Abstract
Adipose tissue expansion during obesity is associated with increased macrophage infiltration. Macrophage-derived factors significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. Identification of the major factors that mediate detrimental effects of macrophages on adipocytes may offer potential therapeutic targets. IL-1β, a proinflammatory cytokine, is suggested to be involved in the development of insulin resistance. This study investigated the role of IL-1β in macrophage-adipocyte cross-talk, which affects insulin signaling in human adipocytes. Using macrophage-conditioned (MC) medium and human primary adipocytes, we examined the effect of IL-1β antagonism on the insulin signaling pathway. Gene expression profile and protein abundance of insulin signaling molecules were determined, as was the production of proinflammatory cytokine/chemokines. We also examined whether IL-1β mediates MC medium-induced alteration in adipocyte lipid storage. MC medium and IL-1β significantly reduced gene expression and protein abundance of insulin signaling molecules, including insulin receptor substrate-1, phosphoinositide 3-kinase p85α, and glucose transporter 4 and phosphorylation of Akt. In contrast, the expression and release of the proinflammatory markers, including IL-6, IL-8, monocyte chemotactic protein-1, and chemokine (C-C motif) ligand 5 by adipocytes were markedly increased. These changes were significantly reduced by blocking IL-1β activity, its receptor binding, or its production by macrophages. MC medium-inhibited expression of the adipogenic factors and -stimulated lipolysis was also blunted with IL-1β neutralization. We conclude that IL-1β mediates, at least in part, the effect of macrophages on insulin signaling and proinflammatory response in human adipocytes. Blocking IL-1β could be beneficial for preventing obesity-associated insulin resistance and inflammation in human adipose tissue.
Highlights
OBESITY IS A MAJOR RISK FACTOR for the development of insulin resistance and the progression to type 2 diabetes [23]
By using in vitro human cell models, we have provided novel evidence that IL-1 is a critical factor that mediates the detrimental effect of macrophages on insulin signal transduction in adipocytes; this was demonstrated by a series of experiments by inhibiting IL-1 activity, receptor http://www.ajpendo.org
We found that IL-1 blockade can substantially reduce macrophage-stimulated release of the proinflammatory cytokines and lipid mobilization in human adipocytes, which could provide a mechanistic link between IL-1 and insulin resistance at local and systemic levels
Summary
OBESITY IS A MAJOR RISK FACTOR for the development of insulin resistance and the progression to type 2 diabetes [23]. In addition to skeletal muscle and liver, is a key organ that displays insulin resistance in obesity [15]. The decreased responsiveness to insulin in adipocytes may promote fatty acid release into the circulation, leading to hepatic and muscle insulin resistance [43]. Little is known about the impact of macrophage-adipocyte cross-talk on insulin signaling in human adipose tissue. We found that IL-1 blockade can substantially reduce macrophage-stimulated release of the proinflammatory cytokines and lipid mobilization in human adipocytes, which could provide a mechanistic link between IL-1 and insulin resistance at local and systemic levels
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