Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity

Abstract

SUMMARY During obesity, adipose tissue macrophages (ATMs) adopt a ‘metabolically-activated’ (MMe) phenotype. However, the functions of MMe macrophages are poorly understood. Here we combine proteomic and functional methods to demonstrate that in addition to potentiating inflammation, MMe macrophages also promote dead adipocyte clearance through lysosomal exocytosis. We identify NADPH-oxidase-2 (NOX2) as a driver of the inflammatory and adipocyte-clearing properties of MMe macrophages, and show that compared to wild-type, Nox2−/− mice exhibit a time-dependent metabolic phenotype during diet-induced obesity. After 8-weeks of high-fat feeding, Nox2−/− mice exhibit attenuated ATM inflammation and mildly improved glucose tolerance. After 16-weeks of high-fat feeding, Nox2−/− mice develop severe insulin resistance, hepatosteatosis, and visceral lipoatrophy characterized by dead adipocyte accumulation and defective ATM lysosomal exocytosis, a phenotype reproduced in myeloid cell-specific Nox2−/− mice. Collectively, our findings suggest that MMe macrophages perform detrimental and beneficial functions, whose contribution to metabolic phenotypes during obesity is determined by disease progression.

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

“…The role of NOX2‐dependent ROS in modulating the severity of obesity‐associated glucose dysmetabolism is controversial . Hence, the development of glucose dysmetabolism and insulin resistance was examined.…”

Properties and functions of adipose tissue macrophages in obesity

“…1). [17][18][19] Evidence has suggested that obesity-associated ATMs include highly plastic cell populations, whose immuno-phenotype is determined in response to multiple stimuli in their surrounding microenvironment. [17][18][19] Evidence has suggested that obesity-associated ATMs include highly plastic cell populations, whose immuno-phenotype is determined in response to multiple stimuli in their surrounding microenvironment.…”

“…It is now evident that more than one population of ATMs exist in obese AT, 20 and these distinct populations express specific markers, have unique tissue distributions, transcriptional profiles and functions. 19 Obese ATMs display surface markers that resemble neither classical (M1) nor alternative (M2) activation, but rather a state of metabolic activation (MMe) induced by diverse metabolic stimuli (e.g. In obesity, ATMs adopt a metabolic activation state with prominent lysosomal activity, 17,18 with the main purpose to clear dead adipocytes.…”

“…43 These phenomena could contribute to the prevention of potential damage and lipotoxicity caused by ectopic accumulation of saturated FFAs. 75,76 Studies from Coats et al 19 observed that FFAs-induced MMe macrophages are the major subclass responsible for dead adipocyte clearance and inflammatory cytokine production in obesity. While these are analogous to atherosclerotic foam cells, the lipid droplets in ATMs are primarily laden with FFA and not cholesterol as in atherosclerotic lesions.…”

Leptin in the regulation of the immunometabolism of adipose tissue-macrophages

“…Obesity leads to exacerbated leptin release by the adipose tissue. In obese mice, saturated free fatty acids (FFAs) produce a pro‐inflammatory Mϕ phenotype that is mechanistically distinct from M1 or M2 activation . During differentiation of monocytes into Mϕs, Ob‐Rb is up‐regulated and maintained after differentiation, providing stronger responses to leptin by Mϕs .…”