Cardiomyocyte-specific deletion of PTP1B protected mice against high fat diet-induced cardiac hypertrophy and dysfunction by promoting a substrate switch from glucose to fatty acid metabolism.
Does cardiomyocyte-specific deletion of PTP1B protect against high-fat diet-induced cardiomyopathy in mice?
Cardiomyocyte-specific deletion of PTP1B protects against high-fat diet-induced cardiomyopathy by shifting substrate utilization from glucose to fatty acid metabolism via a PTP1B/PKM2/AMPK axis.
Background Heart failure is the number one cause of death worldwide and mortality is directly correlated with the high incidence of obesity and diabetes. Indeed, the epidemic phenomenon of obesity was projected to reach 50% in the US by the year 2030. However, the mechanisms linking metabolic dysfunction with heart disease are not clear. Protein Tyrosine Phosphatase 1B (PTP1B), a negative regulator of insulin signaling, is considered to be an emerging therapeutic target against the development of obesity, insulin resistance, and diabetes. Increased PTP1B levels and activity have been observed in brain, muscle and adipose tissues isolated from obese and/or diabetic animals, as well as in human obese human patients. Its role, however, and the mechanisms by which it modulates metabolic processes in the heart remain unknown. Method and Results We generated cardiomyocyte (CM)-specific PTP1B knock-out (PTP1B fl/fl ::ꭤMHC Cre/+ ) mice to investigate the cardiomyocyte-specific role of PTP1B in response to high fat diet (HFD)-induced cardiac dysfunction. While we did not observe any physiological or functional cardiac differences at baseline, in response to HFD, we found that PTP1B fl/fl ::ꭤMHC Cre/+ mice were protected against development of cardiac hypertrophy, mitochondrial dysfunction, and diminished cardiac steatosis. Metabolomics data revealed that hearts with CM-specific deletion of PTP1B had increased fatty acid oxidation and NAD + metabolism, but reduced glucose metabolism; we further validated these findings by real-time qPCR analysis. Mechanistically, we identified a novel PTP1B PKM2-AMPK axis in the heart, which acts as a molecular switch to promote fatty acid oxidation. In this regard, we identified that hearts from PTP1B fl/fl ::ꭤMHC Cre/+ mice had upregulated levels of nicotinamide adenine dinucleotide (NAD + ) and NAD phosphate (NADPH), leading to higher levels of nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting step of the NAD + salvage pathway and an enzyme associated with obesity and diabetes. Conclusions Together, these results suggest that CM-specific deletion of PTP1B mediates a substrate switch from glucose to fatty acid metabolism, protecting hearts against development of HFD-induced cardiac hypertrophy and dysfunction through mechanisms involving a novel PTP1B/PKM2/AMPK axis that is critical for the regulation of NAMPT and NAD + biosynthesis.
Sun et al. (Sun,) conducted a other in High fat diet (HFD)-induced cardiac dysfunction. Cardiomyocyte-specific PTP1B deletion was evaluated on Cardiac hypertrophy, mitochondrial dysfunction, and cardiac steatosis in response to high fat diet. Cardiomyocyte-specific deletion of PTP1B protected mice against high fat diet-induced cardiac hypertrophy and dysfunction by promoting a substrate switch from glucose to fatty acid metabolism.