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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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“Many pathways and transcription factors are involved in macrophage polarization, such as signal transducer and activator of transcription (STATs) [71], nuclear factor (NF)-κB [26], activator protein-1 (AP-1) [71], PI3K/Akt [72, 73], C-Jun Nterminal kinase (JNK) [74], and peroxisome proliferatoractivated receptor (PPAR…”
BackgroundRosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke
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“The studies on the molecular mechanism underlying macrophage polarization have found that the activation of proliferator-activated receptor g (PPAR g) plays very important role in the polarization.(16,17) IL-4 was shown to induce STAT6 phosphorylation, then activate STAT6 to coordinate and synergize with both PPARg an…”
BackgroundMacrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone
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BackgroundInfluentiall -Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ
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“Recently, peroxisome proliferator-activated receptor γ (PPARγ) and δ (PPARδ) were identified as critical promoters of macrophage polarisation towards the M2 phenotype and, consequently, macrophage-specific deletion of PPARγ or PPARδ resulted in a reduced expression of M2macrophage-specific genes in adipose tissue and…”
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“Additionally, their nutrient restriction signaling is associated with altered macrophage metabolism, such as activation of adenosine monophosphate-activated protein kinase (AMPK),(10) and various anti-inflammatory activities.(11,12) Intriguingly, PPARg agonism has also been associated with enhanced host defense agains…”
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Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function
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Obesity and metabolic inflammation
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“Myeloid deletion of PPARd, but not PPARg, led to decreased expression of alternative activation markers in KCs, suggesting that PPARd signaling exerts more transcriptional control in homeostatic KCs than PPARg (Figure 1B) (44, 45).”
BackgroundMinireview: Emerging Concepts in Islet Macrophage Biology in Type 2 Diabetes
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“In addition to IL-4-STAT6, a number of pathways and transcription factors such as PPARγ and IRF4 are also critically involved in driving M2 polarization (Odegaard et al., 2007; Satoh et al., 2010).”
BackgroundThe Microbiome of the Built Environment and Human Behavior
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“Significant improvements in metabolic outcomes, however, can be achieved when macrophages are polarized toward the M2 phenotype (22).”
BackgroundMediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization
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BackgroundInfluentialTranscriptional Control of Macrophage Identity, Self-Renewal, and Function
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BackgroundType 2 responses at the interface between immunity and fat metabolism
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Simvastatin alters M1/M2 polarization of murine BV2 microglia via Notch signaling
Wu, F., Luo, T., Yuanwu, M., Liu, H., Dong, J., Fang, Y., Peng, J., & Guo, Y.-J. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.12.010 · Cited by 55
“Clear evidence indicates that microglia/macrophages present a classical activation pattern (M1 polarization) upon activation by LPS or IFN-γ (Odegaard et al., 2007), and an alternative activation pattern (M2 polarization) after induction by IL-4 or IL-13 (Park et”
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“PPAR γ has been shown to be influential in diminishing the inflammatory response and promoting an alternative M2 macrophage phenotype [8].”
BackgroundChronic Bacterial Pathogens: Mechanisms of Persistence
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“Interestingly, studies using PPARγ-deficient cells have demonstrated that, in the absence of PPARγ signaling, macrophages neither appropriately suppress inflammatory cytokine production nor acquire an oxidative metabolic program that is associated with the AAM phenotype (84, 90).”
BackgroundLi, J., Li, X., Li, Z., Zhang, L., Liu, Y., Ding, H., & Yin, S. (2017) · Food & Function · doi:10.1039/c7fo00290d · Cited by 55
Isoform-specific functions of PPARγ in gene regulation and metabolismPreprint
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“…in mice with severe lipodystrophy (Fiorenza et al. 2011; Soccio et al. 2014), although there is evidence for a role for PPAR γ in nonadipocytes, such asT cells, macrophages, muscle, and brain in response to TZDs (Heveneret al. 2003; Odegaard et al. 2007; Lu et al. 2011; Cipolletta et al. 2012).”
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“…that proliferator-activated receptor γ (PPAR γ ) is essential for anti-in fl ammatory macrophage polarization and intracellular polyamine production [155, 156], Thurlow et al. [157] tested the necessity of bone marrow-speci fi c PPAR γ for the transition of the immune response from an in fl am-matory…”
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“These findings indicate that PPARγ not only influences the immune state of macrophages but also plays a role in regulating the overall metabolic states (Bouhlel et al., 2007; Odegaard et al., 2007).”
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“Previous studies have identified various immune cells as metabolic controllers with pathogenic or regulatory potential (Chawla et al., 2011; ElgazarCarmon et al., 2008; Feuerer et al., 2009; Kang et al., 2008; Liu et al., 2009; Lumeng et al., 2007a, 2007b; Nguyen et al., 2007; Nishimura et al., 2013; Odegaard et al.,…”
BackgroundI-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis
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“Consistently, transgenic mice overexpressing IL-5 are leaner and more glucose tolerant [4], while treating wildtype mice with IL-4 during HFD protects against insulin resistance [5].”
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“Furthermore mice lacking PPARc in myeloid cells exhibit reduced numbers of M2 macrophages and are susceptible to HFD-induced IR [41].”
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“21 transrepress pro-inflammatory promoters, which renders these nuclear receptors central players in the dichotomy between M1 and M2 macrophages reflecting the antagonism between oxidative metabolism and inflammatory gene expression [219, 222, 304].”
BackgroundThe Ontogeny and Microenvironmental Regulation of Tumor-Associated Macrophages
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“Adipose tissue-resident macrophages are involved in energy homeostasis, by regulating insulin sensitivity (112, 135, 164) or affecting heat generation by adipose tissue (108).”
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“…et al. 2013; You et al. 2013), while deletion of peroxisome proliferator activated receptor gamma (PPARγ), an important regulator of M2 polarisation, in murine macrophage cells promoted diet-induced systemic insulin resistance and/or glucose intolerance (Hevener et al. 2007; Odegaard et al. 2007).”
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“…by deleting macrophage expression of IL-4 receptor downstream components, such as PPARg, PPARd, and KLF4, results in exacerbated insulin resistance and, in some models, increase in weight gain upon HFD feeding (Kang et al., 2008; Liao et al., 2011; Odegaard et al., 2007; Odegaard et al., 2008).”
BackgroundInfluentialMuir, L. A., Kiridena, S., Griffin, C. A., DelProposto, J. B., Geletka, L. M., Martinez-Santibañez, G., Zamarron, B. F., Lucas, H. R., Singer, K., O’Rourke, R. W., et al. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.3hi1017-422r · Cited by 56
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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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