Macrophage-specific PPARγ controls alternative activation and improves insulin resistance

Justin I. Odegaard, Roberto R. Ricardo-Gonzalez, Matthew H. Goforth, Christine R. Morel, Vidya Subramanian, Lata Mukundan, Alex Red Eagle, Divya Vats, Frank Brombacher, Anthony W. Ferrante and Ajay Chawla ()
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Justin I. Odegaard: Metabolism and Gerontology
Roberto R. Ricardo-Gonzalez: Metabolism and Gerontology
Matthew H. Goforth: Metabolism and Gerontology
Christine R. Morel: Metabolism and Gerontology
Vidya Subramanian: Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
Lata Mukundan: Metabolism and Gerontology
Alex Red Eagle: Metabolism and Gerontology
Divya Vats: Metabolism and Gerontology
Frank Brombacher: Institute of Infectious Disease and Molecular Medicine, Health Science Faculty, University of Cape Town, Werhner Beit South, Observatory, 7925, Anzioroad, Cape Town, South Africa
Anthony W. Ferrante: Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
Ajay Chawla: Metabolism and Gerontology

Nature, 2007, vol. 447, issue 7148, 1116-1120

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05894

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