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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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“Macrophage-specific PPAR-c signaling controls macrophage activation in insulin resistance status.(41) It was reported that a PPAR-c agonist protected kidney from injury via the attenuation of inflammatory actions.”
BackgroundAlam, S., Liu, Q., Liu, S., Liu, Y., Zhang, Y., Yang, X., Liu, G., Fan, K., & Ma, J. (2019) · Experimental Cell Research · doi:10.1016/j.yexcr.2019.06.017 · Cited by 66
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The Interplay Between Tissue Niche and Macrophage Cellular Metabolism in Obesity
Daemen, S., & Schilling, J. D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.03133 · Cited by 68
“With HFD feeding, myeloid-specific PPARγ knockout mice have increased weight gain, adiposity, and glucose intolerance, which was paralleled by decreased expression of classic alternative macrophage activation markers and increased adipose tissue inflammation (124).”
BackgroundAutoimmune responses and inflammation in type 2 diabetes
Prasad, M., Chen, E. W., Toh, S.-A. E. S., & Gascoigne, N. R. J. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0220-243r · Cited by 67
Shu, Y., Qin, M., Song, Y., Tang, Q., Huang, Y., Shen, P., & Lu, Y. Z. (2020) · Immunology · doi:10.1111/imm.13196 · Cited by 66
Multiple roles of cardiac macrophages in heart homeostasis and failure
Moskalik, A., Niderla‐Bielińska, J., & Ratajska, A. (2021) · Heart Failure Reviews · doi:10.1007/s10741-021-10156-z · Cited by 70
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Activation of RXR/PPARγ underlies neuroprotection by bexarotene in ischemic stroke
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The Ability of Exercise-Associated Oxidative Stress to Trigger Redox-Sensitive Signalling Responses
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“As an illustration of the importance of the contributions of monocyte-macrophages (as per the “two-hit model”), it should be noted that monocyte-macrophage-specific pharmacological activation of PPARγ (which is linked to the M2 phenotype [60]) has been shown to be crucial to systemic anti-diabetic actions throughout t…”
BackgroundType 2 immunity in the brain and brain borders
Mamuladze, T., & Kipnis, J. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01043-8 · Cited by 67
Menale, C., Piccolo, M. T., Cirillo, G., Calogero, R., Papparella, A., Mita, L., del Giudice, E. M., Diano, N., Crispi, S., & Mita, D. G. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-14-0282 · Cited by 66
“Overproduction of these molecules within the adipose tissue has been associated with the development of insulin resistance (Odegaard et al. 2007).”
BackgroundActivation of lung macrophage subpopulations in experimental acute pancreatitis
Gea‐Sorlí, S., Guillamat‐Prats, R., Serrano‐Mollar, A., & Closa, D. (2010) · The Journal of Pathology · doi:10.1002/path.2814 · Cited by 64
Human adipose dynamics and metabolic health
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Sheldon, K. E., Shandilya, H. K., Kepka‐Lenhart, D., Poljakovic, M., Ghosh, A., & Morris, S. M. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202102 · Cited by 65
“duction of arginase I by IL-4 (17, 19, 20), and their roles in the synergistic response remain to be determined.”
BackgroundOyarce, C., Vizcaino-Castro, A., Chen, S., Boerma, A., & Daemen, T. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1898753 · Cited by 65
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“Moreover, PPARg expression itself has been reported to be significantly associated with increasedM2 monocytes in the vasculature and maturation of alternatively activated macrophages (6,8).”
Lee, J.-T., Pamir, N., Liu, N.-C., Kirk, E. A., Averill, M. M., Becker, L., Larson, I. A., Hagman, D. K., Foster‐Schubert, K. E., Yserloo, B. V., et al. (2014) · Endocrinology · doi:10.1210/en.2014-1037 · Cited by 70
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“To assess the activation state of macrophages exposed to chitin, we measured expression of arginase I (ArgI), a canonical product of the M2 phenotype (23, 24).”
BackgroundKawano, M., Miyoshi, M., Ogawa, A., Sakai, F., & Kadooka, Y. (2016) · Journal of Nutritional Science · doi:10.1017/jns.2016.12 · Cited by 64
“Furthermore, macrophage-specific disruption of the PPAR-γ gene, which is required for the activation of M2 macrophages, aggravates adipose tissue inflammation and insulin resistance in diet-induced obese mice((24)), suggesting that M2 macrophages have protective effects against inflammation.”
BackgroundMacrophages control innate inflammation
Akira, S., Misawa, T., Satoh, T., & Saitoh, T. (2013) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12151 · Cited by 64
“δ-dependent fashion, respectively [35,41,42].”
Lipid‐sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome
Vacca, M., Degirolamo, C., Mariani‐Costantini, R., Palasciano, G., & Moschetta, A. (2011) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.137 · Cited by 66
Regulation and consequences of monocytosis
Dutta, P., & Nahrendorf, M. (2014) · Immunological Reviews · doi:10.1111/imr.12219 · Cited by 66
“Alternative activation of adipose tissue macrophages depends on peroxisome proliferator activated receptor-c (PPARc) (108).”
BackgroundImpact of obesity on autoimmune arthritis and its cardiovascular complications
Raemdonck, K. V., Umar, S., Szekanecz, Z., Zomorrodi, R. K., & Shahrara, S. (2018) · Autoimmunity Reviews · doi:10.1016/j.autrev.2018.02.007 · Cited by 66
Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors
P. Menendez-Gutierrez, M., Roszer, T., & Ricote, M. (2012) · Current Topics in Medicinal Chemistry · doi:10.2174/156802612799436669 · Cited by 62
“Studies with macrophage-specific deletion of PPAR show that inflammatory M1 macrophage polarization is increased by PPAR deficiency during obesity progression, which leads to the development of IR [36, 121].”
BackgroundC/EBPα regulates macrophage activation and systemic metabolism
Lee, B., Qiao, L., Lu, M. M., Yoo, H. S., Cheung, W., MAK, R. H. K., Schaack, J. B., Feng, G., Chi, N., Olefsky, J. M., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00002.2014 · Cited by 63
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Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis
Rojas, J., Salazar, J. J., Martínez, M. S., Palmar, J., Bautista, J., Chávez-Castillo, M., Gómez, A., & Bermúdez, V. (2015) · Scientifica · doi:10.1155/2015/851252 · Cited by 65
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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