Sun Yan, Mishra Abhishek Kumar, Chanrasekhar Vasanth, Door Michaela, Kessinger Chase W, Xu Bing, Tang Peiyang, Gao Yunan, Kamli-Salino Sarah, Nelson Katherine, Delibegovic Mirela, Abel E Dale, Kirk Jonanthan A, Kontaridis Maria I
Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY 13501, USA.
Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Sci Signal. 2025 Jul 22;18(896):eadp6006. doi: 10.1126/scisignal.adp6006.
Cardiomyocytes (CMs) normally use fatty acid oxidation (FAO) as their primary energy source. In response to pathological stress, the substrate preference of CMs switches from FAO to glucose metabolism, leading to the development of heart failure. Obesity increases this pathological risk of cardiovascular disease. We focused on protein tyrosine phosphatase 1B (PTP1B), an inhibitor of insulin signaling, the abundance and activity of which are increased in brain, muscle, and adipose tissues in obese and/or diabetic animals and in obese human patients. We generated mice with CM-specific deficiency in PTP1B () to investigate the CM-specific role of PTP1B in response to cardiac dysfunction induced by high-fat diet (HFD) feeding. Although no physiological or functional cardiac differences were observed at baseline, mice were protected against development of cardiac hypertrophy, mitochondrial dysfunction, and cardiac steatosis induced by HFD feeding. Metabolomics data revealed that hearts with CM-specific deletion of PTP1B had increased FAO and lipolysis but reduced glucose metabolism. Furthermore, phosphoproteomics analyses and mechanistic studies identified an axis involving the kinases PKM2 and AMPK downstream of PTP1B in the heart, which collectively acted to promote FAO and suppress lipogenesis. Together, these results suggest that CM-specific deletion of PTP1B prevents a substrate switch from FAO to glucose metabolism, protecting the heart against the development of HFD-induced cardiac hypertrophy and dysfunction.
心肌细胞（CMs）通常将脂肪酸氧化（FAO）作为其主要能量来源。在病理应激反应中，心肌细胞的底物偏好从脂肪酸氧化转变为葡萄糖代谢，从而导致心力衰竭的发生。肥胖会增加这种心血管疾病的病理风险。我们关注蛋白酪氨酸磷酸酶1B（PTP1B），它是胰岛素信号传导的抑制剂，在肥胖和/或糖尿病动物以及肥胖人类患者的脑、肌肉和脂肪组织中，其丰度和活性均会增加。我们构建了心肌细胞特异性缺失PTP1B的小鼠（），以研究PTP1B在高脂饮食（HFD）喂养诱导的心脏功能障碍反应中的心肌细胞特异性作用。尽管在基线时未观察到生理或功能上的心脏差异，但PTP1B基因敲除小鼠可免受HFD喂养诱导的心脏肥大、线粒体功能障碍和心脏脂肪变性的影响。代谢组学数据显示，心肌细胞特异性缺失PTP1B的心脏脂肪酸氧化和脂肪分解增加，但葡萄糖代谢减少。此外，磷酸化蛋白质组学分析和机制研究确定了心脏中PTP1B下游涉及激酶丙酮酸激酶M2（PKM2）和腺苷酸活化蛋白激酶（AMPK）的轴，它们共同作用促进脂肪酸氧化并抑制脂肪生成。总之，这些结果表明，心肌细胞特异性缺失PTP1B可防止底物从脂肪酸氧化转变为葡萄糖代谢，保护心脏免受HFD诱导的心脏肥大和功能障碍的影响。
