BackgroundDecreases in estrogen are shown to increase body fat in men. However, obese men have high levels of estrogen and the effects of weight gain on estrogen have not been previously investigated. The objective of this study was to investigate the relationship between regional fat depots and estrogen during modest weight in healthy men.MethodsWe investigated the effects of overfeeding in 25 healthy men (30 ± 7 years, 24.7 ± 3.1 kg/m2). Changes in regional fat depot during weight gain were assessed using dual‐energy X‐ray absorptiometry and abdominal computed tomography scans. Participants gained approximately 5% body weight in 8 weeks. Estrone (E1), 17β‐estradiol (E2) and sex hormone binding globulin (SHBG) were measured at baseline and after weight gain.ResultsOverfeeding was accompanied by 3.9 ± 1.3 kg weight gain. These increases in weight resulted from increases in total body fat mass (18.3 ± 8.5 vs. 21.7 ± 8.8 kg, p<0.001) while the fat free mass did not change (58.4 ± 8.6 vs. 58.9 ± 8.7 kg, p=0.15). E1 (32.28 ± 14.25 vs. 33.44 ± 12.29 pg/mL, p=0.56) and E2 (25.04 ± 8.3 vs. 26.52 ± 7.8 pg/mL, p=0.28) did not change after weight gain. However, weight gain resulted in decreased SHBG (22.8 ± 10.5 vs. 20.8 ± 11.1 nmol/l, p=0.036) and increased E2/SHBG ratio (1.4 ± 1.0 vs 1.63 ± 1.0, p=0.027). The changes in E2/SHBG ratio, a surrogate marker of bioavailable E2, was positively associated with increases in abdominal fat mass (p=0.048, rho=0.39) and increases in visceral fat mass (p=0.049, rho=0.39).ConclusionModest weight gain in healthy men does not alter circulating E1 and E2 levels. However weight gain results in decreased SHBG and increased free E2 (E2/SHBG ratio). The increased E2/SHBG ratio suggesting a pro‐estrogen effect is associated with increases in visceral fat mass during weight gain. Our study therefore suggests a complex relationship between abdominal fat gain and free E2 in men which may conceivably predispose to feminizing characteristics in obese men.Support or Funding InformationPS is supported by AHA Grant 11SDG7260046 and NIH grant DK81014. NC is supported by AHA grant AHA 13POST16420009. MDJ is supported by NIH grants DK45343 and DK40484. VKS is supported by NIH Grants HL73211, and DK81014. This study was made possible by a grant from NCRR (1UL1 RR024150).