Abstract P3058: Cardiac-specific Deletion Of Ptp1b Induces A Global Metabolic And Lean Phenotype

Abstract

About 13% of US adults have diabetes, and more than half of them exhibitcardiac hypertrophy and fibrosis, resulting in cardiac diastolic dysfunction,systolic dysfunction and heart failure. Obesity is the leading risk factor for type2 diabetes. The Global Burden of Disease 2019 listed the high BMI as the fifthrisk of preterm deaths for females, and the sixth for males worldwide. Thecurrent treatments for these diseases are ineffective providing an urgent needof new therapeutic targets. Protein tyrosine phosphatase 1B (PTP1B) is themaster regulator of insulin signaling and its expression in brain, heart, liver andadipose tissues are elevated in obese mice and humans. It has been reportedthat neuronal deletion of PTP1B decreased food intake, increased energyexpenditure and protected mice from diet-induced obesity. However, whetherPTP1B in peripheral tissues would also contribute to diet-induced obesityremains unclear. To test if cardiac-PTP1B plays roles in the development ofobesity, we generated cardiomyocyte-specific PTP1B knockout mice (PTP1BCM-KO mice) and fed them with high-fat diets. Our preliminary datademonstrated that, compared to control mice, the PTP1B CM-KO mice hadreduced body weight and improved glucose homeostasis. Further analysisrevealed that deletion of PTP1B in cardiomyocytes increased energyexpenditure but didn’t affect the food intake. Metabolomics data suggested fattyacid oxidation is elevated in PTP1B CM-KO mice heart, whereas the glycolysispathway is suppressed, the amount of AMP (Adenosine Monophosphate) inPTP1B CM-KO mice is elevated 86 times than control mice on HFD. Thesefindings were further verified by qPCR analysis and ELISA. PTP1B knockoutupregulated not only NAD+ (nicotinamide adenine dinucleotide) but alsoNADPH in the heart. Nicotinamide phosphoribosyltransferase (Nampt) is therate-limiting enzyme of the NAD + salvage pathway and exists in an intracellular(iNampt) and an extracellular (eNampt) form. iNampt plays a regulatory role inNAD + biosynthesis and affects energy homeostasis. eNampt has been reportedto act as a cytokine and associated with obesity and diabetes. In the PTP1BCM-KO mice, we observed a higher level of both iNampt and eNampt,suggesting a mechanism through iNampt locally and/or through eNamptsystematically. Based on these observations, we hypothesize that the deficiency of PTP1B in cardiomyocytes increases energy expenditure,protects mice from diet-induced obesity and attenuates cardiacmalfunction induced by obesity, and cardiac-PTP1B governs whole bodyenergy homeostasis through Nampt and NAD + . We will test our hypothesisin the following specific Aims: Aim1: To elucidate the role of PTP1B in cardiac function and glucosehomeostasis.Aim2: To determine if and how the deletion of cardiac-PTP1B affectenergy balance and metabolic status through iNampt locally and/oreNampt systemically.