Invited critical reviewAdiponectin as an anti-inflammatory factor
Introduction
Increasing evidence indicates that chronic mild inflammation linked to obesity is closely associated with the development of insulin resistance and cardiovascular disorders [1]. A number of bioactive substances secreted from fat tissue, referred to as adipokines, could contribute to the complications of obesity through the regulation of inflammatory and immune responses [2], [3]. Adipokines include pro-inflammatory cytokines/chemokines such as leptin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) [2], [3]. In contrast, the adipokine adiponectin exerts anti-inflammatory actions on a number of cell types.
Adiponectin, also referred to as ACRP30, AdipoQ and gelatin-binding protein-28 [4], [5], [6], is expressed almost exclusively in adipose tissue [5], [6]. Adiponectin is abundantly present in blood stream, and the average levels of plasma adiponectin in human range 3 to 30 μg/ml [2], [7]. Adiponectin is a 244-amino acid protein that contains a putative signal sequence and a collagen-like domain followed by a globular domain similar to collagens VIII and X and compliment factor C1q. Of importance, plasma adiponectin levels are paradoxically decreased in obese subjects [7]. Low plasma adiponectin levels, known as hypoadiponectinemia, are closely associated with obesity-linked complications including type 2 diabetes, coronary heart disease and hypertension. A number of experimental studies suggest that adiponectin can act as a protective factor against insulin resistance and cardiovascular disease. In this review, we focus on the possible role of adiponectin in obesity-associated inflammatory states.
Section snippets
Atherosclerosis
Atherosclerosis is characterized by chronic systemic inflammation. Endothelial cell activation by pro-inflammatory stimuli and subsequent monocyte adherent to injured endothelium is a precipitating event in atherogenesis [8]. Adiponectin treatment reduces TNF-α-stimulated expression of vascular cell adhesion molecule-1 (VCAM-1), E-selectin, intracellular adhesion molecule-1 and IL-8 in human aortic endothelial cells as well as monocyte attachment to TNF-α-stimulated endothelial cells (Fig. 1)
Obesity-linked metabolic disorders
Numerous epidemiological studies emphasized the association between adiponectin levels and obesity-linked conditions. Plasma adiponectin levels are significantly lower in obese subjects compared with non-obese subjects [7]. This inverse correlation is observed between plasma adiponectin concentrations and body mass index (BMI) in both genders [7]. In addition, plasma adiponectin levels negatively correlate with visceral fat accumulation in both men and women [63].
Several clinical studies
Regulation of adiponectin
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].
Conclusion
Adiponectin can function as a modulator of multiple obesity-linked diseases by attenuating excessive inflammatory responses in a variety of tissues. While putative adiponectin receptors are expressed in various cells and tissues where adiponectin exerts anti-inflammatory actions, their involvement in adiponectin-mediated suppression of cellular inflammatory responses has not been definitely established. In contrast, the receptor-mediated signaling events that control metabolic processes
Acknowledgements
This work was supported by NIH grants HL66957, HL77774, AR40197 and AG15052 to K. Walsh. N. Ouchi was supported by an American Heart Association Scientist Development Grant, Northeast Affiliate.
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