Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice

Abstract

OBJECTIVEObesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.RESEARCH DESIGN AND METHODSWe addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.RESULTSWe show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell–like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.CONCLUSIONSOur data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages

“…Along with this hypothesis, in vivo impairment of FA catabolism in ATMs that have accumulated lipids has systemic and local consequences [45]. However, long term lipid accumulation in ATMs promotes M1 polarisation and AT inflammation [46]. Together, these results suggest there is no association between fat cell lipolysisderived FA uptake and subsequent storage as TAGs in ATMs and the induction of inflammatory pathways.…”

Metabolic and immunomodulatory effects of n-3 fatty acids are different in mesenteric and epididymal adipose tissue of diet-induced obese mice

“…This is consistent with the observed more proinflammatory state in EAT than in MAT and with the increased MCP-1 mRNA levels in VAT upon both high-fat diets. In addition, the high CD11c expression in EAT from HF/n-3 mice could indicate that ATM are predominantly of the classical activated M1 state (54) and/or that the number of other dendritic immune cells belonging to the cell family of mononuclear phagocytes (27) increased simultaneously. This consideration may apply partly to MAT from obese HF/n-3 mice.…”

“…This is often associated with a switch in polarization of ATM from an anti-inflammatory M2 state to a proinflammatory M1 state (37,38), possibly caused by processes involving macrophage lipotoxity (54). M1 macrophages accumulate preferentially around dead adipocytes, thereby forming necrotic CLS, whereas M2 macrophages are associated with adipose tissue remodeling and repair processes (10,38).…”

Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance

“…The adipose tissue 'expandability hypothesis' postulates that adipose tissue loses its ability to adequately store excess fat resulting in lipid spill over which promotes ectopic lipid accumulation and inflammation in macrophages (69,77). Transcriptional profile analysis of adipocytes and ATM from leptin-deficient (ob/ob) mice, demonstrated that increasing adiposity was associated with a reduction in lipogenic, lipid uptake and lipid storage gene expression in adipocytes but up-regulation in ATM.…”