Abstract 17746: Cardiomyocyte-Specific KLF5 Deletion Accelerates Diet-Induced Obesity via Cardiac FGF21

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Abstract

Previously, we showed that inhibition of Krüppel-like factor (KLF) 5 decreases cardiac fatty acid oxidation. As cardiac fatty acid metabolism has a significant effect in systemic lipid balance, we hypothesized that cardiomyocyte KLF5 has a role in whole body metabolism. Treatment of cardiomyocyte-specific KLF5 knockout mice (αMHC-KLF5-/-) with high fat diet (HFD) for 6 weeks led to a more profound body weight increase compared to HFD-fed control floxed mice, associated with increased expression of Pparγ2, Lpl, Cd36, Dgat2 and Glut4 in white adipose tissue (WAT). WAT was heavier, and had larger adipocytes. Also increased hepatic triglycerides was found. Metabolic cage analysis identified no significant changes in respiratory exchange ratio, caloric intake and activity. We then investigated the mechanism that mediates cross-talk between cardiomyocytes and WAT. Previous findings have linked reduced levels of natriuretic peptides (BNP and ANP) with increased adiposity. However, cardiac Bnp and Anp expression levels were increased in HFD-fed αMHC-KLF5-/-. Plasma adiponectin and leptin were not different between HFD-fed control floxed mice and αMHC-KLF5-/- mice. HFD-fed αMHC-KLF5-/- mice had increased levels of cardiac and plasma Fgf21. Consistent with studies reporting that FGF21 decreases SUMO-PPARγ, HFD-fed αMHC-Klf5-/- mice had reduced SUMO-PPARγ in WAT, indicating increased PPARγ activity that can account for increased adipogenesis. Then, we generated αMHC-{Klf5-/-;Fgf21-/-} mice. Upon HFD treatment these mice did not show increased body weight gain as did the HFD-fed αMHC-KLF5-/- mice. The double cardiomyocyte-specific knockout of Klf5 and Fgf21 also prevented the increased expression of WAT differentiation markers, increased plasma FGF21 levels, and reduced SUMO-PPARγ in WAT that was found in HFD-fed αMHC-Klf5-/- mice. Conclusively, cardiomyocyte KLF5 regulates systemic fatty acid metabolism and adiposity via alteration of cardiac FGF21.

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