Intermittent fasting (IF) plays an essential role in improving lipid metabolism disorders caused by metabolic cardiomyopathy. Growing evidence revealed that N6-methyladenosine (m6A) RNA methylation is related to obesity and lipid metabolic. Our study aimed to assess the beneficial effects of IF on lipid deposition, apoptosis, and m6A methylation in high-fat diet (HFD)-induced obesity cardiomyopathy. Male C57BL/6J mice were fed a normal diet (ND) or HFD ad libitum for 13 weeks, after which time a subgroup of HFD mice were subjected to IF for 24 h and fed HFD in the other day for 8 weeks. We found that IF intervention significantly improved cardiac functional and structural impairment and serum lipid metabolic disorder induced by HFD. Furthermore, IF intervention decreased the mRNA levels of the fatty acid uptake genes of FABP1, FATP1, and CD36 and the fatty acid synthesis genes of SREBF1, FAS, and ACCα and increased the mRNA levels of the fatty acid catabolism genes of ATGL, HSL, LAL, and LPL in cardiac tissueof HFD-induced obese mice. TUNEL-positive cells, Bax/Bcl-2 ratio, and Cleaved Caspase-3 protein expression in HFD-induced obese mice hearts was down-regulated by IF intervention. In addition, IF intervention decreased the m6A methylation levels and METTL3 expression and increased FTO expression in HFD-induced obesity cardiomyopathy. In conclusion, our findings demonstrate that IF attenuated cardiac lipid deposition and apoptosis, as well as improved cardiac functional and structural impairment in HFD-induced obesity cardiomyopathy, by a mechanism associated with decreased m6A RNA methylation levels.

Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown. N6-methyladenosine (m6A) methylation, the most common and abundant epigenetic modification of eukaryotic mRNA, is regulated by m6A methyltransferase, demethylase, and the m6A binding protein, which affect the transcription, cleavage, translation, and degradation of target mRNA. m6A methylation plays a vital role in the physiological and pathological processes of CMDs. In this review, we summarize the role played by m6A methylation in CMDs, including obesity, hypertension, pulmonary hypertension, ischemic heart disease, myocardial hypertrophy, heart failure, and atherosclerosis. We also describe mechanisms that potentially involve the participation of m6A methylation, such as those driving calcium homeostasis, circadian rhythm, lipid metabolism, autophagy, macrophage response, and inflammation. m6A methylation and its regulators are expected to be targets for the treatment of CMDs.

Exercise is an effective way to improve reproductive function in obese males. Oxidative stress and apoptosis are important pathological factors of obesity-related male infertility. Accumulating studies have demonstrated that N6-methyladenosine (m6A) methylation is associated with obesity and testicular reproductive function. Our study aimed to investigate and compare the effect of 8 weeks of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on testicular oxidative stress, apoptosis and m6A methylation in obese male mice. Male C57BL/6 mice were randomly allocated into the four groups: normal diet (ND) group, high-fat diet (HFD) group, high-fat diet with moderate-intensity continuous training (HFD-MICT) group and high-fat diet with high-intensity interval training (HFD-HIIT) group. Mice in the HFD-MICT and HFD-HIIT groups were subjected to 8 weeks of MICT or HIIT treadmill protocols after 12 weeks of HFD feeding. We found that MICT and HIIT increased the protein expression of Nrf2, HO-1 and NQO-1 in the testes of obese mice, and HIIT increased it more than MICT. The Bax/Bcl-2 ratio, Cleaved Caspase-3 protein expression and TUNEL-positive cells were consistently up-regulated in the testes of obese mice, but MICT and HIIT restrained these HFD-induced effects. In addition, HFDs increased m6A levels and the gene expression of METTL3, YTHDF2 and FTO in the testes, but these effects were reversed by MICT and HIIT. However, HIIT was more effective than MICT in reducing m6A methylation in the testes of obese mice. These results demonstrate that both MICT and HIIT protected against HFD-induced oxidative stress, apoptosis and m6A methylation in testicular tissues; as a result, testicular morphological and functional impairment improved. In particular, HIIT was more beneficial than MICT in increasing the mRNA expression of steroidogenic enzymes and testicular antioxidant capacity and decreasing m6A methylation in the testes of HFD-fed mice.

Obesity-related kidney injury has become a critical health concern, driven by metabolic disturbances, chronic inflammation, oxidative stress, and structural remodeling. While exercise is widely recognized for its broad health benefits, including its ability to mitigate obesity-related complications by improving metabolic homeostasis, reducing inflammation, and enhancing antioxidative capacity, its specific role in protecting renal function - particularly through the modulation of microRNAs (miRNAs) - remains insufficiently understood. This study investigated the effects of an 8-week moderate-intensity treadmill exercise intervention on high-fat diet (HFD)-induced kidney injury in a murine model. Chronic HFD feeding resulted in significant renal dysfunction, evidenced by elevated filtration markers (urinary total protein, urinary microalbumin, urinary creatinine, and serum creatinine) and injury biomarkers (neutrophil gelatinase-associated lipocalin, cystatin C, and kidney injury molecule 1), alongside structural abnormalities, such as glomerular hypertrophy, mesangial expansion, and fibrosis. These changes were accompanied by increased pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), heightened oxidative stress (elevated malondialdehyde, reduced glutathione, glutathione s-transferase, and superoxide dismutase), and dysregulation of several miRNAs, such as miR-150-5p and miR-182-5p, which are known to exacerbate renal injury. Exercise significantly alleviated the adverse effects of HFD by improving renal function, reducing structural damage, suppressing inflammation, enhancing antioxidative capacity, and downregulating miR-150-5p and miR-182-5p. These findings underscore the therapeutic potential of exercise in mitigating obesity-related kidney injury and provide novel insights into its renoprotective effects mediated by miRNA regulation.

Skeletal muscle exhibits remarkable plasticity in response to diverse stimuli, with exercise serving as a potent trigger. Varied exercise modalities, including moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT), induce distinct structural and functional adaptations on skeletal muscle. However, the underlying molecular mechanisms governing these adaptations remain poorly understood. In this study, we utilized RNA-seq to characterize the transcriptomic profile of murine gastrocnemius muscle following 8-week treadmill-based MICT (M group) and HIIT (H group). A total of 1052 DEGs were screened in H vs. M. Among the top 10 significant DEGs, Foxo1 and Myod1 are closely related to muscular physiology. Through KEGG pathway analysis, distinct adaptations were primarily identified in the FoxO, MAPK, and PI3K-AKT pathways. By analyzing the expression of myokines, a significantly higher Igf-1 expression level was observed in the M group compared to the H group. Therefore, IGF-1, a well-known upstream regulator of both the PI3K-AKT-FoxO and MAPK pathways, might drive distinct muscle adaptations through variations in Igf-1 expression induced by these two exercise modalities.

Although physics exercise has been utilized to prevent and treat a variety of metabolic diseases, its role in obesity-related kidney diseases remains poorly understood. In this study, we assessed the protective potential of moderate intensity continuous training (MICT) against high fat diet (HFD)-induced kidney injury and found that MICT could significantly reduce obesity indexes (body weight, serum glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol) and kidney injury indexes (serum creatinine and the expression of Kim-1 mRNA) in HFD-fed mice. PAS staining and Masson staining displayed that MICT maintained the morphological structure of kidney subunits and reduced kidney fibrosis in HFD-fed mice. By kidney RNA-seq, we identified several genes and pathways (Cd9, Foxq1, Mier3, TGF-β signaling pathway etc.) that might underlie HFD-induced kidney injury and MICT-mediated protective effects. In conclusion, this study revealed the protective role of MICT in HFD-induced kidney injury and suggested potential targets for the prevention and treatment of obesity-related kidney diseases.