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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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.

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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