Alternative M2 Activation of Kupffer Cells by PPARδ Ameliorates Obesity-Induced Insulin Resistance

Abstract

Macrophage infiltration and activation in metabolic tissues underlie obesity-induced insulin resistance and type 2 diabetes. While inflammatory activation of resident hepatic macrophages potentiates insulin resistance, the functions of alternatively activated Kupffer cells in metabolic disease remain unknown. Here we show that in response to the Th2 cytokine interleukin-4 (IL-4), peroxisome proliferator-activated receptor delta (PPARdelta) directs expression of the alternative phenotype in Kupffer cells and adipose tissue macrophages of lean mice. However, adoptive transfer of PPARdelta(-/-) (Ppard(-/-)) bone marrow into wild-type mice diminishes alternative activation of hepatic macrophages, causing hepatic dysfunction and systemic insulin resistance. Suppression of hepatic oxidative metabolism is recapitulated by treatment of primary hepatocytes with conditioned medium from PPARdelta(-/-) macrophages, indicating direct involvement of Kupffer cells in liver lipid metabolism. Taken together, these data suggest an unexpected beneficial role for alternatively activated Kupffer cells in metabolic syndrome and type 2 diabetes.

Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice

“…It is possible that this compensatory increase in IL-10 production in the liver and adipose tissue may have suppressed pro-inflammatory responses within these tissues and, therefore, masked the effect of the deletion of IL-10 within the immune cell compartment. With regards to the cellular source contributing to the increased IL-10 production in the Il10-KO BMT mice, the BMT technique not only largely repopulates the recipient's monocytes/macrophages with those of the donor, but also the resident liver Kupffer cells [8,18], which are likely potential sources of liver-derived IL-10 production [29]. In addition, the BMT repopulates other bone-marrow-derived leucocytes, including lymphocytes, which are potent IL-10 producers and have also been shown to infiltrate adipose tissue and are implicated in adipose tissue inflammation and insulin resistance [39][40][41][42][43][44][45][46][47].…”

“…Underscoring the importance of macrophage polarisation state to the development of obesity-induced insulin resistance, the insulin-sensitising agent rosiglitazone dramatically increases the number of macrophages present in the adipose tissue depots of obese mice; however, these ATM are predominantly of the M2 anti-inflammatory state [16]. Recently, peroxisome proliferator-activated receptor γ (PPARγ) and δ (PPARδ) were identified as critical promoters of macrophage polarisation towards the M2 phenotype and, consequently, macrophage-specific deletion of PPARγ or PPARδ resulted in a reduced expression of M2-macrophage-specific genes in adipose tissue and liver, an increase in M1-macrophage-specific genes and, importantly, a worsening of glucose and insulin tolerance [17,18].…”

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

“…The PPARα isoform, which is highly expressed in hepatocytes, controls fatty acid transport and β‐oxidation and dampens the inflammatory response 7, 8. The PPARδ isoform (also known as PPARβ) contributes to the regulation of glucose and lipid metabolism while exerting anti‐inflammatory properties in the liver by skewing M2 polarization of Küpffer cells 9, 10, 11. PPARγ and PPARδ are expressed at various levels in hepatic stellate cells (HSCs), a driver of liver fibrosis; PPARγ is key in keeping HSCs in a quiescent nonfibrogenic state 12, 13…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…Indeed, deficiency of Toll-like receptor 4 (TLR4) or TLR4 signaling protects against obesity-induced M1 macrophage polarization and adipose tissue inflammation in vivo [25][26][27][28]. On the other hand, peroxisome proliferatoractivated receptor γ (PPARγ) and PPARδ stimulate M2 polarization of adipose tissue macrophages and thus improve systemic insulin sensitivity [29][30][31]. Indeed, activation of PPARγ by pioglitazone, a thiazolidinedione class of insulin sensitizer, improves the unbalanced M1/M2 phenotype of adipose tissue macrophages in diet-induced obese mice [32].…”