Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity. Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (Ab42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Ab42, which is increased from adipose tissue of obese mice and is associated with higher plasma Ab42. Increasing circulating Ab42 levels in mice had no effect on systemic glucose homeostasis but had obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. These effects on cardiac function were not observed when circulating Ab40 levels were increased. Administration of an Ab neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Ab neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that Ab42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to Ab42 inhibited mitochondrial function. These data reveal a role for systemic Ab42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer’s disease could be effective in combating obesity-induced heart failure. Overall design: This series consists of two components that were conducted separately. In part 1 of this study, C57BL6 mice were treated with Aβ42, an amyloid beta peptide of 42 amino acids, or a scrambled Aβ42 sequence at a dose of 1mg/day i.p. In the second part of the study, C57BL6 mice given Aβ42 were additionally treated with a Aβ42 neutralising antibody called 3D6 or a control antibody.

肥胖与2型糖尿病、心血管疾病及阿尔茨海默病（Alzheimer’s disease）之间存在明确的流行病学关联。尽管已知部分共通的致病机制，但淀粉样β蛋白42（amyloid beta 42, Ab42）在这些多种慢性病中的作用仍尚不明确。
本研究证实，脂肪组织可释放Ab42，且肥胖小鼠的脂肪组织中该蛋白的释放水平显著升高，并与血浆中更高浓度的Ab42呈正相关。提升小鼠循环系统中的Ab42水平，对全身葡萄糖稳态并无显著影响，但会对心脏产生类肥胖效应，包括心脏葡萄糖清除率降低以及心脏功能受损。当循环Ab40水平升高时，并未观察到上述对心脏功能的影响。
给予淀粉样β蛋白中和抗体，可有效预防肥胖诱导的心脏功能障碍与心肌肥大。此外，在已出现肥胖的小鼠中施用该中和抗体，可阻止心脏功能的进一步恶化。多对比度转录组学分析显示，Ab42会调控线粒体代谢通路，而心肌细胞暴露于Ab42会显著抑制线粒体功能。上述研究结果揭示了循环Ab42在肥胖相关心脏疾病发生发展中的关键作用，并提示针对阿尔茨海默病的治疗策略或许可有效对抗肥胖诱导的心力衰竭。
总体实验设计：本系列研究包含两个独立开展的子实验。在本研究第一部分中，对C57BL6小鼠以每日1mg的剂量腹腔注射（intraperitoneal, i.p.）Ab42（一种由42个氨基酸组成的淀粉样β肽）或乱序Ab42序列肽。在本研究第二部分中，对预先给予Ab42的C57BL6小鼠，额外施用名为3D6的Ab42中和抗体或对照抗体。