Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes

Abstract

Aims/hypothesis Adipose tissue inflammation has recently been implicated in the pathogenesis of insulin resistance and is probably linked to high local levels of cytokines. IL1B, a proinflammatory cytokine, may participate in this alteration. Materials and methods We evaluated the chronic effect (1-10 days) of IL1B (0.1-20 ng/ml) on insulin signalling in differentiating 3T3-F442A and differentiated 3T3-L1 murine adipocytes and in human adipocytes. We also assessed expression of the gene encoding IL1B in adipose tissue of wild-type and insulin-resistant mice (diet-induced and genetically obese ob/ob mice). Results IL1B inhibited insulin-induced phosphorylation of the insulin receptor β subunit, insulin receptor substrate 1, Akt/protein kinase B and extracellular regulated kinase 1/2 in murine and human adipocytes. Accordingly, IL1B suppressed insulin-induced glucose transport and lipogenesis. Long-term treatment of adipose cells with IL1B decreased cellular lipid content. This could result from enhanced lipolysis and/or decreased expression of genes involved in lipid metabolism (acetyl-CoA carboxylase, fatty acid synthase). Down-regulation of peroxisome proliferating-activated receptor γ and CCAAT/enhancer-binding protein α in response to IL1B may have contributed to the altered phenotype of IL1B-treated adipocytes. Moreover, IL1B altered adipocyte differentiation status in longterm cultures. IL1B also decreased the production of adiponectin, an adipocyte-specific protein that plays a positive role in insulin sensitivity. Expression of the gene encoding IL1B was increased in epididymal adipose tissue of obese insulin-resistant mice. Conclusions/interpretation IL1B is upregulated in adipose tissue of obese and insulin-resistant mouse models and may play an important role in the development of insulin resistance in murine and human adipose cells.

Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1β in 3T3-L1 adipocytes

“…Furthermore, long-term IL-1a stimulation of 3T3-L1 adipocytes induced expression of suppressor of cytokine signaling-1 and -3 (He et al 2006), which are well-established inhibitors of insulin signal transduction (Fasshauer et al 2004). In addition, IL-1b dramatically decreased the production of the insulinsensitizing adipokine adiponectin in 3T3-L1 adipocytes and in human primary fat cells (Lagathu et al 2006). Consistent with these findings, Thomas and co-workers have shown that IL-1 receptor-deficient non-obese diabetic mice were partially protected from the development of T2DM (Thomas et al 2004).…”

“…Biologically active proteins secreted from adipose tissue, so-called adipokines, are suggested to link obesity with associated disorders including insulin resistance, type II diabetes mellitus (T2DM), and cardiovascular diseases (Fasshauer & Paschke 2003). Recently, interleukin (IL)-1b has been characterized as a novel fat-secreted adipokine with insulin resistance-inducing and proinflammatory properties besides tumor necrosis factor (TNF)-a and IL-6 (Lagathu et al 2006, Barksby et al 2007, Jager et al 2007. Thus, chronic IL-1b treatment impaired insulininduced glucose transporter (Glut)-4 expression and markedly inhibited its translocation to the plasma membrane through downregulation of insulin receptor substrate-1 (Jager et al 2007).…”

Inflammasome Priming in Sterile Inflammatory Disease

“…Activation of NLRP3 activity in adipose tissue macrophages (ATMs) during diet-induced obesity may mediate insulin resistance in adipocytes via IL-1 secretion [39] . Secreted IL-1 is reported to disrupt the insulin signaling pathway, reduce the expression of insulin receptor substrate 1 (IRS1), and lead to decreased insulinmediated glucose uptake resulting in insulin resistance [89,90] . Secreted IL-1 can also lead to its transcriptional autoregulation by a positive feedback loop via NF-κB pathways [91] , leading to amplification of the priming signal.…”

Lactoferrin increases 172ThrAMPK phosphorylation and insulin-induced p473SerAKT while impairing adipocyte differentiation

“…[1][2][3][4] The mechanisms through which pro-inflammatory cytokines, like tumor necrosis factor-a, interleukin-6 (IL-6) and IL-1b interact with cellular insulin signal transduction cascades have been described in the last years. [5][6][7][8][9] Lactoferrin is a pleiotropic glycoprotein (80 kDa) and a prominent component of the first line of mammalian host defense, acting on specific lactoferrin receptors that exist in a variety of cells, like monocytes, lymphocytes, adipocytes, hepatocytes and endothelial cells. 10 Lactoferrin expression is upregulated in response to inflammatory stimuli.…”