Role and mechanism of FLT4 in high-fat diet-induced obesity in mice.

The FLT4 gene plays an important role in the onset and progression of obesity and is involved in the structure and function of lymphatic vessels. By inducing a mouse obesity model with a high-fat diet and knocking out the FLT4 gene, which is associated with lymphatic vessel growth in mice, FLT4+/- mice were found to be susceptible to high-fat diet-induced obesity, with significant accumulation of visceral fat. BODIPY™ FL C16 imaging revealed dilated and branched mesenteric lymphatic vessels in FLT4+/- mice. Immunofluorescence staining showed that FLT4+/- exacerbated the morphological abnormalities of lymphatic vessels and submucosal lymphatic vessels in visceral adipose tissue of obese mice, accompanied by macrophage infiltration around lymphatic vessels. In addition, FLT4 knock down increased the proportion of M1-type macrophages in the adipose tissue of the epididymis, indicating significant chronic inflammation in FLT4+/- obese mice. These findings provide new evidence for the involvement of lymphatic vessel morphological abnormalities in the onset and progression of obesity and highlight the importance of further investigation of FLT4 to better understand the mechanism of HFD-induced obesity and to develop related treatments.

Exercise training ameliorates myocardial phenotypes in heart failure with preserved ejection fraction by changing N6-methyladenosine modification in mice model.

Heart failure with preserved ejection fraction (HFpEF) shows complicated and not clearly defined etiology and pathogenesis. Although no pharmacotherapeutics have improved the survival rate in HFpEF, exercise training has become an efficient intervention to improve functional outcomes. Here, we investigated N6-methyladenosine (m6A) RNA methylation modification in a "two-hit" mouse model with HFpEF and HFpEF with exercise (HFpEF + EXT). The manner of m6A in HFpEF and HFpEF + EXT hearts was explored via m6A-specific methylated RNA immunoprecipitation followed by high-throughput and RNA sequencing methods. A total amount of 3992 novel m6A peaks were spotted in HFpEF + EXT, and 426 differently methylated sites, including 371 hypermethylated and 55 hypomethylated m6A sites, were singled out for further analysis (fold change >2, p < 0.05). According to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, unique m6A-modified transcripts in HFpEF + EXT were associated with apoptosis-related pathway and myocardial energy metabolism. HFpEF + EXT had higher total m6A levels and downregulated fat mass and obesity-related (FTO) protein levels. Overexpression of FTO cancels out the benefits of exercise in HFpEF + EXT mice by promoting myocyte apoptosis, myocardial fibrosis and myocyte hypertrophy. Totally, m6A is a significant alternation of epitranscriptomic processes, which is also a potentially meaningful therapeutic target.

Changes in N6-Methyladenosine Modification Modulate Diabetic Cardiomyopathy by Reducing Myocardial Fibrosis and Myocyte Hypertrophy.

In this study, we aimed to systematically profile global RNA N6-methyladenosine (m6A) modification patterns in a mouse model of diabetic cardiomyopathy (DCM). Patterns of m6A in DCM and normal hearts were analyzed via m6A-specific methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). m6A-related mRNAs were validated by quantitative real-time PCR analysis of input and m6A immunoprecipitated RNA samples from DCM and normal hearts. A total of 973 new m6A peaks were detected in DCM samples and 984 differentially methylated sites were selected for further study, including 295 hypermethylated and 689 hypomethylated m6A sites (fold change (FC) > 1.5, P < 0.05). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analyses indicated that unique m6A-modified transcripts in DCM were closely linked to cardiac fibrosis, myocardial hypertrophy, and myocardial energy metabolism. Total m6A levels were higher in DCM, while levels of the fat mass and obesity-associated (FTO) protein were downregulated. Overexpression of FTO in DCM model mice improved cardiac function by reducing myocardial fibrosis and myocyte hypertrophy. Overall, m6A modification patterns were altered in DCM, and modification of epitranscriptomic processes, such as m6A, is a potentially interesting therapeutic approach.