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PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization.

ABSTRACT: Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as thiazolidinediones (TZDs) are widely used to treat type 2 diabetes, how its activation in individual tissues contributes to TZD's therapeutic action remains controversial. As TZDs are known to have receptor-independent effects, we sought to establish gain-of-function animal models to delineate the receptor's insulin-sensitizing actions. Unexpectedly, we find that selective activation of PPARgamma in adipocytes, but not in macrophages, is sufficient for whole-body insulin sensitization equivalent to systemic TZD treatment. In addition to improved adipokine, inflammatory, and lipid profiles, PPARgamma activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARgamma-activated adipocytes broadly suppress induction of inflammatory cytokines and C-X-C family chemokines in macrophages. Collectively, these data describe an "adipocentric" model in which adipose activation of PPARgamma is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARgamma modulators in diabetic therapy.

SUBMITTER: Sugii S

PROVIDER: S-EPMC2794650 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization.

Sugii Shigeki S Olson Peter P Sears Dorothy D DD Saberi Maziyar M Atkins Annette R AR Barish Grant D GD Hong Suk-Hyun SH Castro Glenda L GL Yin Yun-Qiang YQ Nelson Michael C MC Hsiao Gene G Greaves David R DR Downes Michael M Yu Ruth T RT Olefsky Jerrold M JM Evans Ronald M RM

Proceedings of the National Academy of Sciences of the United States of America 20091216 52

Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as thiazolidinediones (TZDs) are widely used to treat type 2 diabetes, how its activation in individual tissues contributes to TZD's therapeutic action remains controversial. As TZDs are known to have receptor-independent effects, we sought to establish gain-of-function animal models to delineate the receptor's insulin-sensitizing actions. Unexpectedly, we find that selective activation of PPARgamma in adipocytes ...[more]

PMID: 20018750

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Project description: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.

Dataset Information

PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization.

Publications

PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization.

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