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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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“Peroxisome proliferator-activated receptor γ Macrophage-specific deletion of PPARγ in mice impaired M2 activation despite the mice being on a chow diet (91).”
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PPARs and the Cardiovascular System
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“M1 macrophages are involved in proinflammatory cytokine expression and oxidative stress, whereas M2 macrophages play a role in apoptotic cell phagocytosis, sequestering of pathogens, and wound healing (267, 341).”
Lefterova, M. I., Steger, D. J., Zhuo, D. X., Qatanani, M., Mullican, S. E., Tuteja, G., Manduchi, E., Grant, G. R., & Lazar, M. A. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01651-09 · Cited by 213
“In contrast, macrophages do not require PPAR for differentiation, phagocytic activity, or proinflammatory cytokine production (50) but employ PPAR in more specialized functions, such as maintenance of the alternative macrophage phenotype (5, 20, 55), cholesterol uptake and efflux in atherosclerotic plaques (49), antig…”
BackgroundResultInfluentialMacrophages: sentinels and regulators of the immune system
Franken, L., Schiwon, M., & Kurts, C. (2016) · Cellular Microbiology · doi:10.1111/cmi.12580 · Cited by 225
Innate immunity, insulin resistance and type 2 diabetes
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Insulin Resistance and Atherosclerosis
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“Identification of M1 [TNF, inducible NO synthase [iNOS], and IL-12 (71)] and M2 [IL-10 (71)] mediators, as well as PPARg (59, 72), was performed in macrophages from the decidua basalis (CD45CD14 cells), as shown in Fig.”
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The Cellular and Molecular Basis of Translational Immunometabolism
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“PPAR-g plays a pivotal role in AT biology by favoring the alternative activation of macrophages (Odegaard et al., 2007) and also facilitating lipid metabolism in metabolically activated mac-”
BackgroundMyeloid Colony-Stimulating Factors as Regulators of Macrophage Polarization
Hamilton, T. A., Zhao, C., Pavicic, P. G., & Datta, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00554 · Cited by 200
“PPARγ, in particular, has been reported to be required for development of alternatively activated macrophages in the context of insulin resistance and metabolic inflammatory disease (46).”
BackgroundEpigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity
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“PPARγ activation promotes macrophage alternative activation (12–14), whereas myeloid PPARγ deletion results in impaired macrophage alternative activation and insulin resistance (16).”
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“bone marrow cells were isolated from the tibias and femurs of chow diet-fed C57BL/6J mice as previously described [47].”
MethodImpact of increased adipose tissue mass on inflammation, insulin resistance, and dyslipidemia
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A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease
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“In Balb/c mice, bone marrow‐derived macrophage‐specific PPARγ deletion inhibited maturation of M2 macrophages and promoted insulin resistance as well as diet‐induced obesity.(35) Furthermore, CCL4 ‐induced liver injury caused increased hepatic expression of M1 inflammatory cytokines (TNFα and IL‐1β) and exacerbated fi…”
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“The evidence has shown that activation of PPARγ will increase M2 gene expression in macrophages/microglia, including Arg-1 [35], CD206, and IL-10 [36].”
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“Deletion of M1 macrophages normalizes sensitivity to insulin in obese mice (3,31), whereas reducing the number of M2 macrophages predisposes lean mice to insulin resistance (4).”
BackgroundMetabolic inflammation: Connecting obesity and insulin resistance
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Macrophage polarization in metabolic disorders
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“as 40% of the cell population of adipose tissue (7-9) and can significantly affect insulin resistance (10-18).”
BackgroundMacrophage heterogeneity in atherosclerotic plaques
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“In addition, mice with macrophage-specific deletion of PPAR display obesityinduced insulin resistance, primarily due to exacerbated macrophage inflammation (54), whereas conditional deletion of PPAR in macrophages increases atherosclerosis in Ldlr / mice (39).”
PPAR agonists: multimodal drugs for the treatment of type-2 diabetes
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Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter
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Connecting Type 1 and Type 2 Diabetes through Innate ImmunityPreprint
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“In the absence of PPARg, murine macrophages are incapable of affecting the metabolic shift required for sustained alternative response (Vats et al. 2006; Odegaard et al. 2007), whereas PPARd deficiency disrupts the macrophage’s ability to coordinate and sustain the immunologic phenotype of alternative activation (Kang…”
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“pro-inflammatory cytokines, such as TNF-α and IL-6, which induce insulin resistance via the IKKβ- and JNK-mediated inhibitory serine phosphorylation of insulin receptor substrate (IRS) proteins [21].”
PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity
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“Total serum IgE was measured with capture antibody to mouse IgE (R35-72) and biotinylated detection antibody to mouse IgE (R35-118), with a recombinant IgE standard curve (27-74).”
MethodMacrophage PPARγ and impaired wound healing in type 2 diabetes
Mirza, R. E., Fang, M. M., Novak, M. L., Urao, N., Sui, A., Ennis, W. J., & Koh, T. J. (2015) · The Journal of Pathology · doi:10.1002/path.4548 · Cited by 177
“Although IL-4 can up-regulate Mp PPARγ activity and an alternatively activated Mp phenotype [9,28], our data indicate that the up-regulation of PPARγ activity in ND wound Mp occurred through an IL-4/IL-13-independent mechanism.”
BackgroundMethodResultInfluentialZhu, Y., Zhou, Z., Du, X., Lin, X., Liang, Z.-M., Chen, S., Sun, Y., Wang, Y., Na, Z., Wu, Z., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.03.015 · Cited by 200
Ribas, V., Drew, B. G., Le, J., Soleymani, T., Daraei, P., Sitz, D., Mohammad, L., Henstridge, D. C., Febbraio, M. A., Hewitt, S. C., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104533108 · Cited by 179
“Alternative macrophage activation is associated with antiinflammatory actions, wound healing, and a lean mouse phenotype (25, 35, 36).”
BackgroundResultInfluentialLuci, C., Bourinet, M., Leclère, P. S., Anty, R., & Gual, P. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.597648 · Cited by 195
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“insulin resistance has been extensively investigated in a number of genetic models [4,5,6,7].”
BackgroundDániel, B., Nagy, G., Czimmerer, Z., Horváth, A., Hammers, D. W., Cuaranta‐Monroy, I., Póliska, S., Tzerpos, P., Kolostyák, Z., Hays, T. T., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.09.005 · Cited by 180
“…and ligand-regulated genes is disproportionately low (Szanto et al., 2010) (Welch et al., 2003), 2; PPARγ is required for alternative polarization (Odegaard et al., 2007), but ligand stimulation is not sufficient to drive the polarization- specific gene expression signature (Szanto et al.,…”
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Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions
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“Cipolletta et al. [131] showed that PPAR-γ is involved with adipose tissue-specific lymphocyte accumulation and activation, leading to cell differentiation.”
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“In order to mimic the macrophage phenotype of obese mice in vivo, we established two cell models (M1 and M2) in vitro as shown below.”
MethodNCoR Repression of LXRs Restricts Macrophage Biosynthesis of Insulin-Sensitizing Omega 3 Fatty Acids
Li, P., Spann, N. J., Kaikkonen, M. U., Lu, M. M., Oh, D. Y., Fox, J. N., Bandyopadhyay, G. K., Talukdar, S., Xu, J., Lagakos, W., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.054 · Cited by 179
“…further effect to augment insulin sensitivity in the MNKO mice, possibly because they were already insulin sensitive in the untreated state, or because the anti-inflammatory effects attributable to rosiglitazone (Bouhlel et al., 2007; Odegaard et al., 2007) require NCoR (Pascual et al., 2005).”
Spite, M. R., Hellmann, J. L., Tang, Y., Mathis, S., Kosuri, M., Bhatnagar, A., Jala, V. R., & Haribabu, B. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100196 · Cited by 182
“nuclear receptor is associated with increased insulin sensitivity (43), it is likely that PPARg may be in part responsible for the higher proportion of M2 macrophages in adipose tissue of BLT-1 mice.”
BackgroundHoyer, F. F., Naxerova, K., Schloss, M. J., Hulsmans, M., Nair, A. V., Dutta, P., Calcagno, D. M., Hérisson, F., Anzai, A., Sun, Y., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.10.010 · Cited by 177
“is a tissue inhabited by macrophages that experienced a prior systemic or remote stressor more or less likely to develop subsequent disease? The emerging data on tissue-specific macrophage functions (Haldar et al., 2014; Hulsmans et al., 2017; Odegaard et al., 2007; Paolicelli et al., 2011) raise manifold implications…”
BackgroundIdentification of a Role for the PI3K/AKT/mTOR Signaling Pathway in Innate Immune Cells
Xie, S., Chen, M., Yan, B., He, X., Chen, X.-W., & Li, D.-W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094496 · Cited by 165
“The tissue macrophages display anatomical difference and have diverse functions, including development, metabolic homeostasis, tissue repair, and immune responses to pathogens [5].”
BackgroundMetabolic adaptations of tissue-resident immune cells
Caputa, G., Castoldi, Â., & Pearce, E. J. (2019) · Nature Immunology · doi:10.1038/s41590-019-0407-0 · Cited by 179
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“In contrast, TNFSF14 (LIGHT) is a candidate marker for M2 macrophages (95) and PPARG is required for M2 maturation (96).”
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Inflammation during obesity is not all bad: evidence from animal and human studies
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“Indeed, adipocytes play a key role in obesity-induced activation of adipose tissue macrophages [41, 42].”
BackgroundReduced oxidative capacity in macrophages results in systemic insulin resistance
Jung, S.-B., Choi, M. J., Ryu, D., Yi, H., Lee, S. E., Chang, J. Y., Chung, H. K., Kim, Y. K., Kang, S., Lee, J. H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03998-z · Cited by 174
The Metabolic Requirements of Th2 Cell Differentiation
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Tissue-resident macrophages: guardians of organ homeostasis
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“which confers to PPAR the ability to polarize monocyte differentiation toward an alternative anti-inflammatory phenotype with implications for the ability of macrophages to kill Leishmania parasites (55, 56).”
BackgroundLocal proliferation initiates macrophage accumulation in adipose tissue during obesity
Zheng, C., Yang, Q., Cao, J., Xie, N., Liu, K., Shou, P., Qian, F., Wang, Y., & Shi, Y. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.54 · Cited by 177
Nuclear Receptors License Phagocytosis by Trem2+Myeloid Cells in Mouse Models of Alzheimer's Disease
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Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders
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“Previous studies have linked PPARg with the development of alternatively activated macrophages (39) and with tissue repair in injured muscle (30), and IL-4 is known to promote the production of PPARg ligands (40).”
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“This focus is relevant because it may help researchers that approach clinical and experimental studies on this disease advancing the knowledge of mechanisms that could be targeted in order to revert NAFLD-related fibrosis.”
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“polarization, such as PPARg, PPARd, or KlF4 [32, 56, 57].”
Modulation of macrophage activation and programming in immunity
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“IL-33 could bind to ST2L, a subunit of the IL-33 receptor, to amplify Th2 cytokine effects and M2 macrophage induction (Miller et al., 2012; Ohto-Ozaki et al., 2012).”
BackgroundBmal1 integrates mitochondrial metabolism and macrophage activation
Alexander, R., Liou, Y.-H., Knudsen, N. H., Starost, K. A., Xu, C., Hyde, A. L., Liu, S., Jacobi, D., Liao, N., & Lee, C. (2020) · eLife · doi:10.7554/elife.54090 · Cited by 172
“Because Ppar d /Ppar g are known regulators of mitochondrial function and energy substrate utilization in macrophages (Dai et al., 2017; Kang et al., 2008; Lee et al., 2006; Odegaard et al., 2007), we sought to determine the role of Bmal1 in macrophage bioenergetic control.”
BackgroundThe immune system's involvement in obesity-driven type 2 diabetes
Shu, C. J., Benoist, C. O., & Mathis, D. J. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.12.001 · Cited by 170
“severe insulin resistance compared with that of controls [28, 49].”
Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals
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Origins, Biology, and Diseases of Tissue Macrophages
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“Disease processes complicate matters further by invoking dynamic transcription factor expression and altering requirements; in this context, PPARg is upregulated by IL-4 and controls alternative macrophage activation (Odegaard et al., 2007).”
The heterogeneity of lung macrophages in the susceptibility to disease
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“PPARg agonists induce a surprisingly small number of genes while inhibiting the induction of a broad subset of inflammatory genes, suggesting that transrepression might be a primary mechanism responsible for the anti-inflammatory action of PPARg.88 PPARg was also reported to be indispensible for alternative macrophage…”
BackgroundByndloss, M. X., Winter, M. G., Spees, A. M., den Hartigh, A. B., Nguyen, K., Roux, C. M., Silva, T. M. A., Atluri, V., Kerrinnes, T., Keestra, A. M., et al. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.07.009 · Cited by 166
“A pathway that is crucial to acquisition and maintenance of the AAM phenotype is mediated by peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors that regulates transcription of genes involved in cellular metabolism (Odegaard et al., 2007; Vats et al., 2006).”
BackgroundInfluentialTargeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis
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Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia
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“In accord, PPARc directly regulates alternative activation in peripheral macrophages [82], and KLF2 directly regulates the pro-inflammatory state in monocytes and facilitates the switch to alternative activation to M2 phenotype respectively [82–84], supporting the role of PPARc and KLF2 on M2-skewing.”
BackgroundMechanisms of obesity and related pathology: linking immune responses to metabolic stress
Karalis, K. P., Giannogonas, P., Kodela, E., Koutmani, Y., Zoumakis, M., & Teli, T. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07304.x · Cited by 163
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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