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

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 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. [Display omitted] •Inflammation and dead adipocyte clearance by MMe macrophages require NOX2•Nox2−/− improves the metabolic phenotype in early DIO but worsens it in late DIO•Early improvements associate with suppressed ATM inflammation•Late worsening associates with lower ATM lysosomal exocytosis to dead adipocytes During obesity, adipose tissue macrophages are metabolically activated (MMe). Coats et al. show that MMe macrophages perform detrimental (potentiate inflammation) and beneficial (exocytose lysosomes to clear dead adipocytes) functions, controlled by NOX2. Nox2−/− mice exhibit improved or worsened metabolic phenotypes depending on high-fat-diet duration, highlighting the dynamic contributions of MMe macrophages in obesity.