Autophagic control of cardiac steatosis through FGF21 in obesity-associated cardiomyopathy.

OBJECTIVE: High-fat diet-induced obesity leads to the development of hypertrophy and heart failure through poorly understood molecular mechanisms. We have recently shown that fibroblast growth factor-21 (FGF21) is produced by the heart and exerts protective effects that prevent cardiac hypertrophy development and oxidative stress. The aim of this study was to determine the effects of FGF21 on the cardiomyopathy associated with obesity development. RESULTS: Fgf21-/- mice showed an enhanced increase in the heart weight/tibia length (HW/TL) ratio in response to the high-fat diet. In keeping with this, echocardiographic measurements confirmed enhanced cardiac hypertrophy in Fgf21-/- mice. At the cellular level, the area of cardiomyocytes was increased in Fgf21-/- mice fed a high-fat diet. Furthermore, a high-fat diet induced fatty acid oxidation in the hearts of Fgf21-/- mice accompanied by an increase in cardiac oxidative stress. Oil-red O staining revealed the presence of higher amounts of lipid droplets in the hearts of Fgf21-/- mice fed a high-fat diet relative to wt mice fed this same diet. Finally, Fgf21-/- mice fed a high-fat diet showed impaired cardiac autophagy and signs of inactive cardiac lipophagy, suggesting that FGF21 promotes autophagy in cardiomyocytes. CONCLUSIONS: Our data indicate that a lack of FGF21 enhances the susceptibility of mice to the development of obesity-related cardiomyopathy. Furthermore, we demonstrate that this cardiac dysfunction is associated with deleterious lipid accumulation in the heart. An impaired ability of FGF21 to promote autophagy/lipophagy may contribute to lipid accumulation and cardiac derangements.

C/EBPß is required in pregnancy-induced cardiac hypertrophy.

AIM: Pregnancy is a physiological model of adaptive and reversible heart enlargement, but the molecular mechanisms determining this kind of physiologic cardiac hypertrophy are poorly known. Here, we analyzed the role of the transcription factor C/EBPß in the development of pregnancy-induced cardiac hypertrophy. RESULTS: C/EBPß+/- mice at day 18 of gestation were used as happloinsufficiency model of late pregnancy. We found that C/EBPß expression was specifically increased in hearts from Wt pregnant mice whereas expression of other C/EBP subtypes (α and δ) was not affected by gestation. Pregnancy-induced changes in systemic metabolic and hormonal profiles were not essentially different in Wt versus C/EBPß+/- mice. However, C/EBPß+/- mice developed pregnancy-induced heart hypertrophy to a lower extent relative to Wt mice. Furthermore, hearts from C/EBPß+/- mice have alterations in fatty acid oxidation genes and reductions in the expression levels of glucose transporters that may compromise metabolic cardiac function during pregnancy. Among marker genes of inflammation, interleukin-6 (Il-6) showed a marked differential behavior in C/EBPß+/- pregnant mice: pregnancy strongly induced cardiac Il-6 expression in wt, a phenomenon that did not occur in C/EBPß+/- mice. Moreover, marker genes for M2 macrophages were decreased in C/EBPß+/- pregnant mice and in C/EBPß-/- mice subjected to LPS stimulus. CONCLUSIONS: Here we found that normal levels of C/EBPß are required for hypertrophy development during pregnancy. Events such as the increase in IL-6 in the heart of pregnant mice are prevented in C/EBPß+/- animals. Moreover, C/EBPß controls M2-macrophage gene expression in the heart. Thus, C/EBPß appears as a transcription factor required for cardiac hypertrophy response to gestation.