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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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“A new metabolic reprogramming allows phenotypic change to M2, which is driven by the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) [64, 219] and mammalian target of rapamycin (mTOR) complexes 1 (C1) and 2 (C2) [60, 122, 142] (Fig.”
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“This finding is interesting, because several studies have intimately linked classically activated M1 macrophages with IR (10,31,39).”
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BackgroundMolecular determinants for the polarization of macrophage and osteoclast
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Adipose tissue inflammation in glucose metabolism
Kammoun, H. L., Kraakman, M. J., & Febbraio, M. A. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9274-4 · Cited by 101
Hoo, R. L. C., Wong, J. Y. L., Qiao, C., Xu, A., Xu, H., & Lam, K. S. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-67 · Cited by 101
“It should be noted that PPAR-g is highly expressed in the adipose tissue where it regulates insulin sensitivity, adipocyte differentiation and lipid storage, and is responsible for regulating the alternative activation of macrophages [41].”
BackgroundHall, J. A., Ramachandran, D., Roh, H. C., DiSpirito, J. R., Belchior, T., Zushin, P. H., Palmer, C., Hong, S., Mina, A. I., Liu, B., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.08.016 · Cited by 102
The role of GM-CSF in adipose tissue inflammation
Kim, D., Sandoval, D. A., Reed, J. A. H., Matter, E. K., Tolod, E. G., Woods, S. C., & Seeley, R. J. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00061.2008 · Cited by 105
Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue
Hui, X. H., Zhang, M., Gu, P., Li, K., Gao, Y. Z., Wu, D., Wang, Y., & Xu, A. (2017) · EMBO Reports · doi:10.15252/embr.201643184 · Cited by 99
Hou, Y., Wei, D., Zhang, Z., Guo, H., Li, S., Zhang, J., Zhang, P., Zhang, L., & Zhao, Y. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111668 · Cited by 100
Bassaganya-Riera, J., Misyak, S. A., Guri, A. J., & Hontecillas, R. (2009) · Cellular Immunology · doi:10.1016/j.cellimm.2009.04.003 · Cited by 101
“A series of recent papers [14;15;16; 17] are consistent with the notion that PPAR γ and δ promote regulation while suppress inflammation.”
BackgroundAdipose Tissue Remodeling as Homeostatic Inflammation
Itoh, M., Suganami, T., Hachiya, R., & Ogawa, Y. (2011) · International Journal of Inflammation · doi:10.4061/2011/720926 · Cited by 107
“Since dead adipocytes are surrounded by macrophages in the adipose tissue of obese humans and mice (crown-like structure) [7, 8, 56], it is conceivable that Mincle plays a role in sensing adipocytederived endogenous ligand(s) during adipocyte death.”
BackgroundFernandez-Boyanapalli, R., Frasch, S. C., Riches, D. W. H., Vandivier, R. W., Henson, P. M., & Bratton, D. L. (2010) · Blood · doi:10.1182/blood-2010-02-272005 · Cited by 98
Myelin alters the inflammatory phenotype of macrophages by activating PPARs
Bogie, J. F. J., Jorissen, W., Mailleux, J., Nijland, P. G., Zelcer, N., Vanmierlo, T., van Horssen, J., Stinissen, P., Hellings, N., & Hendriks, J. J. A. (2013) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-1-43 · Cited by 99
“All PPAR subtypes have been described to regulate the differentiation of macrophages towards an anti-inflammatory phenotype [36-39,46-48].”
BackgroundChanges of Dietary Fat and Carbohydrate Content Alter Central and Peripheral Clock in Humans
Pivovarova‐Ramich, O., Jürchott, K., Rudovich, N. N., Hornemann, S., Lu, Y., Möckel, S., Murahovschi, V., Kessler, K., Seltmann, A., Maser‐Gluth, C., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3868 · Cited by 99
“Monocytes play a pivotal role in immune functions and metabolic regulation (16, 17).”
BackgroundDeVallance, E., Li, Y., Jurczak, M. J., Cifuentes-Pagano, E., & Pagano, P. J. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7674 · Cited by 103
“AAMs appear to promote adipocyte insulin signaling, nutrient uptake gene expression, and adiponectin production (147, 212).”
BackgroundZhang, S., Kim, C. C., Batra, S., McKerrow, J. H., & Loke, P. (2010) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0000648 · Cited by 99
“Diacylglycerol lipase beta (Daglb) could be involved in metabolic regulation by alternatively activated macrophages [32].”
BackgroundEpigenetic codes of PPARγ in metabolic disease
Sugii, S., & Evans, R. M. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.007 · Cited by 102
“Macrophage-restricted deletion of PPARc also results in systemic insulin resistance and glucose intolerance [9,18].”
BackgroundXu, H., Li, H., Woo, S., Kim, S.-M., Shende, V. R., Neuendorff, N., Guo, X., Guo, T., Qi, T., Pei, Y., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.539601 · Cited by 98
“Importantly, myeloid cell-specific disruption of PPAR and/or PPAR increases proinflammatory activation of adipose tissue macrophages and exacerbates obesity-associated insulin resistance (6, 23).”
BackgroundMethodInfluentialNuclear receptors linking metabolism, inflammation, and fibrosis in nonalcoholic fatty liver disease
Puengel, T., Liu, H., Guillot, A., Heymann, F., Tacke, F., & Peiseler, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052668 · Cited by 95
Wu, H., Ni, X., Xu, Q., Wang, Q., Li, X., & Hua, J. (2020) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15025 · Cited by 101
The Role of PPAR-γ in Allergic Disease
Stark, J. M., Coquet, J. M., & Tibbitt, C. A. (2021) · Current Allergy and Asthma Reports · doi:10.1007/s11882-021-01022-x · Cited by 103
Xu, L., Yan, X., Zhao, Y., Song, J., Liu, B., Yu, S., Fu, J., Liu, Y., & Su, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169252 · Cited by 109
SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation
Toubal, A., Clément, K., Fan, R., Ancel, P., Pelloux, V., Rouault, C., Veyrie, N., Hartemann, A., Treuter, E., & Venteclef, N. (2012) · Journal of Clinical Investigation · doi:10.1172/jci64052 · Cited by 97
Ghanbari, M., Maragheh, S. M., Aghazadeh, A., Mehrjuyan, S. R., Hussen, B. M., Shadbad, M. A., Dastmalchi, N., & Safaralizadeh, R. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107765 · Cited by 101
Azhdari, S., Moghaddam, A. S., Abdollahi, E., Johnston, T. P., Ghaneifar, Z., Vahedi, P., & Goleij, P. (2022) · Current Molecular Pharmacology · doi:10.2174/1874467215666220324114624 · Cited by 99
Osteoclast receptors and signaling
Fattore, A. D., Teti, A. M., & Rucci, N. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.01.011 · Cited by 105
Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages
Liebold, I., Al Jawazneh, A., Casar, C., Lanzloth, C., Leyk, S., Hamley, M., Wong, M. N., Kylies, D., Gräfe, S. K., Edenhofer, I., et al. (2024) · Science · doi:10.1126/science.abo7027 · Cited by 96
“The molecular and cellular components of the apoptotic cells — e.g., the lipid composition — may modulate the efferocytic macrophages by engaging nuclear receptors, such as PPAR g , known to be required for the activation and sustained maintenance of IL-4 – induced macrophage functions ( 38 , 39 ).”
BackgroundDietert, R. R., DeWitt, J. C., Germolec, D. R., & Zelikoff, J. T. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.1001971 · Cited by 97
“Odegaard et al. (2007) reported that macrophage polarization, including overproduction of CCL2 by macrophages in adipose tissues, is associated with the insulin resistance component of metabolic syndrome.”
BackgroundPPARγ Controls Dectin-1 Expression Required for Host Antifungal Defense against Candida albicans
Galès, A., Conduché, A., Bernad, J., Lefèvre, L., Olagnier, D. P., Béraud, M., Martin‐Blondel, G., Linas, M.-D., Auwerx, J. H., Coste, A., et al. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000714 · Cited by 108
“Moreover, another study showed in genetic models of macrophage specific Peroxisome proliferator-activated receptor c (PPARc) or STAT-6 knockout mice, that the IL-4/IL-13/STAT-6/PPARc axis is required for the maturation of alternatively activated macrophages [22].”
BackgroundResultNuclear receptors as drug targets for metabolic disease
Schulman, I. G. (2010) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2010.07.002 · Cited by 95
Gögebakan, Ö., Osterhoff, M. A., Schüler, R., Pivovarova, O., Kruse, M., Seltmann, A.-C., Mosig, A. S., Rudovich, N., Nauck, M., & Pfeiffer, A. F. H. (2015) · Diabetologia · doi:10.1007/s00125-015-3618-4 · Cited by 95
“Experimental inhibition of the macrophage inflammatory responses or phenotype was shown to markedly improve insulin sensitivity [7, 8].”
BackgroundNuclear receptors in neurodegenerative diseases
Skerrett, R., Malm, T., & Landreth, G. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.019 · Cited by 94
The Nuclear Hormone Receptor PPARγas a Therapeutic Target in Major Diseases
Schmidt, M. V., Brüne, B., & von Knethen, A. (2010) · The Scientific World JOURNAL · doi:10.1100/tsw.2010.213 · Cited by 94
“Macrophage polarization to the M2 phenotype has been linked in part to PPAR activation[84,85,86], mainly attributed to its role in transrepressing proinflammatory gene expression.”
BackgroundThymic Stromal Lymphopoietin Amplifies the Differentiation of Alternatively Activated Macrophages
Han, H., Headley, M. B., Xu, W., Comeau, M. R., Zhou, B., & Ziegler, S. F. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201808 · Cited by 95
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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