心肌自噬缺陷通过减少心钠素介导肥胖和代谢紊乱的研究

The heart “talks” to adipose tissue and may regulate obesity related metabolic disorders by secreting cardiokines. However, the underlying molecular mechanisms remain unclear. In the cardiac specific autophagy related protein 7 (Atg7) deficiency mice (AKO), we found reduced atrial natriuretic peptide (ANP) level in circulation and in ventricle and atrium of heart. Compared with control mice, AKO mice had increased subcutaneous and epididymal fat accumulation with similar food intake. Glucose and insulin tolerance tests showed that cardiac autophagy deficiency induced insulin resistance in mice after three weeks of Atg7 deletion. Thus, it is tempting to speculate that the decreased natriuretic peptides (natriuretic handicap) in the circulation are the major mediators of cardiac autophagy deficiency induced obesity and metabolic disorders. In the present study, we will verify our hypothesis and explore the molecular mechanisms of how cardiac autophagy deficiency downregulates natriuretic peptides in our experimental models (Control and AKO mice, primary cardiomyocytes and H9C2 cell line). Specifically, we will check mRNA translation efficiency of natriuretic peptides, the expression of natriuretic peptides receptors and Neprilysin in myocardia, adipocytes or other tissues. The present study will provide theoretical basis for clinical development of drug therapy for the prevention and treatment of metabolic syndromes.

心脏通过分泌心脏因子，与脂肪组织发生器官间“对话”，从而调控肥胖代谢紊乱。然而潜在分子机制仍不清楚。我们通过建立心肌特异性敲除自噬相关蛋白7的小鼠模型（AKO），发现与对照组小鼠相比，AKO小鼠发生明显心肌自噬缺陷，且心室、心房及血清中ANP的含量减少，在进食量不变的情况下皮下和附睾脂肪堆积，产生胰岛素抵抗。由此我们推测心肌自噬缺陷介导的利钠肽类缺乏是导致AKO小鼠产生肥胖和代谢紊乱的直接原因。在本项目中，我们拟通过AKO小鼠，心肌原代细胞，H9C2心肌细胞系，结合Atg7腺病毒转染，给予自噬阻断剂3-MA在整体及细胞水平上验证上述假说，并进一步研究心肌自噬缺陷导致利钠肽类缺乏的分子机制。探索AKO小鼠中利钠肽类产生障碍是否涉及mRNA翻译效率下降，或是在心肌、脂肪等组织中利钠肽清除型受体以及脑啡肽酶表达增加所致，将为临床开发防治代谢综合征的药物疗法提供理论依据。

心脏通过分泌心脏因子，与脂肪组织发生器官间“对话”，从而调控肥胖代谢紊乱。我们利用心肌细胞Atg7自噬缺失的小鼠模型发现心肌自噬缺陷介导的利钠肽类缺乏是导致.AKO小鼠产生肥胖和代谢紊乱的直接原因；在高脂喂食的小鼠模型中我们发现心肌细胞特异性敲除Atg7在mRNA水平下调ANP的表达。此外，我们对减重人群术前血液中的ANP水平进行测量，发现随着体重指数的增加，ANP水平显著下降，且在减重人群的内脏脂肪中随着BMI的升高，ANP清除型受体NPRC的mRNA水平显著升高，而在皮下脂肪中却显著降低。我们的研究结果提示在肥胖人群中ANP缺乏或障碍是心肌自噬水平降低以及内脏脂肪NPRC表达升高综合作用的呈现，而皮下脂肪中NPRC和NEP mRNA水平的显著降低，可以部分对抗内脏脂肪NPRC升高所产生的后果，这可能是其被认为是“好”脂肪另一证据。我们的研究结果对肥胖代谢紊乱的机制提供了更深入理解，也为寻找肥胖治疗策略提供了新思路。