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  • Our study revealed elevated basal Akt phosphorylation in die

    2021-01-15

    Our study revealed elevated basal Akt phosphorylation in diet-induced obesity, the effect of which was reversed by ETAKO. Activation of Akt promotes cardiac hypertrophy via a number of cellular mechanisms including activation of its downstream targets such as mTOR and GSK3β [45, 46]. Short-term activation of Akt stimulates physiological hypertrophy and is thought to be cardio-protective. On the other side of the coin, chronic activation of Akt leads to pathological hypertrophy and eventually heart failure [[47], [48], [49], [50]]. The presence of contractile dysfunction, interstitial fibrosis, apoptosis and re-expression of fetal cardiac genes (e.g., ANP and β-MHC) are strong indicative of presence of pathological hypertrophy in our high-fat diet-induced obesity model. Consequently, activation of Akt (basal phosphorylation) in chronic high-fat diet fed mice should represent a detrimental event and inhibition of Akt activation with ETA knockout may therefore be protective. mTOR is linked to nutrient sensing and protein synthesis in the heart, and is involved in cardiomyocyte hypertrophy [51]. Our current study showed that high-fat diet intake (or palmitic acid) turned on Akt/mTOR pro-hypertrophic signaling, the effect of which was abrogated by ETA receptor knockout (in vivo) or BQ123 (in vitro). Previous studies by Wang and coworkers showed that ET-1 inhibited ribosomal S6 kinase (p70s6k), a downstream sonidegib sale of mTOR [52], which is consistent with our current observation. In addition, rapamycin, an inhibitor of mTOR (and an inducer of autophagy), reversed palmitic acid-mediated hypertrophic responses in murine cardiomyocytes. While the interaction of mTOR with Rictor stimulates cell growth and protein synthesis via phosphorylation of p70s6k, the Rictor complex is implicated in cytoskeletal rearrangement and cell survival [53]. Our data of restored levels of Raptor and Rictor in ETAKO mice fed high-fat diet suggest that possible involvement of both mTOR-dependent and -independent mechanisms in ETA receptor knockout-offered beneficial response against high-fat diet intake. Taken together, it is plausible that ET-1/ETA signaling mediates cardiac hypertrophy by upregulating the Akt/mTOR signaling as depicted in Fig. 10. Our results indicated that ETAKO effectively restored compromised autophagy in diet-induced obesity. Autophagy is a conserved cellular process through which cytoplasmic contents including proteins and organelles are degraded in lysosomes [54]. Autophagy maintains cellular homeostasis in the heart and serves as a ‘double-edged sword’ for both metabolic and cardiac homeostasis [2, 55, 56]. Both suppressed and over-activated autophagy have been documented in obesity and other metabolic anomalies [2]. In the realm of obesity, it is generally perceived that autophagy is upregulated in adipose tissues, while it is mostly downregulated in the liver, heart and pancreas [2, 57]. Recent evidence has demonstrated suppressed autophagy in diet-induced and genetically-predispose obese hearts [2, 58, 59], similar to our current study. However, contrary finding of elevated autophagy was also noted in high-fat diet-induced obese hearts [60]. These findings suggest the complex nature of autophagy regulation in obesity possibly due to experimental models and duration of adiposity. The Akt/mTOR signaling cascade negatively regulates autophagy [61] whereas rapamycin induces autophagy through inhibiting mTOR. Last but not least, the ETAKO-induced restoration of autophagy may contribute to the improved lipid metabolism noted in our study (cardiac triglycerides, PPARα, PPARγ and PGC1α) as depicted in Fig. 10. Although ETAKO is unlikely to improve cardiac homeostasis through correcting obesity-induced changes in energy sensing and substrate utilization (AMPK-ACC- or MCD-mediated malonyl Co-A production or degradation, or cardiac energy metabolism through PDH phosphorylation), improved autophagy should help to clear lipid deposit from the obese hearts as suggested by “lipophagy” [2].