Interactive Changes between Macrophages and Adipocytes

Abstract

Obesity is associated with a proinflammatory state, with macrophage infiltration into adipose tissue. We tested the hypothesis that communication between macrophages and adipocytes affects insulin resistance by disrupting insulin-stimulated glucose transport, adipocyte differentiation, and macrophage function. To test this hypothesis, we cocultured 3T3-L1 adipocytes with C2D macrophages or primary peritoneal mouse macrophages and examined the impacts of macrophages and adipocytes on each other. Adipocytes and preadipocytes did not affect C2D macrophage TNF-␣, IL-6, or IL-1␤ transcript concentrations relative to those obtained when C2D macrophages were incubated alone. However, preadipocytes and adipocytes increased PEC-C2D macrophage IL-6 transcript levels, while preadipocytes inhibited IL-1␤ transcript levels compared to those obtained when PEC-C2D macrophages were incubated in medium alone. We found that adipocyte coculture increased macrophage consumption of tumor necrosis factor alpha (TNF-␣), interleukin 1␤ (IL-1␤), and, in some cases, IL-6. C2D macrophages increasingly downregulated GLUT4 transcript levels in differentiated adipocytes. Recombinant TNF-␣, IL-1␤, and IL-6 also downregulated GLUT4 transcript levels relative to those for the control. However, only IL-6 was inhibitory at concentrations detected in macrophage-adipocyte cocultures. IL-6 and TNF-␣, but not IL-1␤, inhibited Akt phosphorylation within 15 min of insulin stimulation, but only IL-6 was inhibitory 30 min after stimulation. Lastly, we found that adipocyte differentiation was inhibited by macrophages or by recombinant TNF-␣, IL-6, and IL-1␤, with IL-6 having the most impact. These data suggest that the interaction between macrophages and adipocytes is a complex process, and they support the hypothesis that the macrophage-adipocyte interaction affects insulin resistance by disrupting insulin-stimulated glucose transport, adipocyte differentiation, and macrophage function.

Activins and Inhibins: Roles in Development, Physiology, and Disease

“…Obesity results in recruitment of M1 macrophages to adipose tissues, and also triggers M2 to M1 adipose-resident macrophage conversion (Lumeng et al 2007(Lumeng et al , 2008, with higher levels of secreted activin A in M1 than in M2 macrophages (Sierra-Filardi et al 2011). Proinflammatory cytokines secreted by macrophages inhibit differentiation of preadipocytes (Lacasa et al 2007;Xie et al 2010). Activin A inhibits adipocyte differentiation in human and mouse cells (Hirai et al 2005;Zaragosi et al 2010), and human preadipocytes cultured in conditioned media from adipose-resident macrophages show increased Inhba mRNA expression (Zaragosi et al 2010).…”

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes

“…Obesity is associated with low-grade systemic inflammation and increased levels of pro-inflammatory cytokines such as IL-6 and TNF-α [2]. These cytokines are produced from adipocytes and ATM, contributing to insulin resistance [35,36]. Thus, we examined whether rAd-GLP-1-treatment reduces macrophage infiltration and pro-inflammatory cytokine production in adipose tissue.…”

Mitigation of isolation-associated adipocyte interleukin-6 secretion following rapid dissociation of adipose tissue

“…Previous work by Ruan et al has shown that the primary adipocyte isolation process itself induces an infl ammatory response as measured by secretion of TNF-␣ and IL-6, which have been shown to have insulin-desensitizing effects (14)(15)(16)(17)(18)(19)24 ). This prior study additionally demonstrated that the isolation process leads to the downregulation of several genes involved in insulin signaling.…”

“…2D ). Importantly, the concentrations of IL-6 secreted from adipocytes isolated by rotating at 30 and 75 rpm ( ‫ف‬ 2,500 pg/ml and ‫ف‬ 1,500 pg/ml, respectively) approach the concentrations reported to reduce insulin sensitivity in adipocytes (5,000-20,000 pg/ml) ( 16,19 ).…”

“…Ruan et al showed that isolating adipocytes by collagenase digestion induced an acute and chronic release of the proinfl ammatory factors tumor necrosis factor-␣ (TNF-␣ ) and interleukin-6 (IL-6), respectively ( 14 ). Importantly, treatment with these cytokines has been shown to promote insulin resistance in 3T3-L1 adipocytes (15)(16)(17)(18)(19). Consistent with these fi ndings, Ruan et al also showed that collagenase digestion of mouse epididymal adipose tissue triggered a downregulation of the expression of several genes involved in insulin Abstract Primary adipocyte isolation by collagenase digestion is a widely used technique to study metabolic regulation and insulin action in adipocytes.…”