Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages

Abstract

Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance between proinflammatory M1 and antiinflammatory M2 macrophage phenotypes within visceral adipose tissue appears to be crucially involved in the development of obesity-associated IR and consequent metabolic abnormalities. The ligand-dependent transcription factors peroxisome proliferator activated receptors (PPARs) have recently been implicated in the determination of the M1/M2 phenotype. Liver X receptors (LXRs), which form another subgroup of the nuclear receptor superfamily, are also important regulators of proinflammatory cytokine production in macrophages. Disregulation of macrophage-mediated inflammation by PPARs and LXRs therefore underlies the development of IR. This review summarizes the role of PPAR and LXR signaling in macrophages and current knowledge about the impact of these actions in the manifestation of IR and obesity comorbidities such as liver steatosis and diabetic osteopenia.

Figure 1

Cytokine release by adipose tissue macrophages contributes to insulin resistance. Free fatty acids (FFAs) released from visceral adipose tissue (VAT) promote polarization toward the M1 phenotype through activation of Toll-like receptors (TLRs), and also impair insulin secretion and action. Differentiation to the M1 phenotype is inhibited by PPARγ signaling, and activation of PPARγ or PPARδ, in response to IL-4, promotes polarization toward the M2 phenotype. IL-13 is also suggested to be involved in the M2 phenotype switch. Inflammatory monocytes migrating into VAT can also differentiate into M1 macrophages. Inflammatory mediators produced by M1 ATMs alter insulin responsiveness. CCR2: chemokine receptor-2, TNFα: tumor necrosis factor, iNOS: inducible nitric oxide synthase, IL-6: interleukin-6, TGF-β: transforming growth factor beta, IL-10: interleukin-10, Ym1: secretory chitinase protein-1, MCP-1: monocyte chemoattractant protein-1 (MCP-1).

Figure 2

Tissue-resident macrophages are sources and targets of inflammatory mediators in obesity. (a) Liver-resident macrophages (Kupffer cells) are major sources of inflammatory cytokines in obesity and IR. Free fatty acids (FFAs) and oxidized low density lipoproteins (oxLDL) released from VAT promote M1 phenotype polarization through activation of TLRs. The switch to the M2 phenotype is promoted by PPARδ signaling. Inflammatory mediators (IL-6, TNFα, and IL-1β) originating from M1 Kupffer cells or adipose tissue macrophages (ATMs) induce hepatocyte apoptosis, IR, and lipid accumulation. (b) Osteoclastogenesis is induced by ATM-derived inflammatory cytokines in obesity and IR. Activation of PPARs blocks osteoclastogenesis and impedes bone loss, while LXR promotes osteoclast resorptive activity.