High fat diet intake contributes to undesired cardiac geometric and functional changes although the underlying mechanism remains elusive. Akt and AMPK govern to cardiac homeostasis. This study examined the impact of deletion of Akt2 (main cardiac isoform of Akt) and AMPKα2 on high fat diet intake-induced cardiac remodeling and contractile anomalies and mechanisms involved. Cardiac geometry, contractile, and intracellular Ca²⁺ properties were evaluated using echocardiography, IonOptix® edge-detection and fura-2 techniques in wild-type (WT) and Akt2-AMPK double knockout (DKO) mice receiving low fat (LF) or high fat (HF) diet for 4 months. Our results revealed that fat diet intake elicit obesity, cardiac remodeling (hypertrophy, LV mass, LVESD, and cross-sectional area), contractile dysfunction (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, and intracellular Ca²⁺ handling), ultrastructural disarray, apoptosis, O₂⁻, inflammation, dampened autophagy and mitophagy. Although DKO did not affect these parameters, it accentuated high fat diet-induced cardiac remodeling and contractile anomalies. High fat intake upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and STING phosphorylation while suppressing phosphorylation of ULK1 (Ser⁷⁵⁷ and Ser⁷⁷⁷), with a more pronounced effect in DKO mice. In vitro data revealed that inhibition of cGAS and STING using PF-06928215 and Astin C negated palmitic acid-induced cardiomyocyte contractile dysfunction. Biological function analysis for all differentially expressed genes (DEGs) depicted that gene ontology terms associated with Akt and AMPK signaling processes were notably changed in high fat-fed hearts. Our data indicate that Akt2-AMPK ablation accentuated high fat diet-induced cardiac anomalies possibly through a cGAS-STING-mechanism.

尽管潜在的机制仍然难以捉摸，但高脂肪饮食摄入会导致不希望的心脏几何和功能变化。Akt 和 AMPK 控制心脏稳态。本研究检查了 Akt2（Akt 的主要心脏同种型）和 AMPKα2 缺失对高脂肪饮食诱导的心脏重塑和收缩异常的影响以及所涉及的机制。心脏几何、收缩和细胞内 Ca ²⁺在接受低脂 (LF) 或高脂 (HF) 饮食 4 个月的野生型 (WT) 和 Akt2-AMPK 双敲除 (DKO) 小鼠中，使用超声心动图、IonOptix® 边缘检测和 fura-2 技术评估特性。我们的研究结果表明，脂肪饮食会导致肥胖、心脏重塑（肥大、LV 质量、LVESD 和横截面积）、收缩功能障碍（部分缩短、峰值缩短、最大缩短/重新延长速度、90% 重新延长时间和细胞内 Ca ²⁺处理）、超微结构紊乱、细胞凋亡、O ₂ ^-、炎症、抑制自噬和线粒体自噬。虽然 DKO 不影响这些参数，但它加重了高脂肪饮食引起的心脏重塑和收缩异常。高脂肪摄入上调环 GMP-AMP 合酶 (cGAS)、干扰素基因刺激物 (STING) 和 STING 磷酸化水平，同时抑制 ULK1 磷酸化（Ser ⁷⁵⁷和 Ser ⁷⁷⁷)，在 DKO 小鼠中效果更明显。体外数据显示，使用 PF-06928215 和 Astin C 抑制 cGAS 和 STING 可以消除棕榈酸诱导的心肌细胞收缩功能障碍。所有差异表达基因 (DEG) 的生物功能分析表明，与 Akt 和 AMPK 信号传导过程相关的基因本体术语在高脂肪喂养的心脏中发生了显着变化。我们的数据表明，Akt2-AMPK 消融可能通过 cGAS-STING 机制加重了高脂肪饮食诱导的心脏异常。