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Macrophage-specific PPARγ controls alternative activation and improves insulin resistance
Open accessAbstract
Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
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“Specifically, STAT1 and IRF5 have been shown to be involved in polarization and maintenance of an M1 phenotype while STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in polarization and maintenance of an M2 phenotype [23–30].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [29]
In the citing paper
“Studies in PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance [29,65–67].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [29]
In the citing paper
“In normal, non-obese subjects ATMs have a polarized M2 phenotype characterized by increased baseline STAT6 and PPARγ expression [29].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [29]
In the citing paper
“Importantly, the PPARγ nuclear receptor appears to be required for the maturation of alternatively activated macrophages (112, 113).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [113]
In the citing paper
“Accordingly, because of their proinflammatory properties, these macrophages are implicated in the pathogenesis of insulin resistance (103, 105, 112, 113).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [113]
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Self-citationIL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity
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BackgroundMethodResultInfluentialSelf-citationPPARγ activation in adipocytes is sufficient for systemic insulin sensitization
Sugii, S., Olson, P., Sears, D. D., Saberi, M., Atkins, A. R., Barish, G. D., Hong, S.-H., Castro, G. L., Yin, Y.-Q., Nelson, M. C., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912487106 · Cited by 255
“In addition, it was recently reported that macrophage-specific deletion of PPAR results in systemic insulin resistance and glucose intolerance (11, 12).”
BackgroundMetabolic regulation of macrophage phenotype and function
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PPAR Agonists and Metabolic Syndrome: An Established Role?
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“While PPAR-γ is not needed for macrophage differentiation, it is fundamental for a proper anti-inflammatory activity in adipose tissue macrophages [54].”
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Toxoplasma Polymorphic Effectors Determine Macrophage Polarization and Intestinal Inflammation
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“M2 activation is promoted by STAT6 and PPARg transcription factors (Odegaard et al., 2007), and mice deficient in IL-4, a potent mediator of M2 polarization, aremore susceptible to acute Toxoplasma infection (Roberts et al.”
BackgroundInfluentialOntogeny and Polarization of Macrophages in Inflammation: Blood Monocytes Versus Tissue Macrophages
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“Genetic deletion of PPARδ and/or PPARγ in macrophages directs the differentiation of monocytes toward a pro-inflammatory M1 phenotype (88, 118).”
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Nuclear sirtuins and inflammatory signaling pathways
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PPARγand the Innate Immune System Mediate the Resolution of Inflammation
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“PPAR𝛾 ligands play a particularly strong role in M2 polarization in the neural system.”
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Epigenetic Regulation of Macrophage Polarization by DNA Methyltransferase 3b
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Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system
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“Loss of peroxisome proliferator-activated receptor-γ (PPARγ) (induced by IL4) expression in macrophages can also result in impaired insulin sensitivity in the liver and muscle [85].”
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The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases
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“Besides, both animal experiments and cell experiments confirmed that the activation of PPARg is necessary for the polarization of anti-inflammatory M2 macrophages (85, 86).”
BackgroundRole of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components
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TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation
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Macrophage Polarization in Leishmaniasis: Broadening Horizons
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“(120) demonstrated that PPARγ-knockout mice have delayed in disease progress, with less footpad swelling and reduced parasitic burden.”
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“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript macrophage-specific PPARγ-deficient mice are more resistant to L. major and Listeria monocytogenes (Abdullah et al., 2012; Odegaard et al., 2007).”
BackgroundInfluentialSelf-citationPhenotypic and functional switch of macrophages induced by regulatory CD4 + CD25 + T cells in mice
Liu, G., Ma, H., Qiu, L., Li, L., Cao, Y., Ma, J., & Zhao, Y. X. (2010) · Immunology and Cell Biology · doi:10.1038/icb.2010.70 · Cited by 223
“CD124 is known as a co-receptor for IL-4 and IL-13”
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Metadata
- Authors
- Odegaard, J. I., Ricardo-Gonzalez, R. R., Goforth, M. H., Morel, C. R., Subramanian, V., Mukundan, L., Eagle, A. R., Vats, D., Brombacher, F., Ferrante, A. W., & Chawla, A.
- Affiliations
- Stanford Medicine (US)
- Columbia University Irving Medical Center (US)
- University of Cape Town (ZA)
- Corresponding author
- Chawla, Ajay
- Venue
- Nature
- Published
- 2007-05-21
- Volume
- 447
- Issue
- 7148
- Pages
- 1116-1120
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2587297
- OpenAlex
- W2167485774
- Cited by
- 2,107
- References
- 32
- Citations by year
- 2026: 91 · 2025: 67 · 2024: 98 · 2023: 101 · 2022: 103 · 2021: 139 · 2020: 131 · 2019: 118 · 2018: 117 · 2017: 126 · 2016: 110 · 2015: 132 · 2014: 124 · 2013: 151 · 2012: 125
- FWCI
- 36.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL076746)
- National Institute of Allergy and Infectious Diseases (F31AI066402, T32AI007290)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK062386, R01DK076760, R01DK066525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- PPARγ, macrophage polarization, alternative activation, insulin resistance, obesity, adipose tissue inflammation, CCR2, diet-induced obesity, impaired glucose tolerance, oxidative phosphorylation, skeletal muscle, liver, type 2 diabetes, myeloid cells, nutrient homeostasis
- MeSH terms
- Adipose Tissue, Animals, Cell Line, Dietary Fats, Glucose, Homeostasis, Insulin, Insulin Resistance, Macrophage Activation, Macrophages, Male, Mice, Inbred BALB C, Organ Size, Weight Gain, Leishmaniasis, Cutaneous, Leishmania major, Mice, Knockout, Genetic Predisposition to Disease, PPAR gamma, Mice, Adiponectin
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