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Loss of protein kinase D activity demonstrates redundancy in cardiac glucose metabolism and preserves cardiac function in obesity
Molecular Metabolism ( IF 8.1 ) Pub Date : 2020-10-21 , DOI: 10.1016/j.molmet.2020.101105
Kirstie A De Jong 1 , Liam G Hall 2 , Mark C Renton 3 , Timothy Connor 2 , Sheree D Martin 2 , Greg M Kowalski 4 , Christopher S Shaw 3 , Clinton R Bruce 3 , Kirsten F Howlett 3 , Sean L McGee 2
Affiliation  

Objective

Protein kinase D (PKD) signaling has been implicated in stress-induced cardiac remodeling and function as well as metabolic processes including contraction-mediated cardiac glucose uptake. PKD has recently emerged as a nutrient-sensing kinase that is activated in high-lipid environments, such as in obesity. However, the role of PKD signaling in cardiac glucose metabolism and cardiac function in both normal and obese conditions remains unknown.

Methods

A cardiac-specific and inducible dominant negative (DN) PKD mouse model was developed. Echocardiography was used to assess cardiac function, while metabolic phenotyping was performed, including stable isotope metabolomics on cardiac tissue in mice fed either regular chow or a high-fat diet (43% calories from fat).

Results

Cardiac PKD activity declined by ∼90% following DN PKD induction in adult mice. The mice had diminished basal cardiac glucose clearance, suggesting impaired contraction-mediated glucose uptake, but normal cardiac function. In obesity studies, systolic function indices were reduced in control mice, but not in cardiac DN PKD mice. Using targeted stable isotope metabolomic analyses, no differences in glucose flux through glycolysis or the TCA cycle were observed between groups.

Conclusions

The data show that PKD contributes to cardiac dysfunction in obesity and highlight the redundancy in cardiac glucose metabolism that maintains cardiac glucose flux in vivo. The data suggest that impairments in contraction-mediated glucose uptake are unlikely to drive cardiac dysfunction in both normal and metabolic disease states.



中文翻译:

蛋白激酶 D 活性的丧失表明心脏葡萄糖代谢存在冗余并保持肥胖患者的心脏功能

客观的

蛋白激酶 D (PKD) 信号传导与应激诱导的心脏重塑和功能以及代谢过程有关,包括收缩介导的心脏葡萄糖摄取。PKD 最近已成为一种营养感应激酶,在高脂环境(如肥胖)中被激活。然而,PKD 信号在正常和肥胖条件下的心脏葡萄糖代谢和心脏功能中的作用仍然未知。

方法

开发了心脏特异性和可诱导显性阴性 (DN) PKD 小鼠模型。超声心动图用于评估心脏功能,同时进行代谢表型分析,包括对常规食物或高脂肪饮食(来自脂肪的 43% 卡路里)喂养的小鼠心脏组织的稳定同位素代谢组学。

结果

在成年小鼠中诱导 DN PKD 后,心脏 PKD 活性下降了约 90%。小鼠的基础心脏葡萄糖清除率降低,表明收缩介导的葡萄糖摄取受损,但心脏功能正常。在肥胖研究中,对照小鼠的收缩功能指数降低,但心脏 DN PKD 小鼠没有。使用靶向稳定同位素代谢组学分析,未观察到组间通过糖酵解或 TCA 循环的葡萄糖通量存在差异。

结论

数据表明,PKD 导致肥胖患者的心脏功能障碍,并突出了维持体内心脏葡萄糖通量的心脏葡萄糖代谢的冗余数据表明,收缩介导的葡萄糖摄取受损不太可能导致正常和代谢疾病状态下的心脏功能障碍。

更新日期:2020-11-16
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