Abstract 3950: Deficiency of PPARγ in Cardiomyocytes Results in Myocardial Inflammation and Cardiac Insulin Resistance
Insulin resistance predicts the incidence of congestive heart failure. The myocardial expression of the ligand-activated nuclear hormone receptor PPARγ is decreased in these patients. However, the pathogenetic role of cardiomyocyte PPARγ in this process remains unknown. We have previously demonstrated that PPARγ is expressed in cardiomyocytes and plays a role in cardiomyocyte hypertrophy. Using the Cre-lox P system we generated mice with a cardiomyocyte specific deletion of PPARγ (cPPARγ −/−). Littermate mice (WT) were used as controls. cPPARγ−/− showed an increased cardiac pro-inflammatory milieu with an increased myocardial expression of the macrophage marker CD68 and osteopontin compared to WT mice. Using small animal positron emisson tomography (microPET) technology, we measured cardiac 18F-DG uptake before and after prior subcutaneous insulin (2 IU/kg*BW) injection. Under conscious uptake, a significant difference was measured between WT and cPPARγ−/− mice (1.38%±0.20% vs 2.01%±0.18%; p<0.05). Insulin significantly increased cardiac 18F-DG uptake in WT (p<0.02), but not in cPPARγ−/− (1.96%±0.09% vs. 2.12%±0.10%). At the cellular level, insulin-stimulated glucose uptake was reduced in cardiomyocytes isolated from adult cPPARγ−/−. Despite this myocardial insulin resistance in cPPARγ−/−, whole body insulin sensitivity was not altered. Western blot analysis revealed attenuated insulin-stimulated protein kinase B (Akt/PKB) and Akt substrate (AS-160) phosphorylation as well as glucose transporter 4 (GLUT4) translocation to the plasma membrane 20 minutes after insulin injection in the myocardium of cPPARγ−/−. Providing an anti-inflammatory treatment by administering acetyl salicylic acid (30mg/mouse*day) for 4 days the alterations seen in the insulin signaling pathway could be reversed. These results suggest that
PPARγ in the cardiomyocyte regulates insulin-mediated cardiac glucose uptake, involving mechanisms controlling GLUT4 translocation to the plasma membrane.
Anti-inflammatory treatment reverses cardiac insulin resistance caused by lack of cardiomyocyte PPARγ.