Androgens and adipose tissue in males: a complex and reciprocal interplay

Abstract

Clinical evidence shows that in males obesity is frequently associated with hypogonadism and vice versa; also, low testosterone levels have been considered a "hallmark" of metabolic syndrome in men. These observations indicate that there is a strict connection between anatomically and functionally distinct cell types such as white adipocytes and Leydig cells, that synthesize testosterone. Adipose tissue is able to control several functions of the testis through its products secreted in the bloodstream. On the other hand, circulating levels of testosterone and estradiol deeply affect adipocyte proliferation, differentiation, and fat mass distribution, hereby controlling critical metabolic functions, such as food intake, insulin sensitivity, vascular reactivity, and immunity. This paper highlights the existing clinical and experimental evidence linking androgens and adipose tissue and illustrates the consequences occurring when the balance between fat mass distribution and eugonadism is lost.

Figure 1

Effect of testosterone on 3T3-L1 adipose differentiation. Red oil staining of mature 3T3-L1 adipocytes (scale bar, 70 μm) (Caprio M. et al., unpublished), classically differentiated in the absence (left) or in the presence (right) of 10⁻⁷ M testosterone. Testosterone treatment determines a marked reduction in size and number of lipid droplets, in accordance with previous reports [73].

Figure 2

Reciprocal interplay between white adipose tissue (WAT) and testis. (a) In normal conditions, circulating androgens control adipocyte size and adipose mass. On the other hand, plasmatic leptin, mainly produced by adipose tissue, regulate testicular steroidogenesis. Dashed bars indicate the reciprocal interplay between testis (through androgens) and adipose tissue (mainly through leptin). (b) Androgen deficiency induces expansion of fat mass and subsequent dysregulation of several functions controlled by adipose tissue such as insulin sensitivity, blood pressure, vascular reactivity, and immunity. The state of insulin resistance determined by obesity leads to reduced production of SHBG. The consequent reduction in testosterone triggers expansion of adipose mass with subsequent increase in aromatase (ARO) activity, which in turn mediates peripheral conversion of testosterone to estradiol. Increased estrogen levels induce a reduction of LH pulse which contributes to the reduction in androgen production. On the other hand, excess of circulating leptin, due to increased adipose mass, disrupts testicular steroidogenesis, with consequent suppression of androgen production. The vicious cycle is triggered. AR: androgen receptor.