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Macrophage-specific PPARγ controls alternative activation and improves insulin resistance

Nature volume 447, pages 1116–1120 (2007)Cite this article

Abstract

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation1,2. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance3,4. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance5,6. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity5,7. 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 microenvironment8. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage5,8, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype9. Despite their higher capacity to repair tissue10, 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-γ (PPARγ), we show here that PPARγ is required for maturation of alternatively activated macrophages. Disruption of PPARγ 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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Figure 1: PPARγ regulates alternative macrophage activation.
Figure 2: Mac-PPARγ KO mice are less susceptible to infection by Leishmania major.
Figure 3: Alterations in adipose tissue mass and function in Mac-PPARγ KO mice.
Figure 4: Impaired glucose homeostasis in male Mac-PPARγ KO mice fed a high fat diet.

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Acknowledgements

We thank members of the Chawla laboratory for comments, and A. Loh and C. H. Lee for critiquing the manuscript. We also thank P. Murray, J. McKerrow and O. McGuinness for providing key reagents and technical guidance. This work was supported by grants made available to A.C. from the NIH, the Astellas Foundation, Takeda Pharmaceuticals North America, the Rockefeller Brothers Fund and by Goldman Philanthropic Partnerships; and to A.W.F. from the NIH and Columbia DERC. A.C. is a Charles E. Culpeper Medical Scholar. Support was provided by Stanford MSTP (to J.I.O. and A.R.E.), the AHA (to J.I.O.), a HHMI Gilliam fellowship (to A.R.E.), the NRSA (to R.R.R.-G.), and an NIH Training Grant (to L.M.). All animal care was in accordance with Stanford University’s A-PLAC committee guidelines.

Author Contributions J.I.O and R.R.R.-G were involved in project planning, experimental work and data analysis; M.H.G, C.R.M, V.S, L.M., D.V. and A.R.E. performed experimental work; F.B. was involved in project planning; and A.W.F. and A.C. were involved in project planning, data analysis and manuscript preparation.

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  1. Justin I. Odegaard and Roberto R. Ricardo-Gonzalez: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, Metabolism and Gerontology,

    Justin I. Odegaard, Roberto R. Ricardo-Gonzalez, Matthew H. Goforth, Christine R. Morel, Lata Mukundan, Alex Red Eagle, Divya Vats & Ajay Chawla

  2. Graduate Program in Immunology,,

    Justin I. Odegaard, Roberto R. Ricardo-Gonzalez & Ajay Chawla

  3. Department of Genetics, Stanford University School of Medicine, Stanford, California 94305-5103, USA,

    Alex Red Eagle

  4. Department of Medicine, Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA,

    Vidya Subramanian & Anthony W. Ferrante

  5. Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Science Faculty, University of Cape Town, Werhner Beit South, Observatory, 7925, Anzioroad, Cape Town, South Africa,

    Frank Brombacher

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Correspondence to Ajay Chawla.

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Odegaard, J., Ricardo-Gonzalez, R., Goforth, M. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007). https://doi.org/10.1038/nature05894

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