The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

Abstract

Aims/hypothesis. The relationship of androgens to the metabolic syndrome has not been resolved. The polymorphic number of CAG repeats within the androgen receptor gene is inversely associated with the transcriptional activity of target genes.This polymorphism might thus influence testosterone effects on body fat content and serum concentrations of leptin and insulin. The direct and indirect role of androgens within the metabolic syndrome should become clearer if this genetically determined effector is taken into account. Methods. The hypothesis was investigated in a crosssectional study involving 106 healthy 20-50 year old males. Results. Multiple regression models showed a positive independent correlation of the CAG repeat number with body fat content, leptin and insulin (partial r=0.39, 0.36 and 0.28, p<0.001, p<0.001 and p=0.006, respectively). Factor analysis yielded a five-dimensional model: two dimensions were influenced by the androgen receptor polymorphism, namely "body composition" which consisted of leptin, body fat mass, insulin, the number of CAG repeats (positive loadings) and physical activity (negative loading), and "lipid profile" which comprised low density lipoprotein cholesterol, cigarette smoking, triglycerides (positive loadings) as well as high density lipoprotein cholesterol and number of CAG repeats (negative loadings). Conclusions/interpretation. A low number of CAG repeats were independently associated with protective parameters (low body fat mass and plasma insulin) as well as with adverse parameters (low high density lipoprotein cholesterol concentrations). This suggests that the pivotal role of this polymorphism in modulating androgen effects on cardiovascular risk factors is of a complex nature and implies that its clinical impact, similar to that of androgens, is dependent on exogenous cofactors. [Diabetologia (2003) 46:31-39] Keywords Testosterone, body fat, leptin, insulin, androgen receptor, CAG repeat polymorphism. Corresponding author: E. Nieschlag, Institute of Reproductive Medicine of the University, Domagkstr. 11, 48129 Münster, Germany, E-mail: nieschl@uni-muenster.de Abbreviations: Ar, Adrogen Receptor; BFM, body fat mass; CAG, cytosin-adenin-guanin; CAGr, CAG repeats; FFM, fat free mass; HDL, high density lipoprotein; SHBG, sex hormone binding globuline; TBW, total body water; WHR, waist-to-hip ratio. Diabetologia (2003) 46:31-39 DOI 10.1007 The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men The term "metabolic syndrome" describes a pre-diabetic and pro-atherogenic state which is characterized by overweight, impaired glucose tolerance, hyperinsulinaemia, arterial hypertension, low concentrations of high density lipoprotein (HDL) cholesterol, hypertriglyceridaemia and disturbed haemostasis [1,2,3,4,5,6]. Several cross-sectional population studies found correlations between serum concentrations of testosterone and these cardiovascular risk factors, which, however, were opposi...

Androgen receptor CAG repeat length polymorphism modifies the impact of testosterone on insulin sensitivity in men

“…This contrasts to previous studies reporting a correlation with fasting insulin (22) or an association with the risk for suffering from the metabolic syndrome (23). Remarkably, the directions of the association between the CAG length polymorphism and the metabolic parameters were contradictory in these two studies (22,23).…”

“…Limitations of this study are mentioned, which include the relatively small size of the investigated cohort, although within the range of others exploring Table 3 HOMA %S depending on free testosterone (f-testo) and the androgen receptor CAG repeat length for a 60-year-old man with a body mass index of 30 kg/m 2 as predicted from a regression model (see Table 2 the association of the AR CAG repeat length polymorphism on components of the metabolic syndrome (22,23). Furthermore, we reproduced our results obtained in women suffering from hyperandrogenism (24), which support the relevance of the present findings.…”

“…Associations between CAG repeats and components of the metabolic syndrome in men have been reported by some more recent studies. Data, however, regarding the association between the CAG polymorphism and the metabolic syndrome are conflicting (22,23).…”

The impact of the CAG repeat polymorphism of the androgen receptor gene on muscle and adipose tissues in 20–29-year-old Danish men: Odense Androgen Study

“…It may be a direct effect of increased AR activity in men with shorter alleles, because the AR has been shown to mediate the inhibitory effects of TT and DHT on mesenchymal stem cell differentiation toward adipocytes (30). Our results are in agreement with Zitzmann et al (2003), who found the same relationship with FM in a crosssectional study involving 106 healthy 20-50-year-old men. The median age of their cohort (28 years) was very close to that of our cohort (25.7 years).…”

Androgen receptor (AR) gene CAG trinucleotide repeat length associated with body composition measures in non-syndromic obese, non-obese and Prader-Willi syndrome individuals

“…The androgen receptor is a steroid hormone-activated transcription factor key to regulating androgen activity in both males and females and responsible for secondary sexual characteristics, sex hormone responses and infertility in both sexes. It has been shown to influence body mass and composition [10,[15][16][17][18][19].…”