Phenotypic Switching of Adipose Tissue Macrophages With Obesity Is Generated by Spatiotemporal Differences in Macrophage Subtypes

By C. Lumeng, Jennifer B. Delproposto, Daniel J. Westcott, Alan R. Saltiel. Diabetes, 2008

898 citations recorded by the source corpus.

OBJECTIVE—To establish the mechanism of the phenotypic switch of adipose tissue macrophages (ATMs) from an alternatively activated (M2a) to a classically activated (M1) phenotype with obesity. RESEARCH DESIGN AND METHODS—ATMs from lean and obese (high-fat diet–fed) C57Bl/6 mice were analyzed by a combination of flow cytometry, immunofluorescence, and expression analysis for M2a and M1 genes. Pulse labeling of ATMs with PKH26 assessed the recruitment rate of ATMs to spatially distinct regions. RESULTS—Resident ATMs in lean mice express the M2a marker macrophage galactose N-acetyl-galactosamine specific lectin 1 (MGL1) and localize to interstitial spaces between adipocytes independent of CCR2 and CCL2. With diet-induced obesity, MGL1+ ATMs remain in interstitial spaces, whereas a population of MGL1−CCR2+ ATMs with high M1 and low M2a gene expression is recruited to clusters surrounding necrotic adipocytes. Pulse labeling showed that the rate of recruitment of new macrophages to MGL1− ATM clusters is significantly faster than that of interstitial MGL1+ ATMs. This recruitment is attenuated in Ccr2−/− mice. M2a- and M1-polarized macrophages produced different effects on adipogenesis and adipocyte insulin sensitivity in vitro. CONCLUSIONS—The shift in the M2a/M1 ATM balance is generated by spatial and temporal differences in the recruitment of distinct ATM subtypes. The obesity-induced switch in ATM activation state is coupled to the localized recruitment of an inflammatory ATM subtype to macrophage clusters from the circulation and not to the conversion of resident M2a macrophages to M1 ATMs in situ.

Subfields: Epidemiology, Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/bff93baf6cc95e873472cf721b8e3c891422f86a

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In Epidemiology

1. Myung‐Sook Choi
2. Jerrold M. Olefsky
3. U. Jung

In Immunology

1. F. Munari
2. R. Sánchez-Rodríguez
3. Tommaso Scolaro
4. A. Viola
5. Jerrold M. Olefsky
6. Alessandra Castegna

In Physiology

1. Myung‐Sook Choi
2. Jerrold M. Olefsky
3. U. Jung
4. Alessandra Castegna

Citations in the corpus

• Regulatory Mechanisms for Adipose Tissue M1 and M2 Macrophages in Diet-Induced Obese Mice (2009, methodology): “(14) identified MglI-positive F4/80 macrophages as M2a fraction.”
• GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. (2010, positive): “Omega-3 FA Enriched Diet Decreases Inflammatory Macrophage Infiltration in Adipose Tissue (A) Confocal merged images from epididymal fat pads from HFD and u-3 FA enriched HFD (HFD+u3)-fed WT and GPR120 KO mice, costained with anti-F4/80 (green) and anti-Caveolin1 (blue) antibodies, left 4 panels, or”
• Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease (2014, background): “Over-expression of CCL2/MCP-1 in adipose tissue increases macrophage recruitment and worsens the metabolic phenotype [71,72], whereas a deficiency of CCL2/MCP-1 or its receptor CCR2 reduces pro-inflammatory macrophages accumulation in adipose tissue and provides protection from insulin resistance as”
• The Metabolic Signature of Macrophage Responses (2019, background): “Adipose tissue macrophages in lean animals have an alternatively activated (M2) phenotype, are anti-inflammatory and are uniformly dispersed throughout the adipose tissue, whereas adipose tissue macrophages of obese mice have a pro-inflammatory, classical (M1) phenotype and are primarily found in “c”
• Low-grade inflammation, diet composition and health: current research evidence and its translation (2015, neutral): “IL-6 and IL-1b impede the insulin signalling cascade to induce insulin resistance((11,12)).”
• Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity. (2017, positive): “One of the striking components of this obesity-induced tissue inflammatory response is the accumulation of proinflammatory macrophages, particularly in adipose tissue and liver (Lumeng et al., 2007, 2008; Morinaga et al., 2015; Nguyen et al., 2007; Oh et al., 2012; Weisberg et al., 2003).”