Abstract
Objective A growing body of evidence indicates that AMP-activated protein kinase (AMPK) contributes to not only energy metabolic homeostasis but also the inhibition of inflammatory responses. However, the underlying mechanisms remain unclear. To elucidate the role of AMPK, in this study, we observed the effects of AMPK activation on monocyte chemoattractant protein-1 (MCP-1) release in mature 3T3-L1 adipocytes. Methods We observed signal transduction pathways regulating MCP-1, which increased in obese adipocytes, in an in vitro model of hypertrophied 3T3-L1 adipocytes preloaded with palmitate. Results Palmitate-preloaded cells exhibited significant increase in MCP-1 release and triglyceride (TG) deposition. Increased MCP-1 release and TG deposition were significantly decreased by an AMPK activator. In addition, the AMPK activator not only markedly diminished MCP-1 secretion but also augmented phosphorylation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK) 1/2. In contrast, MCP-1 release suppression was abolished by the AMPK inhibitor compound C and the MEK inhibitor U0126. Conclusions MCP-1 release from hypertrophied adipocytes is suppressed by AMPK activation through the NF-κB and ERK pathways. These findings provide evidence that AMPK plays a crucial role in ameliorating obesity-induced inflammation.
Highlights
Chronic low-grade inflammation in adipose tissues of obesity models has been proven to play crucial roles in the development of obesity, which in turn induces systemic insulin resistance, the early step in the pathogenesis of type 2 diabetes mellitus (T2DM) [1,2,3]
We previously reported that activation of endogenous AMPK by 2,4-dinitrophenol or AICAR significantly decreases the release of monocyte chemoattractant protein-1 (MCP-1) from mature 3T3-L1 adipocytes [13]
To elucidate the role of AMPK, we demonstrated the direct effects of AMPK using an in vitro model of artificially hypertrophied mature 3T3-L1 adipocytes preloaded with palmitate by applying the three aforementioned AMPK activators, AICAR, A769662, and metformin, focusing especially on the AMPK-mediated mechanisms regulating the expressions and secretions of adipokines playing central roles in the induction of peripheral insulin resistance
Summary
Chronic low-grade inflammation in adipose tissues of obesity models has been proven to play crucial roles in the development of obesity, which in turn induces systemic insulin resistance, the early step in the pathogenesis of type 2 diabetes mellitus (T2DM) [1,2,3]. We previously showed that MCP-1 release is increased by activated c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) pathways in hypertrophied adipocytes [8]. Such increased levels of MCP-1 release recruit more macrophages to sites of infiltration, and these activated macrophages stimulate further production of MCP-1. Taking these observations together, the secretory system of MCP-1 can be understood as being critical for regulating inflammation in the adipose tissues of obesity models, which leads to exacerbation of obesity-related insulin resistance
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