Zhe Zhang

The molecular clock exhibits distinct characteristics across various tissues and can be synchronized by particular stimuli. Furthermore, there is an intricate interplay among the molecular clocks within different tissues. In this context, we present an overview of the tissue‐specific molecular clock and discuss pivotal nonphotic regulators that govern the host's circadian rhythms and metabolic processes. Intermittent time‐restricted feeding establishes rhythmicity and harmony in hepatic proteasome activity through various pathways and modulates hormone levels and lifespan extension via the synergistic action of molecular clocks and autophagy (AMPK, mTOR, SIRT1). High‐fat diet (HFD) alters the molecular clock rhythms in the mediobasal hypothalamus (MBH), adipose tissue, and liver, with particularly pronounced changes observed in adipose tissue. HFD alters rhythm by inhibiting CLOCK:BMAL1 chromatin recruitment and activating the PPARγ pathway in the liver. The absence of liver CLOCK or intestinal BMAL1 mitigates metabolic disturbances, such as obesity, induced by long‐term HFD. Meanwhile, intestinal microbiota also directly or indirectly regulates the host's circadian network and metabolism through micromolecules. Correspondingly, deletion of molecular clock genes alters the diurnal variations, composition, and function of the gut microbiome at the genus level in mice. The mechanisms underlying the tissue‐specific effects of the gut microbiota on peripheral clocks are currently being unraveled and require further elucidation, with PPAR emerging as a pivotal factor in this process. The effect of exercise on the molecular clock of skeletal muscle varies depending on distinct muscle fiber types and the intensity of exercise. Identifying the optimal combination of chrono‐exercise and intermittent fasting represents a substantial research opportunity. Additionally, the interplay between the molecular clocks of various tissues in response to specific rhythmic cues merits thorough investigation.

Objective: Mitochondria‐associated membranes (MAMs) serve pivotal functions in hepatic insulin resistance (IR). Our aim was to explore the potential role of MAMs in mitigating hepatic IR through exercise and to compare the effects of different intensities of exercise on hepatic MAMs formation in high‐fat diet (HFD) mice.Methods: Male C57BL/6J mice were fed an HFD and randomly assigned to undergo supervised high‐intensity interval training (HIIT) or moderate‐intensity continuous training (MICT). IR was evaluated using the serum triglyceride/high‐density lipoprotein cholesterol ratio (TG/HDL‐C), glucose tolerance test (GTT), and insulin tolerance test (ITT). Hepatic steatosis was observed using hematoxylin–eosin (H&E) and oil red O staining. The phosphatidylinositol 3‐kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K‐AKT‐GSK3β) signaling pathway was assessed to determine hepatic IR. MAMs were evaluated through immunofluorescence (colocalization of voltage‐dependent anion‐selective channel 1 [VDAC1] and inositol 1,4,5‐triphosphate receptor [IP3R]).Results: After 8 weeks on an HFD, there was notable inhibition of the hepatic PI3K/Akt/GSK3β signaling pathway, accompanied by a marked reduction in hepatic IP3R‐VDAC1 colocalization levels. Both 8‐week HIIT and MICT significantly enhanced the hepatic PI3K/Akt/GSK3β signaling and colocalization levels of IP3R‐VDAC1 in HFD mice, with MICT exhibiting a stronger effect on hepatic MAMs formation. Furthermore, the colocalization of hepatic IP3R‐VDAC1 positively correlated with the expression levels of phosphorylation of protein kinase B (p‐AKT) and phosphorylation of glycogen synthase kinase 3 beta (p‐GSK3β), while displaying a negative correlation with serum triglyceride/high‐density lipoprotein cholesterol levels.Conclusion: The reduction in hepatic MAMs formation induced by HFD correlates with the development of hepatic IR. Both HIIT and MICT effectively bolster hepatic MAMs formation in HFD mice, with MICT demonstrating superior efficacy. Thus, MAMs might wield a pivotal role in exercise‐induced alleviation of hepatic IR. image

The communication between mitochondria and the endoplasmic reticulum (ER) is facilitated by a dynamic membrane structure formed by protein complexes known as mitochondria-associated membranes (MAMs). The structural and functional integrity of MAMs is crucial for insulin signal transduction, relying heavily on their regulation of intracellular calcium homeostasis, lipid homeostasis, mitochondrial quality control, and endoplasmic reticulum stress (ERS). This article reviews recent research findings, suggesting that exercise may promote the remodeling of MAMs structure and function by modulating the expression of molecules associated with their structure and function. This, in turn, restores cellular homeostasis and ultimately contributes to the amelioration of insulin resistance (IR). These insights provide additional possibilities for the study and treatment of insulin resistance-related metabolic disorders such as obesity, diabetes, fatty liver, and atherosclerosis.

Metabolic diseases are growing in prevalence worldwide. Although the pathogenesis of metabolic diseases remains ambiguous, the correlation between cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) and metabolic diseases has been identified recently. Exercise is an effective intervention protecting against metabolic diseases, however, the role of the cGAS-STING signaling pathway in this process is unclear, and the effect and mechanism of different exercise intensities on metabolic disorders are still unknown. Thus, we explored the association between exercise to ameliorate HFD-induced metabolic disorders and the cGAS-STING signaling pathway and compared the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Male C57BL/6 mice (6–8 weeks old) were fed HFD for 8 weeks to establish a metabolic disease model and were subjected to 8-week MICT or HIIT training. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were used to assess glucose metabolism. Serum triglyceride (TG) and total cholesterol (TC) were measured to evaluate lipid metabolism. Oil red staining was used to observe the lipid droplets in the gastrocnemius muscle. An enzyme-linked immunosorbent assay was used to detect the serum inflammatory factors IL-6 and IFN-β. The protein expression of the cGAS-STING signaling pathway was detected by the Wes^TM automatic protein expression analysis system. We reported that HFD induced metabolic disorders with obesity, abnormal glucolipid metabolism, and significant inflammatory responses. Both HIIT and MICT ameliorated the above adverse reactions, but MICT was superior to HIIT in improving glucolipid disorders. Additionally, HIIT significantly increased the expression of STING protein, as well as the phosphorylation of TBKI and the ratio of p-IRF3/IRF3. MICT only increased the expression of STING protein. Our findings suggest that HIIT may alleviate HFD-induced metabolic disorder phenotype through the cGAS-STING signaling pathway. However, the improvement of MICT on metabolic disorder phenotype is less associated with the cGAS-STING pathway, which needs to be further explored.

Heart diseases (HDs) are the leading cause of mortality worldwide, with mitochondrial dysfunction being a significant factor in their development. The recently discovered mitophagy receptor, FUNDC1, plays a critical role in regulating the homeostasis of the Mitochondrial Quality Control (MQC) system and contributing to HDs. The phosphorylation of specific regions of FUNDC1 and varying levels of its expression have been shown to have diverse effects on cardiac injury. This review presents a comprehensive consolidation and summary of the latest evidence regarding the role of FUNDC1 in the MQC system. The review elucidates the association of FUNDC1 with prevalent HDs, such as metabolic cardiomyopathy (MCM), cardiac remodeling/heart failure, and myocardial ischemia-reperfusion (IR) injury. The results indicate that the expression of FUNDC1 is elevated in MCM but reduced in instances of cardiac remodeling, heart failure, and myocardial IR injury, with divergent impacts on mitochondrial function among distinct HDs. Exercise has been identified as a powerful preventive and therapeutic approach for managing HDs. Additionally, it has been suggested that exercise-induced enhancement of cardiac function may be attributed to the AMPK/FUNDC1 pathway.

Although the benefits of aerobic exercise on obesity and type 2 diabetes are well-documented, the pathogenesis of type 2 diabetes and the intervention mechanism of exercise remain ambiguous. The correlation between mitochondrial quality and metabolic diseases has been identified. Disruption of the central or peripheral molecular clock can also induce chronic metabolic diseases. In addition, the interactive effects of the molecular clock and mitochondrial quality have attracted extensive attention in recent years. Exercise and a high-fat diet have been considered external factors that may change the molecular clock and metabolic state. Therefore, we utilized a DB/DB (BSK.Cg-Dock7m +/+ Leprdb/JNju) mouse model to explore the effect of chrono-aerobic exercise on the metabolic state of type 2 diabetic mice and the effect of timing exercise as an external rhythm cue on liver molecular clock-mitochondrial quality. We found that two differently timed exercises reduced the blood glucose and serum cholesterol levels in DB/DB mice, and compared with night exercise (8:00 p.m., the active period of mice), morning exercise (8:00 a.m., the sleeping period of mice) significantly improved the insulin sensitivity in DB/DB mice. In contrast, type 2 diabetes mellitus (T2DM) increased the expression of CLOCK and impaired the mitochondrial quality (mitochondrial networks, OPA1, Fis1, and mitophagy), as well as induced apoptosis. Both morning and night exercise ameliorated impaired mitochondrial quality and apoptosis induced by diabetes. However, compared with morning exercise, night exercise not only decreased the protein expression of CLOCK but also decreased excessive apoptosis. In addition, the expression of CLOCK was negatively correlated with the expression of OPA1 and Fis1. In summary, our research suggests that morning exercise is more beneficial for increasing insulin sensitivity and promoting glucose transport in T2DM, whereas night exercise may improve lipid infiltration and mitochondrial abnormalities through CLOCK–mitophagy–apoptosis in the liver, thereby downregulating glucose and lipid disorders. In addition, CLOCK-OPA1/Fis1–mitophagy might be novel targets for T2DM treatment.

Purpose: Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are associated with metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). Mitochondria and ER are connected via mitochondria-associated membranes (MAM) that are involved in glucose homeostasis and insulin resistance. We postulated that exercise might positively benefit T2DM-induced ER and mitochondrial dysfunction that might be associated with MAM. Materials and Methods: Mice were fed a high-fat diet and injected with streptozotocin (STZ) to create T2DM models. Glucose tolerance, mitochondrial quality, MAM quality, and ERS were investigated in diabetic mice after six weeks of swimming. Results: Type 2 DM induced decreased MAM quantity, impaired mitochondrial quality, and deteriorated ERS in skeletal muscle that led to endoplasmic reticulum-associated degradation (ERAD). Swimming alleviated strong ERS caused by T2DM. Importantly, MAM quantity was positively associated with mitochondrial function and tended to negatively correlate with the ERS branch, ATF6. Moreover, both ATF6 branches of ERS and ERAD were positively associated with the pIRE1α branch of ERS. Conclusion: Type 2 DM induced glucose intolerance, powerful ERS, and mitochondrial dysfunction associated with decreased amounts of MAM. Swimming improved glucose intolerance and selectively mitigated the ERS in skeletal muscle. Therefore, MAM quality and ATF6 might be novel and important targets for T2DM treatment. Endoplasmic reticulum stress might be an effective target of swimming to improve diabetes.

This study aimed to investigate the possible association between diabetes susceptibility gene transcription factor 7-like 2 (TCF7L2) and gestational diabetes mellitus (GDM) in a Chinese Han population. A total of 556 GDM patients and 500 Non-GDM were included. Eighteen single nucleotide polymorphisms (SNPs) were evaluated. Fifteen tag SNPs were selected from HapMap CHB database with a minor allele frequency of >0.2 and r²of >0.8. Three additional SNPs were also chosen because these SNPs are associated with type 2 diabetes in East Asians.TCF7L2rs290487, rs6585194, and rs7094463 polymorphisms were found to be significantly associated with GDM. In multivariate analysis, rs290487 genetic variation (OR = 2.686 per each C allele,P = 0.002), pre-BMI > 24 kg/m²(OR = 1.592,P = 0.018), age > 25 years (OR = 1.780,P = 0.012) and LDL-C > 3.6 mmol/L (OR = 2.034, P = 0.009) were identified as independent risk factors of GDM, rs7094463 genetic variation (OR = 0.429 per each G allele,P = 0.005) was identified as independent protect factor of GDM. This finding suggests thatTCF7L2rs290487, and rs7094463 were a potential clinical value for the prediction of GDM.