As mentioned above, obesity promotes hypoadiponectinemia. It is believed that chronic inflammation associated with excess adiposity is a key feature of adiponectin downregulation under these conditions. Pro-inflammatory cytokines suppress adiponectin expression in adipocytes. TNF-α treatment suppresses adiponectin expression at the level of transcription in cultured 3T3-L1 adipocytes [94
] and reduces the expression and secretion of adiponectin protein in primary human adipocytes [95
]. Adiponectin mRNA expression and protein secretion are also inhibited by treatment with IL-6 in 3T3-L1 adipocytes [96
]. In epidemiological studies, a positive correlation is found between plasma levels of TNF-α and IL-6 and BMI [85
], whereas a negative correlation exists between BMI and adiponectin levels [7
]. Conversely, weight reduction correlates with decrease in levels of TNF-α and IL-6 in plasma [97
]. Weight loss also results in a significant increase in circulating adiponectin levels [98
Treatment with insulin-sensitizing agents, thiazolidinediones (TZDs), that activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are reported to increase plasma adiponectin levels in humans [94
]. TZDs treatment increases adiponectin expression and secretion in 3T3-L1 adipocytes as well as circulating adiponectin in obese mice [94
]. Recent experimental studies with obese mice lacking adiponectin showed that the beneficial actions of TZDs on insulin resistance are partly dependent on adiponectin [52
]. TZDs are believed to exhibit anti-inflammatory and anti-atherogenic properties [103
]. TZDs treatment is found to decrease plasma CRP and TNF-α levels in humans [104
]. It is conceivable that anti-inflammatory action of TZDs may be mediated by their ability to upregulate adiponectin, but a direct causal link has yet to be established.
Finally, a recent report has shown that adiponectin is expressed in human hearts, and that adiponectin transcripts are downregulated in dilated cardiomyopathy [106
]. Thus, dysregulation of adiponectin synthesized in myocardium may contribute to the development of obesity-linked heart diseases.