Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet

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 (PTP1B^fl/fl::ꭤMHC^Cre/+) 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, PTP1B^fl/fl::ꭤMHC^Cre/+ 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.