterone facilitates triglyceride storage in adipocytes by allowing increased lipoprotein lipase activity (2) and stimulating pluripotent stem cells to mature into adipocytes (blue arrow). Increased adipocyte mass is associated with greater insulin resistance (3). Oestradiol and adipocytokines TNFα, IL6 and leptin (as a result of leptin resistance in human obesity) inhibit the hypothalamic–pituitary–testicular axis response to decreasing androgen levels (4). Kisspeptin neurons are inhibited by oestradiol, inflammation and leptin resistance and thus reduce GNRH stimulation of the pituitary and subsequent LH release. Reduced LH pulse decreases gonadal stimulation and testosterone release, thus causing a state of hypogonadotrophic hypogonadism. Furthermore, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production. +, positive effect; −, negative effect (Jones 2010a,b).
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   Figure 2

   Obesity-induced insulin resistance. Chronic excessive dietary fat and carbohydrate intake coupled with a decrease in energy expenditure leads to a sustained rise in circulating free fatty acids (FFA) and blood glucose concentration. Excess FFA (yellow arrows) are incorporated into adipocyte triglyceride storage increasing visceral and subcutaneous fat mass. Adipose accumulation promotes the release of FFA into the circulation via lipolysis and these are taken up by muscle and liver in a ‘spillover’ effect. With accumulation of intramyocellular lipid, insulin-mediated skeletal muscle glucose uptake and utilisation is impaired along with decreased glycogen synthesis and lipid oxidation. As a result, excess glucose is diverted to the liver. In the liver, increased liver lipid also impairs the ability of insulin to regulate gluconeogenesis and activate glycogen synthesis. Hepatic lipogenesis further increases lipid content and can lead to hepatic steatosis. Impaired insulin action in the adipose tissue allows for increased lipolysis, which additionally promotes re-esterification of lipids in other tissues (such as liver and muscle) and further exacerbates insulin resistance. At the same time, adipose-derived inflammatory mediators contribute to the development of tissue insulin resistance (dark blue arrows). In particular, IL6 and TNFα inhibit the normal tyrosine phosphorylation of IRS1 and downstream signalling in hepatic tissue reducing insulin sensitivity. Similarly, TNFα promotes insulin resistance in skeletal muscle via IRS1 degradation and inhibition of insulin signalling. Although IL6 has been shown to exert some insulin sensitising effects in muscle, evidence also indicates a negative impact on insulin action and glucose homoeostasis by decreasing gene transcription of Irs1, Glut4 and Pparγ as well as IRS1 activity and thus reducing insulin-stimulated glucose uptake (see Wei et al. (2007)). Hyperglycaemia ensues. Testosterone deficiency contributes to tissue-specific mechanisms involved in the development of insulin resistance in liver, adipose and muscle tissue and promotes inflammation (green arrows). TRT may potentially improve the negative consequences of tissue-specific insulin insensitivity and improve metabolic function.

• © 2013 Society for Endocrinology