Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance Export

@article{Odegaard:2007p920, abstract = {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.}, author = {Odegaard, Justin I. and Roberto and Goforth, Matthew H. and Morel, Christine R. and Subramanian, Vidya and Mukundan, Lata and Eagle, Alex R. and Vats, Divya and Brombacher, Frank and Ferrante, Anthony W. and Chawla, Ajay}, citeulike-article-id = {3046177}, citeulike-linkout-0 = {http://www.nature.com/nature/journal/v447/n7148/abs/nature05894.html;jsessionid=5D479496BBE4D26C30C3EAAE0E13802D}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nature05894}, doi = {10.1038/nature05894}, journal = {Nature}, keywords = {activation, adiponectin, adipose, animals, balb, c, cell, cutaneous, dietary, disease, fats, file-import-08-07-27, gain, gamma, genetic, glucose, homeostasis, inbred, insulin, knockout, leishmania, leishmaniasis, line, macrophage, macrophages, major, male, mice, organ, ppar, predisposition, resistance, size, tissue, to, weight}, local-url = {file://localhost/Users/ken/Documents/Papers/2007/Odegaard/Nature\%202007\%20Odegaard.pdf}, month = {Jun}, number = {7148}, pages = {1116--20}, posted-at = {2008-07-27 14:45:58}, priority = {2}, title = {Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance}, url = {http://dx.doi.org/10.1038/nature05894}, volume = {447}, year = {2007} }

TY - JOUR ID - Odegaard:2007p920 L3 - citeulike-article-id:3046177 N2 - 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. IS - 7148 JF - Nature EP - 20 TI - Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance VL - 447 SP - 1116 KW - activation KW - adiponectin KW - adipose KW - animals KW - balb KW - c KW - cell KW - cutaneous KW - dietary KW - disease KW - fats KW - file-import-08-07-27 KW - gain KW - gamma KW - genetic KW - glucose KW - homeostasis KW - inbred KW - insulin KW - knockout KW - leishmania KW - leishmaniasis KW - line KW - macrophage KW - macrophages KW - major KW - male KW - mice KW - organ KW - ppar KW - predisposition KW - resistance KW - size KW - tissue KW - to KW - weight AU - Odegaard, Justin AU - Roberto AU - Goforth, Matthew AU - Morel, Christine AU - Subramanian, Vidya AU - Mukundan, Lata AU - Eagle, Alex AU - Vats, Divya AU - Brombacher, Frank AU - Ferrante, Anthony AU - Chawla, Ajay PY - 2007/Jun// UR - http://dx.doi.org/10.1038/nature05894 ER -