It has been reported that adiponectin enhances interleukin-6 (IL-6) production in cardiac fibroblasts derived from neonatal rats and adult mice, but the mechanisms involved remain unknown. In the present study, we explored the effect and mechanisms of adiponectin on IL-6 production in adult rat cardiac fibroblasts. Globular adiponectin (gAd) increased IL-6 mRNA expression and protein secretion in cultured adult rat cardiac fibroblasts. gAd-induced IL-6 release was attenuated after RNA interference inhibition of adiponectin receptor 1 (AdipoR1), but not AdipoR2 or an adaptor protein APPL1. gAd increased the phosphorylation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun-N-terminal kinase (JNK). Inhibitors of AMPK (araA), p38MAPK (SB202190), and ERK1/2 (PD98059 and U0126) but not JNK (SP600125) suppressed gAd-induced IL-6 production. In transient transfection assays of IL-6 promoter/luciferase reporter plasmids, gAd increased the transcriptional activity of the full-length IL-6 promoter. Deletion analysis of the IL-6 promoter indicated that activator protein-1 (AP-1), nuclear factor for IL-6 (NF-IL-6) and nuclear factor κB (NF-κB) binding sites were important for gAd-induced IL-6 transcription. Our data suggest that gAd enhances IL-6 synthesis and release in adult rat cardiac fibroblasts through AdipoR1. Activation of AMPK, p38MAPK, and ERK1/2 mediates the intracellular signal transduction. AP-1, NF-IL-6, and NF-κB cis-elements are required for gAd-induced IL-6 transcription. J. Cell. Physiol. 226: 1793–1802, 2011. © 2010 Wiley-Liss, Inc.