Abstract
Rationale: PPARα/γ agonist tesaglitazar effectively improves insulin sensitivity and dyslipidemia in diabetic mice and human subjects. The cellular and molecular mechanisms whereby this occurs remain unclear. Given the established expression of PPARs in macrophages and in vitro findings demonstrating attenuated inflammation with PPAR agonism, we hypothesized that tesaglitazar attenuates macrophage-mediated inflammation within the adipose to improve metabolic outcomes in diabetic mice. Methods & Results: To validate that tesaglitazar reduces diabetic symptoms, we treated Ob/ob mice with tesaglitazar or vehicle control for one week and observed significant reductions in fasting blood glucose, insulin, and triglyceride levels with drug treatment when compared to vehicle treatment. Using flow cytometry, we determined that treatment with tesaglitazar results in reduced numbers of total macrophages (CD45+CD11b+F4/80+) in the epididymal and subcutaneous adipose depots. Furthermore, this reduction in macrophages numbers is primarily due to reduced numbers within the M1, or pro-inflammatory, compartment (CD11b+F4/80+CD11c+CD206-) of the macrophage population. Given the established role of inflammation in inhibiting adipocyte Ucp-1 expression, we measured Ucp-1 expression levels in epididymal adipocytes and observed a significant induction of Ucp-1 mRNA expression with tesaglitazar treatment. Conclusion: As anticipated, treatment with tesaglitazar improves insulin sensitivity and dyslipidemia in Ob/ob mice. Interestingly, tesaglitazar treatment also reduced the number of inflammatory macrophages in adipose and induced adipocyte Ucp-1 mRNA expression. Taken together, our findings suggest that tesaglitazar has anti-inflammatory effects indicated by reduced numbers of pro-inflammatory macrophages and increased thermogenic capacity as seen by increased Ucp-1 expression.
Published Version
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