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

Fuentes L, Roszer T, Ricote M - Mediators Inflamm. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain.

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.

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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).
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fig1: 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).

Mentions: IR correlates positively with obesity, and the rapidly growing incidence of T2DM and MetS is therefore often attributed to lifestyle factors such as excess caloric intake and insufficient physical exercise in urbanized human populations [5]. The main predisposing factor for IR is intra-abdominal accumulation of adipose tissue (AT), which leads to central obesity [5, 6]. The total load of visceral adipose tissue (VAT) and the rate of free fatty acid (FFA) mobilization from VAT to the portal venous system are well-established correlates of IR and high circulating levels of insulin [7–9]. Several mechanisms link visceral adiposity and elevated FFA levels to IR. The elevated VAT mass liberates excess amount FFAs to the bloodstream, which contribute to muscle and liver IR by triggering reduced insulin signaling and increased hepatic gluconeogenesis. High levels of FFA shift the substrate preference of mitochondrial oxidation from glucose to FFA, and this can diminish the insulin secretory response to glucose of islet β-cells, leading to relative insulin insufficiency [10, 11]. Moreover, FFAs induce an inflammatory response in macrophages, adipocytes, and muscle cells via toll-like receptor (TLR) activated pathways (Figure 1). Modified lipoproteins such as oxidized and glycated low-density lipoproteins derived from excess VAT can accumulate in certain tissues, including subendothelial spaces, muscle cells, liver or kidney mesangium and tubular epithelial cells, where they can give rise to atherogenesis, lipotoxic injury, and inflammation [12]. VAT is also an active endocrine organ able to secrete a wide variety of inflammatory cytokines with key functions in the development of IR [13].


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

Fuentes L, Roszer T, Ricote M - Mediators Inflamm. (2010)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2874923&req=5

fig1: 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).
Mentions: IR correlates positively with obesity, and the rapidly growing incidence of T2DM and MetS is therefore often attributed to lifestyle factors such as excess caloric intake and insufficient physical exercise in urbanized human populations [5]. The main predisposing factor for IR is intra-abdominal accumulation of adipose tissue (AT), which leads to central obesity [5, 6]. The total load of visceral adipose tissue (VAT) and the rate of free fatty acid (FFA) mobilization from VAT to the portal venous system are well-established correlates of IR and high circulating levels of insulin [7–9]. Several mechanisms link visceral adiposity and elevated FFA levels to IR. The elevated VAT mass liberates excess amount FFAs to the bloodstream, which contribute to muscle and liver IR by triggering reduced insulin signaling and increased hepatic gluconeogenesis. High levels of FFA shift the substrate preference of mitochondrial oxidation from glucose to FFA, and this can diminish the insulin secretory response to glucose of islet β-cells, leading to relative insulin insufficiency [10, 11]. Moreover, FFAs induce an inflammatory response in macrophages, adipocytes, and muscle cells via toll-like receptor (TLR) activated pathways (Figure 1). Modified lipoproteins such as oxidized and glycated low-density lipoproteins derived from excess VAT can accumulate in certain tissues, including subendothelial spaces, muscle cells, liver or kidney mesangium and tubular epithelial cells, where they can give rise to atherogenesis, lipotoxic injury, and inflammation [12]. VAT is also an active endocrine organ able to secrete a wide variety of inflammatory cytokines with key functions in the development of IR [13].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain.

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.

Show MeSH
Related in: MedlinePlus