| First Author | Hu T | Year | 2023 |
| Journal | Metabolism | Volume | 146 |
| Pages | 155658 | PubMed ID | 37433344 |
| Mgi Jnum | J:341052 | Mgi Id | MGI:7518027 |
| Doi | 10.1016/j.metabol.2023.155658 | Citation | Hu T, et al. (2023) PRDM16 exerts critical role in myocardial metabolism and energetics in type 2 diabetes induced cardiomyopathy. Metabolism 146:155658 |
| abstractText | BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) has increased over the past decades. Diabetic cardiomyopathy (DCM) is the leading cause of death in T2DM patients, however, the mechanism underlying DCM remains largely unknown. Here, we aimed to investigate the role of cardiac PR-domain containing 16 (PRDM16) in T2DM. METHODS: We modeled mice with cardiac-specific deletion of Prdm16 by crossing the floxed Prdm16 mouse model with the cardiomyocyte-specific Cre transgenic mouse. The mice were continuously fed a chow diet or high-fat diet combining with streptozotocin (STZ) for 24 weeks to establish a T2DM model. DB/DB and adequate control mice were given a single intravenous injection of adeno-associated virus 9 (AAV9) carrying cardiac troponin T (cTnT) promoter-driven small hairpin RNA targeting PRDM16 (AAV9-cTnT-shPRDM16) from the retro-orbital venous plexus to knockout Prdm16 in the myocardium. There were at least 12 mice in each group. Mitochondrial morphology and function were detected using transmission electron microscopy, western blot determining the protein level of mitochondrial respiratory chain complex, mitotracker staining and Seahorse XF Cell Mito Stress Test Kit. Untargeted metabolomics analysis and RNA-seq analysis were performed to determine the molecular and metabolic changes associated with Prdm16 deficiency. BODIPY and TUNEL staining were used to detect lipid uptake and apoptosis. Co-immunoprecipitation and ChIP assays were conducted to examine the potential underlying mechanism. RESULTS: Prdm16 cardiac-specific deficiency accelerated cardiomyopathy and worsened cardiac dysfunction in mice with T2DM, aggravating mitochondrial dysfunction and apoptosis both in vivo and in vitro, while PRDM16 overexpression the deterioration. Prdm16 deficiency also caused cardiac lipid accumulation resulting in metabolic and molecular alterations in T2DM mouse models. Co-IP and luciferase assays confirmed that PRDM16 targeted and regulated the transcriptional activity, expression and interaction of PPAR-alpha and PGC-1alpha, while the overexpression of PPAR-alpha and PGC-1alpha reversed Prdm16 deficiency-induced cellular dysfunction in T2DM model. Moreover, PRDM16 regulated PPAR-alpha and PGC-1alpha and affected mitochondrial function by mainly depending on epigenetic regulation of H3K4me3. CONCLUSIONS: These findings suggest that PRDM16 exerted its protective role in myocardial lipid metabolism and mitochondrial function in T2DM in a histone lysine methyltransferase activity-dependent manner by regulating PPAR-alpha and PGC-1alpha. |
