Caffeine Upregulates Hepatic Sex Hormone-Binding Globulin Production by Increasing Adiponectin Through AKT/FOXO1 Pathway in White Adipose Tissue.

Scope Epidemiological studies have shown that caffeine increases serum sex hormone-binding globulin (SHBG) levels. The relationship between caffeine and SHBG production has never been studied before at molecular level. The aim of this study is to examine whether caffeine regulates SHBG production and to determine the associated molecular mechanisms. Methods and results Two different studies are performed; in vitro studies using human HepG2 cells treated with caffeine (100 and 500 mu m) and in vivo studies using a humanized SHBG transgenic mice drinking caffeine in the water (0.1 mg mL(-1)) for 12 days. The results show that caffeine does not change SHBG production in HepG2 cells. By contrast, caffeine treatment increases significantly hepatic SHBG production in human SHBG transgenic mice when compared with control mice. Caffeine increases adiponectin levels in epididymal adipose tissue of human SHBG transgenic mice. Moreover, caffeine increases adiponectin production by reducing protein kinase B (AKT) phosphorylation which increases forkhead box protein O1 (FOXO1) protein levels in 3T3-L1 mature adipocytes and human SHBG transgenic mice. Finally, caffeine-induced increase in adiponectin in turn upregulates hepatic hepatocyte nuclear receptor 4-alpha (HNF-4 alpha) levels in human SHBG transgenic mice. Conclusions The results show that caffeine upregulates hepatic SHBG expression by increasing adiponectin production through AKT/FOXO1 pathway in the adipose tissue.