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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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InfluentialRegulatory Mechanisms for Adipose Tissue M1 and M2 Macrophages in Diet-Induced Obese Mice
Fujisaka, S., Usui, I., Bukhari, A., Ikutani, M., Oya, T., Kanatani, Y., Tsuneyama, K., Nagai, Y., Takatsu, K., Urakaze, M., et al. (2009) · Diabetes · doi:10.2337/db08-1475 · Cited by 731
Mechanisms of insulin resistance in obesity
Ye, J. (2013) · Frontiers of Medicine · doi:10.1007/s11684-013-0262-6 · Cited by 699
“An increase in M1 and decrease in M2 were found in adipose tissue of obese mice [34,36].”
Macrophage polarization in pathology
Sica, A., Erreni, M., Allavena, P., & Porta, C. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1995-y · Cited by 673
“In line with the established association between M1 inflammation and insulin resistance, genetic ablation of key transcription factors guiding M2 macrophage polarization [21] demonstrated that myeloid-specific disruption of PPARc, PPARd, and Krüppel-like factor 4 (KLF4) predisposes to development of diet-induced obesi…”
BackgroundKang, K., Reilly, S. M., Karabacak, V., Gangl, M. R., Fitzgerald, K., Hatano, B., & Lee, C.-H. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.04.002 · Cited by 699
“in PPARd / macrophages (Figure 1) but remain intact in PPARg / macrophages (Odegaard et al., 2007).”
BackgroundInfluentialTargeting adipose tissue in the treatment of obesity-associated diabetes
Kusminski, C. M., Bickel, P. E., & Scherer, P. E. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.75 · Cited by 678
Lee, B.-C., & Lee, J. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.017 · Cited by 714
Chiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.018 · Cited by 651
“In inflammatory conditions, M2 macrophages are involved in wound healing and regulation of insulin resistance (Odegaard et al., 2007).”
Regulation of metabolism by the innate immune system
Lackey, D. E., & Olefsky, J. M. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.189 · Cited by 667
Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Foretz, M., Guigas, B., & Viollet, B. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0242-2 · Cited by 686
Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention
Kumar, A., & Loane, D. J. (2012) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2012.06.008 · Cited by 710
“Notably, PPARc receptor agonist are used clinically for the treatment of type 2 diabetes, and PPARc modulates macrophage M2 alternative activation states thereby improving resistance to insulin (Odegaard et al., 2007).”
Type 2 cytokines: mechanisms and therapeutic strategies
Wynn, T. A. (2015) · Nature reviews. Immunology · doi:10.1038/nri3831 · Cited by 683
Possible involvement of the M2 anti‐inflammatory macrophage phenotype in growth of human gliomas
Komohara, Y., Ohnishi, K., Kuratsu, J., & Takeya, M. (2008) · The Journal of Pathology · doi:10.1002/path.2370 · Cited by 738
“Obesity changes adipose tissue macrophages from an M2 phenotype to an M1 phenotype, and M1 macrophages play a prominent role in obesity-induced insulin resistance of adipocytes [10,11].”
BackgroundPPARs at the crossroads of lipid signaling and inflammation
Wahli, W., & Michalik, L. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.05.001 · Cited by 692
Macrophage phenotypes in atherosclerosis
Colin, S., Chinetti‐Gbaguidi, G., & Staels, B. (2014) · Immunological Reviews · doi:10.1111/imr.12218 · Cited by 657
“A macrophage-specific deletion of PPARc impaired alternative activation of mouse macrophages (108).”
BackgroundAlternative macrophage activation and metabolism
Odegaard, J. I., & Chawla, A. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130138 · Cited by 640
“Not surprisingly, these approaches identified activation of STAT6, IL-4’s well-studied transcriptional effector, as the critical initiating event in macrophage alternative activation (66); however, PPARγ and PPARδ (see sidebar), the body’s fatty acid sensors, were identified as responsible for sustaining it (Figure 5)…”
InfluentialSelf-citationAlternatively activated microglia and macrophages in the central nervous system
Franco, R., & Fernández‐Suárez, D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.003 · Cited by 674
Chhor, V., Charpentier, T. L., Lebon, S., Oré, M. V., Lara‐Celador, I., Josserand, J., Degos, V., Jacotot, E. D., Hagberg, H., Sävman, K., et al. (2013) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.02.005 · Cited by 676
Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis
Odegaard, J. I., & Chawla, A. (2013) · Science · doi:10.1126/science.1230721 · Cited by 643
Self-citationMacrophages: Their role, activation and polarization in pulmonary diseases
Arora, S., Dev, K., Agarwal, B., Das, P., & Syed, M. A. (2017) · Immunobiology · doi:10.1016/j.imbio.2017.11.001 · Cited by 653
JNK Expression by Macrophages Promotes Obesity-Induced Insulin Resistance and Inflammation
Han, M. S., Jung, D. Y., Morel, C., Lakhani, S. A., Kim, J. K., Flavell, R. A., & Davis, R. J. (2012) · Science · doi:10.1126/science.1227568 · Cited by 646
Self-citationThe TSC-mTOR pathway regulates macrophage polarization
Byles, V., Covarrubias, A. J., Ben‐Sahra, I., Lamming, D. W., Sabatini, D. M., Manning, B. D., & Horng, T. (2013) · Nature Communications · doi:10.1038/ncomms3834 · Cited by 646
“Additionally, activation of the nuclear receptors PPAR γ and PPAR δ is necessary for full implementation of the M2 program 4, 5 .”
Targeting macrophages in cancer immunotherapy
Duan, Z., & Luo, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00506-6 · Cited by 656
Dixon, L. J., Barnes, M., Tang, H., Pritchard, M. T., & Nagy, L. E. (2013) · Comprehensive Physiology · doi:10.1002/cphy.c120026 · Cited by 628
PPARγ and the global map of adipogenesis and beyond
Lefterova, M. I., Haakonsson, A. K., Lazar, M. A., & Mandrup, S. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.04.001 · Cited by 656
Takeda, N., O'Dea, E. L., Doedens, A. L., Kim, J., Weidemann, A., Stockmann, C., Asagiri, M., Simon, M. C., Hoffmann, A., & Johnson, R. S. (2010) · Genes & Development · doi:10.1101/gad.1881410 · Cited by 646
Distribution of macrophage polarization markers in human atherosclerosis
Stöger, J. L., Gijbels, M. J., van der Velden, S., Manca, M., van der Loos, C. M., Biessen, E. A. L., Daemen, M. J. A. P., Lutgens, E., & de Winther, M. P. J. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.09.013 · Cited by 646
“Notably, adipose tissue macrophages assist healthy metabolism under lean conditions through their anti-inflammatory M2 properties [30].”
Metabolic Regulation of Macrophage Polarization in Cancer
Mehla, K., & Singh, P. K. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.10.007 · Cited by 621
Transcriptional Control of Mitochondrial Biogenesis and Function
Hock, M. B., & Kralli, A. (2009) · Annual Review of Physiology · doi:10.1146/annurev.physiol.010908.163119 · Cited by 626
“PPARγ and PPARδ promote oxidative metabolism and mitochondrial biogenesis during alternative activation in macrophages (60, 61).”
Background
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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