Overfeeding-induced weight gain elicits decreases in sex hormone-binding globulin in healthy males-Implications for body fat distribution.

OBJECTIVE: Obesity and upper-body fat elevates cardiometabolic risk. However, mechanisms predisposing to upper-body fat accumulation are not completely understood. In males, low testosterone (T) frequently associates with obesity, and estrogen deficiency may contribute to upper-body adiposity. This study examines the effects of overfeeding-induced weight gain on changes in gonadal hormones in healthy males and its association with regional fat depots. METHODS: Twenty-five males (age: 29.7 ± 6.9 years; BMI: 24.7 ± 3.1 kg/m2 ) were overfed for 8 weeks to gain approximately 5% body weight. Changes in total and regional fat depots were assessed using dual-energy x-ray absorptiometry and abdominal computed tomography scans. Circulating T, estrone (E1), 17-ß estradiol (E2), and sex hormone-binding globulin (SHBG) concentrations were measured at baseline and after weight gain. RESULTS: Overfeeding resulted in 3.8 (3.3, 4.9) kg weight gain with increased total body fat. Weight gain did not alter circulating T (p = 0.82), E1 (p = 0.52), or E2 (p = 0.28). However, SHBG decreased (p = 0.04) along with consequent increases in T/SHBG (p = 0.02) and E2/SHBG (p = 0.03) ratios. Importantly, baseline E2/SHBG ratio was inversely associated with increases in upper-body fat mass (ρ = -0.43, p = 0.03). CONCLUSIONS: Modest weight gain does not alter circulating gonadal hormones in males but may increase bioavailability of T and E2 via decreases in SHBG. The association between baseline E2/SHBG and regional fat mass suggests that higher levels of bioavailable E2 may protect from upper-body fat accumulation during overfeeding-induced modest weight gain in healthy males. Our study suggests a complex relationship between adipose tissue, gonadal hormones, and fat accumulation in males.

Leptin signaling in adipose tissue: role in lipid accumulation and weight gain.

RATIONALE: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. OBJECTIVE: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. METHODS AND RESULTS: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. CONCLUSIONS: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.

Independent association between plasma leptin and C-reactive protein in healthy humans.

BACKGROUND: C-reactive protein (CRP) is synthesized from the liver and is regulated by cytokines, especially interleukin-6. Leptin, the adipocyte-derived protein product of the ob gene, is related to amount of body fat. The long form of the leptin receptor resembles cytokine receptors, which include the interleukin-6 receptor. Both leptin and CRP may be increased in women, in obesity, and in inflammation, and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. We tested the hypothesis that leptin is associated with CRP levels independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables. METHODS AND RESULTS: We studied 100 healthy volunteers (48 men, and 52 women). For all subjects, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P=0.0007). There was a strong and significant positive relationship between leptin and CRP in both women (R=0.61, P<0.0001) and men (R=0.55, P<0.0001) considered separately. The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P=0.01) and men (F=5.69, P=0.02). When only subjects with BMI <25 kg/m2 were considered (n=47), CRP was not linked to BMI (R=0.02, P=0.96), but a significant association between leptin and CRP was still evident (R=0.55, P<0.0001). CONCLUSIONS: Leptin and CRP levels are independently associated in normal humans, providing further evidence linking metabolic and inflammatory cardiovascular disease mechanisms.