Abstract
Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK) is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone). In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3) pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.
Highlights
Obesity has become a global epidemic that is closely associated with the development of insulin resistance, type 2 diabetes and cardiovascular diseases [1,2]
As NFkB signaling plays a central role in insulin resistance and can be activated by MK in other cell types [32,33], we examined the actions of MK on this pathway in adipocytes. 3T3-L1 adipocytes were treated with recombinant MK, and the phosphorylaion of NFkB as well as the expression of inflammatory mediators was assessed
As a novel endocrine and immune organ, adipose tissue secretes a variety of adipokines that are directly involved in inflammation and insulin resistance
Summary
Obesity has become a global epidemic that is closely associated with the development of insulin resistance, type 2 diabetes and cardiovascular diseases [1,2]. Viewed as a major site for energy storage, adipose tissue has recently been identified as an important endocrine and immune organ [3,4] It secretes a variety of bioactive molecules, including adiponectin, leptin, and various inflammatory mediators (e.g., TNF-a, IL-6 and MCP-1), which are collectively termed as adipokines [3,4]. Obesity leads to a dramatically changed secretory profile of adipose tissue, characterized by increased production of proinflammatory cytokines, such as TNF-a, IL-1b and IL-6 [5,6] These cytokines exert direct actions on adipocytes and other insulin target cells, inducing chronic inflammation and insulin resistance [5,6]. Many novel adipokines with proinflammatory properties have been identified and linked to obesity-induced inflammation and insulin resistance [7]
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