Androgen receptor gene polymorphisms and maximal fat oxidation in healthy men. A longitudinal study.

INTRODUCTION: Androgens play a major role in fat oxidation; however, the effects of androgens depend, among other factors, on the intrinsic characteristics of the androgen receptor (AR). Lower repetitions of CAG and GGN polymorphism appear to have a protective effect on fat accumulation in the transition from adolescent to mid-twenties. Whether a similar protective effect is present later in life remains unknown. The aims of this study were: a) to evaluate if extreme CAG and GGN repeat polymorphisms of the androgen receptors influence body fat mass, its regional distribution, resting metabolic rate (RMR), maximal fat oxidation capacity (MFO) and serum leptin, free testosterone and osteocalcin in healthy adult men; and b) to determine the longitudinal effects on fat tissue accumulation after 6.4 years of follow-up. METHODS: CAG and GGN repeats length were measured in 319 healthy men (mean ± standard deviation [SD]: 28.3 ± 7.6 years). From these, we selected the subjects with extreme short (CAGS < or equal 19; n = 7) and long (CAGL > or equal 24; n = 10) CAG repeats, and the subjects with short (GGNS < or equal to 22; n = 9) and long (GGNL > or equal to 25; n = 10) GGN repeats. Body composition was assessed by DXA and serum levels of leptin, free testosterone and osteocalcin by ELISA. After 6.4 years of follow-up, DXA was repeated, and resting metabolic rate (RMR), MFO and VO2max determined by indirect calorimetry. RESULTS: CAGS and CAGL subjects had similar RMR and accumulated comparable amounts of fat tissue over 6.4 ± 1.0 years of follow-up. However, CAGL had higher MFO and total lean mass than CAGS (p < 0.05). Men with GGNS accumulated greater amount of total fat mass than men with GGNL, particularly in the trunk region seven years later. This concurred with a greater MFO in the GGNL group (p < 0.05), who accumulated less fat mass. Free testosterone was associated with MFO in absolute values (r = 0.45; p < 0.05) and MFO per kg of lower extremity lean mass per height squared (r = 0.35; p < 0.05). CONCLUSIONES: CAG and GGN repeat polymorphisms may influence muscle fat oxidation capacity and may have a role in the accumulation of fat over the years.

Androgen receptor gene polymorphisms and maximal fat oxidation in healthy men. A longitudinal study / Polimorfismo del gen del receptor de andrógenos y oxidación máxima de grasa en hombres sanos. Estudio longitudinal

Introduction: Androgens play a major role in fat oxidation; however, the effects of androgens depend, among other factors, on the intrinsic characteristics of the androgen receptor (AR). Lower repetitions of CAG and GGN polymorphism appear to have a protective effect on fat accumulation in the transition from adolescent to mid-twenties. Whether a similar protective effect is present later in life remains unknown. The aims of this study were: a) to evaluate if extreme CAG and GGN repeat polymorphisms of the androgen receptors influence body fat mass, its regional distribution, resting metabolic rate (RMR), maximal fat oxidation capacity (MFO) and serum leptin, free testosterone and osteocalcin in healthy adult men; and b) to determine the longitudinal effects on fat tissue accumulation after 6.4 years of follow-up. Methods: CAG and GGN repeats length were measured in 319 healthy men (mean ± standard deviation [SD]: 28.3 ± 7.6 years). From these, we selected the subjects with extreme short (CAGS ≤ 19; n = 7) and long (CAGL ≥ 24; n = 10) CAG repeats, and the subjects with short (GGNS ≤ 22; n = 9) and long (GGNL ≥ 25; n = 10) GGN repeats. Body composition was assessed by DXA and serum levels of leptin, free testosterone and osteocalcin by ELISA. After 6.4 years of follow-up, DXA was repeated, and resting metabolic rate (RMR), MFO and VO2max determined by indirect calorimetry. Results: CAGS and CAGL subjects had similar RMR and accumulated comparable amounts of fat tissue over 6.4 ± 1.0 years of follow-up. However, CAGL had higher MFO and total lean mass than CAGS (p < 0.05). Men with GGNS accumulated greater amount of total fat mass than men with GGNL, particularly in the trunk region seven years later. This concurred with a greater MFO in the GGNL group (p < 0.05), who accumulated less fat mass. Free testosterone was associated with MFO in absolute values (r = 0.45; p < 0.05) and MFO per kg of lower extremity lean mass per height squared (r = 0.35; p < 0.05). Conclusions: CAG and GGN repeat polymorphisms may influence muscle fat oxidation capacity and may have a role in the accumulation of fat over the years (AU)

Introducción: los andrógenos juegan un papel importante en la oxidación de grasas; sin embargo, el efecto de los andrógenos depende, entre otros factores, de las características intrínsecas del receptor de andrógenos (RA). Un menor número de repeticiones CAG y GGN del RA parecen tener un efecto protector sobre la acumulación de grasa en la transición de la adolescencia hasta la veintena. Se desconoce si adelante en la vida persiste un efecto protector similar. Los objetivos de este estudio fueron: a) evaluar si repeticiones extremas de los polimorfismos CAG y GGN del RA influyen sobre la masa grasa corporal, su distribución regional, la tasa metabólica en reposo (RMR), la máxima oxidación de grasas (MFO) y la concentración sérica de leptina, testosterona libre y osteocalcina en hombres sanos; y b) determinar los efectos longitudinales sobre la acumulación de grasa después de 6.4 años de seguimiento. Métodos: la longitud de las repeticiones de CAG y GGN fueron medidas en 319 hombres sanos (media ± desviación estándar [SD]: 28,3 ± 7,6 años). De estos, seleccionamos los sujetos con repeticiones del CAG extremas cortas (CAGS ≤ 19; n = 7) y largas (CAGL ≥ 24; n = 10), y los sujetos con repeticiones del GGN extremas cortas (GGNS ≤ 22; n = 9) y largas (GGNL ≥ 25; n = 10). Se evaluaron la composición corporal mediante DXA y los niveles séricos de leptina, testosterona libre y osteocalcina por ELISA. Tras 6.4 años de seguimiento el DXA fue repetido, y la tasa metabólica en reposo (RMR), máxima oxidación de grasas (MFO) y VO2max fueron determinados mediante calorimetría indirecta. Resultados: los grupos CAGS y CAGL fueron comparables en RMR y cantidad de tejido graso tras 6,4 ± 1,0 años de seguimiento. Sin embargo, el grupo CAGL tuvo mayor MFO y masa libre de grasa que el grupo CAGS (p < 0,05). Los hombres con GGNS acumularon mayor cantidad de masa grasa total que los hombres con GGNL, particularmente en la región del tronco siete años después. Esto concordó con un mayor MFO en el grupo GGNL (p < 0,05), que acumuló menos masa grasa. La testosterona libre se asoció con el MFO en valores absolutos (r = 0,45; p < 0,05) y con MFO expresado por kg de masa libre de grasa de las piernas al cuadrado (r = 0,35; p < 0,05). Conclusiones: las repeticiones del polimorfismo del CAG y GGN pueden influenciar la capacidad muscular de oxidación de grasas y pueden tener un rol en la acumulación de grasa con los años (AU)

Androgen receptor gene polymorphisms and the fat-bone axis in young men and women.

Androgen receptor (AR) CAG(n) (polyglutamine) and GGN(n) (polyglycine) repeat polymorphisms determine part of the androgenic effect and may influence adiposity. The association of fat mass, and its regional distribution, with the AR CAG(n) and GGN(n) polymorphisms was studied in 319 and 78 physically active nonsmoker men and women (mean ± SD: 28.3 ± 7.6 and 24.8 ± 6.2 years old, respectively). The length of CAG and GGN repeats was determined by polymerase chain reaction and fragment analysis, and confirmed by DNA sequencing of selected samples. Men were grouped as CAG short (CAG(S)) if harboring repeat lengths ≤ 21, the rest as CAG long (CAG(L)). The corresponding cutoff CAG number for women was 22. GGN was considered short (GGN(S)) if GGN ≤ 23, the rest as GGN long (GGN(L)). No association between AR polymorphisms and adiposity or the hormonal variables was observed in men. Neither was there a difference in the studied variables between men harboring CAG(L) + GGN(L),CAG(S) + GGN(S),CAG(S) + GGN(L), and CAG(L) + GGN(S) combinations. However, in women, GGN(n) was linearly related to the percentage of body fat (r = 0.30, P < .05), the percentage of fat in the trunk (r = 0.28, P < .05), serum leptin concentration (r = 0.40, P < .05), and serum osteocalcin concentration (r = 0.32, P < .05). In men, free testosterone was inversely associated with adiposity and serum leptin concentration, and positively with osteocalcin, even after accounting for differences in CAG(n), GGN(n), or both. In summary, this study shows that the AR repeat polymorphism has little influence on absolute and relative fat mass or its regional distribution in physically active men. In young women, GGN length is positively associated with adiposity, leptin, and osteocalcin.

Bone mass and the CAG and GGN androgen receptor polymorphisms in young men.

BACKGROUND: To determine whether androgen receptor (AR) CAG (polyglutamine) and GGN (polyglycine) polymorphisms influence bone mineral density (BMD), osteocalcin and free serum testosterone concentration in young men. METHODOLOGY/PRINCIPAL FINDINGS: Whole body, lumbar spine and femoral bone mineral content (BMC) and BMD, Dual X-ray Absorptiometry (DXA), AR repeat polymorphisms (PCR), osteocalcin and free testosterone (ELISA) were determined in 282 healthy men (28.6+/-7.6 years). Individuals were grouped as CAG short (CAG(S)) if harboring repeat lengths of < or = 21 or CAG long (CAG(L)) if CAG > 21, and GGN was considered short (GGN(S)) or long (GGN(L)) if GGN < or = 23 or > 23. There was an inverse association between logarithm of CAG and GGN length and Ward's Triangle BMC (r = -0.15 and -0.15, P<0.05, age and height adjusted). No associations between CAG or GGN repeat length and regional BMC or BMD were observed after adjusting for age. Whole body and regional BMC and BMD values were similar in men harboring CAG(S), CAG(L), GGN(S) or GGN(L) AR repeat polymorphisms. Men harboring the combination CAG(L)+GGN(L) had 6.3 and 4.4% higher lumbar spine BMC and BMD than men with the haplotype CAG(S)+GGN(S) (both P<0.05). Femoral neck BMD was 4.8% higher in the CAG(S)+GGN(S) compared with the CAG(L)+GGN(S) men (P<0.05). CAG(S), CAG(L), GGN(S), GGN(L) men had similar osteocalcin concentration as well as the four CAG-GGN haplotypes studied. CONCLUSION: AR polymorphisms have an influence on BMC and BMD in healthy adult humans, which cannot be explained through effects in osteoblastic activity.