Testosterone Selectively Reduces the High Molecular Weight Form of Adiponectin by Inhibiting Its Secretion from Adipocytes

Abstract

The antidiabetic hormone adiponectin circulates in blood as several oligomeric complexes, and the ratios between them are critical in determining insulin sensitivity. In this study we investigated the role of testosterone in regulating the oligomeric complex distribution of adiponectin. Gel filtration analysis revealed that circulating adiponectin existed as the forms of high molecular weight (HMW), middle molecular weight, and low molecular weight complexes in both human and mice. The concentration of HMW adiponectin in female was significantly higher than that in male, whereas there were no gender differences for the other two forms. Castration induced a dramatic elevation of the HMW form but had no effect on either the middle molecular weight or the low molecular weight form in mice. Testosterone treatment, on the other hand, caused a specific reduction of HMW adiponectin in the circulation. Pulse-chase labeling experiments in rat adipocytes revealed that the three oligomeric forms of adiponectin were secreted into the culture medium at different rates and that testosterone selectively impeded the secretion of HMW adiponectin but not the other two forms. The inhibitory effect of testosterone on secretion of HMW adiponectin was largely restored by the transcription inhibitor actinomycin D, suggesting the involvement of a transcriptional event in this process. The selective inhibition of HMW adiponectin by testosterone might contribute to the sex dimorphism of adiponectin in terms of its oligomeric complex distribution and could partly explain why men have higher risk to insulin resistance and atherosclerosis than women.

Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum

“…Testosterone has been shown to selectively impede secretion of the HMW form of adiponectin from adipocytes, possibly by activating intracellular sequestering molecules [44]. Interestingly, testosterone elevates the relative levels of trimeric and hexameric adiponectin forms at the expense of the HMW form in circulation [44], consistent with the increased susceptibility of men to hepatic insulin resistance. Androgens may therefore serve as one of many factors modulating the pattern of adiponectin oligomeric complex distribution within target tissues.…”

“…The rate of HMW adiponectin secretion from adipocytes is slower than that of the other two oligomeric complexes [44]. Testosterone has been shown to selectively impede secretion of the HMW form of adiponectin from adipocytes, possibly by activating intracellular sequestering molecules [44]. Interestingly, testosterone elevates the relative levels of trimeric and hexameric adiponectin forms at the expense of the HMW form in circulation [44], consistent with the increased susceptibility of men to hepatic insulin resistance.…”

“…The three oligomeric adiponectin complexes have differential secretion rates [44], possibly dependent on the status of energy expenditure and on peripheral and hepatic insulin sensitivity. The rate of HMW adiponectin secretion from adipocytes is slower than that of the other two oligomeric complexes [44].…”

“…The rate of HMW adiponectin secretion from adipocytes is slower than that of the other two oligomeric complexes [44]. Testosterone has been shown to selectively impede secretion of the HMW form of adiponectin from adipocytes, possibly by activating intracellular sequestering molecules [44].…”

Polymorphisms of the gene encoding adiponectin and glycaemic outcome of Chinese subjects with impaired glucose tolerance: a 5-year follow-up study

“…Adiponectin was measured for subjects with available stored baseline serum (n=159) using an in-house adiponectin sandwich ELISA assay (inter-assay and intra-assay coefficients of variance of 6.2-8.3% and 5.1-6.4%, respectively) [15].…”