Effect of cardiomyocyte-specific lipid phosphate phosphatase 3 overexpression on high-fat diet-induced cardiometabolic dysfunction in mice

Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3^OE mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3^FL) and LPP3^OE mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 weeks, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3^OE mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared to LPP3^FL mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3^OE mice were protected from an increase in plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared to LPP3^FL mice. Female LPP3^OE mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy.