Adipose tissue browning and thermogenesis under physiologically energetic challenges: a remodelled thermogenic system.

Metabolic diseases such as obesity and diabetes are often thought to be caused by reduced energy expenditure, which poses a serious threat to human health. Cold exposure, exercise and caloric restriction have been shown to promote adipose tissue browning and thermogenesis. These physiological interventions increase energy expenditure and thus have emerged as promising strategies for mitigating metabolic disorders. However, that increased adipose tissue browning and thermogenesis elevate thermogenic consumption is not a reasonable explanation when humans and animals confront energetic challenges imposed by these interventions. In this review, we collected numerous results on adipose tissue browning and whitening and evaluated this bi-directional conversion of adipocytes from the perspective of energy homeostasis. Here, we propose a new interpretation of the role of adipose tissue browning under energetic challenges: increased adipose tissue browning and thermogenesis under energy challenge is not to enhance energy expenditure, but to reestablish a more economical thermogenic pattern to maintain the core body temperature. This can be achieved by enhancing the contribution of non-shivering thermogenesis (adipose tissue browning and thermogenesis) and lowering shivering thermogenesis and high intensity shivering. Consequently, the proportion of heat production in fat increases and that in skeletal muscle decreases, enabling skeletal muscle to devote more energy reserves to overcoming environmental stress.

Unveiling the potential of estrogen: Exploring its role in neuropsychiatric disorders and exercise intervention.

Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which may be involved in depression, Alzheimer's disease (AD) and Parkinson's disease (PD), and other neuropsychiatric disorders as well in their sex differences. In nervous system, estrogen is an important regulator of cell development, synaptic development, and brain connectivity. Therefore, this review aimed to investigate the potential of estrogen system in the exercise intervention of neuropsychiatric disorders to better understand the exercise in neuropsychiatric disorders and its sex specific. Exercise can exert a protective effect in neuropsychiatric disorders through regulating the expression of estrogen and estrogen receptors, which are involved in neuroprotection, neurodevelopment, and neuronal glucose homeostasis. These processes are mediated by the downstream factors of estrogen signaling, including N-myc downstream regulatory gene 2 (Ndrg2), serotonin (5-HT), delta like canonical Notch ligand 1 (DLL1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), etc. In addition, exercise can act on the estrogen response element (ERE) fragment in the genes of estrogenic downstream factors like ß-amyloid precursor protein cleavase 1 (BACE1). However, there are few studies on the relationship between exercise, the estrogen signaling pathway, and neuropsychiatric disorders. Hence, we review how the estrogen signaling mediates the mechanism of exercise intervention in neuropsychiatric disorders. We aim to provide a theoretical perspective for neuropsychiatric disorders affecting female health and provide theoretical support for the design of exercise prescriptions.

Codon-optimized FAM132b gene therapy prevents dietary obesity by blockading adrenergic response and insulin action.

BACKGROUND: FAM132b (myonectin) has been identified as a muscle-derived myokine with exercise and has hormone activity in circulation to regulate iron homeostasis and lipid metabolism via unknown receptors. Here, we aim to explore the potential of adeno-associated virus to deliver FAM132b in vivo to develop a gene therapy against obesity. METHODS: Adeno-associated virus AAV9 were engineered to induce overexpression of FAM132b with two mutations, A136T and P159A. Then, AAV9 was delivered into high-fat diet mice through tail vein, and glucose homeostasis and obesity development of mice were observed. Methods of structural biology were used to predict the action site or receptor of the FAM132b mutant. RESULTS: Treatment of high-fat diet-fed mice with AAV9 improved glucose intolerance and insulin resistance, and resulted in reductions in body weight, fat depot, and adipocyte size. Codon-optimized FAM132b (coFAM132b) reduced the glycemic response to epinephrine (EPI) in the whole body and increased the lipolytic response to EPI in adipose tissues. However, FAM132b knockdown by shRNA significantly increased the glycemic response to EPI in vivo and reduced adipocyte response to EPI and adipose tissue browning. Structural analysis predicted that the FAM132b mutant with A136T and P159A may form a weak bond with ß2 adrenergic receptor (ADRB2) and may have more affinity for insulin and insulin-receptor complexes. CONCLUSIONS: Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating the adrenergic response and insulin action. Both structural biological analysis and in vivo experiments suggest that the adrenergic response and insulin action are most likely blockaded by FAM132b mutants.

Exercise-Induced Adipose Tissue Thermogenesis and Browning: How to Explain the Conflicting Findings?

Brown adipose tissue (BAT) has been widely studied in targeting against metabolic diseases such as obesity, type 2 diabetes and insulin resistance due to its role in nutrient metabolism and energy regulation. Whether exercise promotes adipose tissue thermogenesis and browning remains controversial. The results from human and rodent studies contradict each other. In our opinion, fat thermogenesis or browning promoted by exercise should not be a biomarker of health benefits, but an adaptation under the stress between body temperature regulation and energy supply and expenditure of multiple organs. In this review, we discuss some factors that may contribute to conflicting experimental results, such as different thermoneutral zones, gender, training experience and the heterogeneity of fat depots. In addition, we explain that a redox state in cells potentially causes thermogenesis heterogeneity and different oxidation states of UCP1, which has led to the discrepancies noted in previous studies. We describe a network by which exercise orchestrates the browning and thermogenesis of adipose tissue with total energy expenditure through multiple organs (muscle, brain, liver and adipose tissue) and multiple pathways (nerve, endocrine and metabolic products), providing a possible interpretation for the conflicting findings.

The Role of Fgf9 in the Antidepressant Effects of Exercise and Fluoxetine in Chronic Unpredictable Mild Stress Mice.

OBJECTIVE: The neurotrophic hypothesis of depression posits that stress and depression decrease neurotrophic factor expression in brain, whereas antidepressants and exercise can contribute to the blockade of stress effects and produce antidepressant effects. Fibroblast growth factor 9 (FGF9), a member of the fibroblast growth factor (FGF) family, has been reported to be dysregulated in depression. The present study aimed to determine whether and how Fgf9 mediates the antidepressant effects of fluoxetine and exercise in chronic unpredictable mild stress (CUMS) mice. METHODS: Male C57BL/6 mice were exposed to CUMS for 7 weeks. From the fourth week, CUMS-exposed mice were subjected to fluoxetine treatment or swimming exercise for 4 weeks. Forced swim test, tail suspension test, and hole-board test were used to assess behaviors of mice. Real-time polymerase chain reaction was used to examine hippocampal messenger RNA levels of Fgf9, Fgf2, FgfR1, FgfR2, and FgfR3. Western blotting was used to examine the protein levels of Fgf9, protein kinase B (Akt), and phosphorylation of Akt at Ser473 in mouse hippocampus. RESULTS: Our results demonstrated that CUMS induced depression-like behaviors, which were reversed by fluoxetine treatment and swimming exercise. Moreover, we found that CUMS resulted in a dysregulation of Fgf9, Fgf2, and FgfR2 expression, whereas fluoxetine and swimming restored the FGF expression in CUMS-exposed mice. An analysis of the proteins suggests that the antidepressant effects of fluoxetine and exercise in CUMS-exposed mice were associated with ameliorated Fgf9/Akt signaling. CONCLUSIONS: Our findings have demonstrated that swimming exercise mimics the antidepressant effects of fluoxetine by regulating Fgf9 in CUMS-exposed mice, which may offer new mechanism-based therapeutic targets for depression.

Moderate endurance training reduced hepatic tumourigenesis associated with lower lactate overload compared to high-intensity interval training.

The anti-tumour effects of exercise are still poorly understood. In recent years, high-intensity interval exercise has been recognised as one of the best choices for better health. However, high-intensity interval exercise induces lactate production in muscles and elevates blood lactic acid levels, and the resulting acidic microenvironment may promote tumour progression. Therefore, it is important to compare the anti-tumour effects of different types of exercise. OBJECTIVE: In this study, we aimed to compare the anti-tumour effects of moderate endurance training and high-intensity interval training on diethylnitrosamine (DEN)-induced liver tumours and to explore the underlying mechanisms. METHODS: Three-week-old male C57BL/6 mice were injected intraperitoneally with DEN for 10 weeks to induce hepatocellular carcinoma. DEN-treated mice were grouped and subjected to moderate endurance training (MET) or high-intensity interval training (HIIT) for 18 weeks. We performed real-time PCR to evaluate the mRNA expressions of key enzymes involved in lactate metabolism pathway and western blotting to examine the protein expressions of LDHA, AMPK/P-AMPK, PCK1, and G6Pase in the paracancerous liver tissue. We performed high-performance liquid mass spectrometry (HPLC) to detect lactate in liver. RESULTS: Our results revealed that compared with HIIT, MET decreased hepatic tumour incidence, as HIIT increased blood lactate concentration at rest. Moreover, MET reduced the transcript-level expression of LDH subunit and significantly increased the mRNA levels of COX1 and ND1 in liver. However, no significant changes were observed in liver lactate levels and the expression of LDHA among the groups. In addition, no significant differences in the mRNA levels of critical enzymes involved in the gluconeogenesis pathway in liver were observed among the groups. Additionally, no significant differences were observed in the mRNA levels of MPC2, pdha2, and pdk4 among the groups. CONCLUSIONS: Our findings suggest that MET may be more efficient than HIIT at reducing hepatic tumourigenesis, and that it is associated with improved mitochondrial function in liver and lower lactate load in the circulation at rest.

Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways.

Nonalcoholic fatty liver disease (NAFLD) is globally prevalent and characterized by abnormal lipid accumulation in the liver, frequently accompanied by insulin resistance (IR), enhanced hepatic inflammation, and apoptosis. Recent studies showed that endoplasmic reticulum stress (ERS) at the subcellular level underlies these featured pathologies in the development of NAFLD. As an effective treatment, exercise significantly reduces hepatic lipid accumulation and thus alleviates NAFLD. Confusingly, these benefits of exercise are associated with increased or decreased ERS in the liver. Further, the interaction between diet, medication, exercise types, and intensity in ERS regulation is more confusing, though most studies have confirmed the benefits of exercise. In this review, we focus on understanding the role of exercise-modulated ERS in NAFLD and ERS-linked molecular pathways. Moderate ERS is an essential signaling for hepatic lipid homeostasis. Higher ERS may lead to increased inflammation and apoptosis in the liver, while lower ERS may lead to the accumulation of misfolded proteins. Therefore, exercise acts like an igniter or extinguisher to keep ERS at an appropriate level by turning it up or down, which depends on diet, medications, exercise intensity, etc. Exercise not only enhances hepatic tolerance to ERS but also prevents the malignant development of steatosis due to excessive ERS.

Leptin receptor knockout-induced depression-like behaviors and attenuated antidepressant effects of exercise are associated with STAT3/SOCS3 signaling.

Relatively little has been known about pathophysiological mechanisms contributing to the development of neuropsychiatric symptoms in the context of metabolic syndrome. Impaired leptin signaling activation in db/db mice has been proposed as a potential link between behavioral and metabolic disorders. Our previous studies have shown that exercise has the beneficial effects on a depression-like and insulin-resistant state in mice. The present study aimed to determine whether and how leptin receptor knockout (db/db) induces depression-like behaviors, and to identify the antidepressant effects of swimming exercise in db/db mice. Our results support the validity of db/db mice as an animal model to study depression with metabolic abnormalities, but fail to confirm the improvement of exercise on depression. LepRb knockout-induced depression-like behaviors are associated with STAT3/SOCS3 signaling but independent of IKKß/NFκB signaling. Our findings suggest the potential importance of LepRb as an exercise-regulated target for depression, also representing a new target underlying treatment-resistant depression.

Acute exercise stress promotes Ref1/Nrf2 signalling and increases mitochondrial antioxidant activity in skeletal muscle.

NEW FINDINGS: What is the central question of this study? How does acute exercise affect the redox effector factor-1 (Ref1) and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling and its association with mitochondrial H(2)O(2) production and antioxidant capacity? What is the main finding and its importance? Ref1/Nrf2 signalling in skeletal muscles was activated by acute exercise, and this activation was correlated with increased mitochondrial H(2)O(2) content and antioxidant capacity (reduced glutathione and manganese superoxide dismutase). The finding indicates that the oxidative stress induced by acute exercise in skeletal muscle mitochondria is associated with the upregulation of Ref1/Nrf2 signalling and enhancement of antioxidant defense pathways. This mechanism may play a role in preventing cellular oxidative stress resistance during acute exercise. The molecular mechanism of exercise-induced oxidative stress and adaptive activation of antioxidant responses in skeletal muscle has not been fully elucidated. This study aimed to investigate the effect of acute exercise on redox effector factor-1 (Ref1) and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling and associations with mitochondrial H(2)O(2) production and antioxidant mechanisms in skeletal muscles. Groups of male ICR/CD-1 mice were subjected to an acute exercise bout of different durations (45, 90, 120 or 150 min). Muscle tissues (gastrocnemius and quadriceps femoris) were harvested after exercise to measure mitochondrial manganese superoxide dismutase (MnSOD) and copper-zinc superoxide dismutase (CuZnSOD) activities, reduced glutathione (GSH) content and expression of Ref1/Nrf2 genes and Ref1/Nrf2 proteins. The acute exercise increased oxidative stress and activated Ref1/Nrf2 signalling in a time-dependent manner, with a linear correlation between the mitochondrial H(2)O(2) content and Ref1/Nrf2 expressions. The GSH content and MnSOD activity were also significantly increased, but CuZnSOD activity was not significantly affected. The findings indicate that the H(2)O(2) production induced by acute exercise in skeletal muscle mitochondria in the mouse is closely associated with upregulation of the Ref1/Nrf2 signalling pathway and enhancement of antioxidant defense components, including GSH and MnSOD. Activation of Ref1/Nrf2/antioxidant defense pathways may play a role in preventing cellular oxidative stress resistance during acute exercise.

PC 18:1/18:1 mediates the anti-inflammatory effects of exercise and remodels tumor microenvironment of hepatocellular carcinoma.

AIM: Phosphatidylcholine (PC) is essential for membrane structural integrity and lipid-dependent signaling pathways, and is an essential component required for cancer cell growth. Using hepatocellular carcinoma (HCC) as a tumor model, this study aims to further screen phospholipid biomarkers of the tumor microenvironment and explore the anti-tumor effects and mechanisms of aerobic exercise. MAIN METHODS: The HCC of C57BL/6J mice was induced by the injection of the carcinogen diethylnitrosamine (DEN). Exercise was performed on an ungraded treadmill for weeks. The inflammation-related markers were detected by ELISA, PCR and immunohistochemistry, hepatic metabolic profile was analyzed by GC/MS, and lipid metabolism profile was further detected by lipid-targeted LC/MS. Cell culture was used to verify the anti-inflammatory effect of PC. KEY FINDINGS: Exercise reduced hepatic inflammation, tumor incidence and volume. Metabolomics analysis showed that palmitic acid is a key metabolic marker for exercise to improve tumor microenvironment. Injection of exogenous palmitic acid following exercise impaired the anti-inflammatory and anti-tumor effects of exercise. Lipid metabolomics analysis further showed that metabolites for exercise were enriched in glycerol phospholipid metabolism, including 14 phosphatidylcholines (PCs), 18 phosphatidylethanolamines (PEs), and 6 triglycerides (TGs). These biomarkers contain different lengths of fatty acid chains and different numbers of unsaturated bonds, respectively. Cell culture verified that PC (18:1/18:1) mediated lipopolysaccharide (LPS)-induced inflammation in HepG2 cell. SIGNIFICANCE: Our results suggest that exercise remodels glycerophospholipid metabolism and reduces hepatic palmitic acid loading and PC (18:1/18:1) level, thereby reconstructing a microenvironment that is hostile to HCC.

Sugar-sweetened beverage consumption retarded weight gain but not induced depression and anxiety-like behaviors in mice.

AIMS: To assess the effects of sugar-sweetened beverage (SSB) consumption and exercise on behaviors. METHODS: Twenty-four male mice were divided into four groups: the water + sedentary (WS), the SSB + sedentary (CS), the water + exercise (WE), and the SSB + exercise (CE). After three-month of interventions, forced swim test (FST), open field test (OFT), and morris water maze (MWM) were conducted. Then, mRNA levels of MAO-A, COMT, and 5-HT1A and protein levels of synapsin, STAT3, A2AR, CRTC1, CREB, and BDNF were measured. RESULTS: Under a similar baseline body weight condition, SSB consumption reduced the weight gain from the 3rd week (p < 0.05, or p < 0.01). Exercise decreased the escape latency in the CE group when compared to the CS group on day5 (p < 0.01) and increased the time in the target quadrant in the WE group than the WS group on day4 (p < 0.05) and 5 (p < 0.01) during MWM. No significant differences were found during the FST and OFT. COMT mRNA level was increased after SSB consumption (p < 0.05), but no differences were found in the MAO-A and 5-HT1A mRNA levels and the concerned biomarkers, all of which were previously reported to be associated with depression and anxiety-like behaviors. CONCLUSION: SSB consumption reduced weight gain but not result in depression and anxiety-like behaviors in mice. Therefore, the behavioral effects of exercise were not significant. This is not consistent with the results of previous epidemiological surveys of humans.

ASMT determines gut microbiota and increases neurobehavioral adaptability to exercise in female mice.

N-acetylserotonin O-methyltransferase (ASMT) is responsible for melatonin biosynthesis. The Asmt gene is located on the X chromosome, and its genetic polymorphism is associated with depression in humans. However, the underlying mechanism remains unclear. Here, we use CRISPR/Cas9 to delete 20 bp of exon 2 of Asmt, and construct C57BL/6J mouse strain with Asmt frameshift mutation (Asmtft/ft). We show that female Asmtft/ft mice exhibit anxiety- and depression-like behaviors, accompanied by an obvious structural remodeling of gut microbiota. These behavioral abnormalities are not observed in male. Moreover, female Asmtft/ft mice show a lower neurobehavioral adaptability to exercise, while wild-type shows a "higher resilience". Cross-sectional and longitudinal analysis indicates that the structure of gut microbiota in Asmtft/ft mice is less affected by exercise. These results suggests that Asmt maintains the plasticity of gut microbiota in female, thereby enhancing the neurobehavioral adaptability to exercise.

Mild stress of caffeine increased mtDNA content in skeletal muscle cells: the interplay between Ca2+ transients and nitric oxide.

Caffeine increases mitochondrial biogenesis in myotubes by evoking Ca(2+) transients. Nitric oxide (NO) also induces mitochondrial biogenesis in skeletal muscle cells via upregulation of AMP-activated protein kinase (AMPK) activity and PGC-1α. However, the interplay and timing sequence between Ca(2+) transients and NO releases remain unclear. Herein, we tested the hypothesis that caffeine-evoked Ca(2+) transients triggered NO production to increase mtDNA in skeletal muscle cells. Ca(2+) transients were recorded with Fura-2 AM and confocal microscopy; mtDNA staining, mitochondrial membrane potential and NO level were determined using fluorescent probes PicoGreen, tetramethylrhodamine methyl ester (TMRM) and DAF-FM, respectively. In primary cultured myotubes, a subtle and moderate stress of caffeine increased mtDNA exclusively. Mitochondrial membrane potential and mtDNA were increased by 1 mM as well as 5 mM caffeine, whereas 10 mM caffeine did not change the fluorescence intensity of PicoGreen and TMRM. NO level in myocytes increased gradually following the first jump of Ca(2+) transients evoked by caffeine (5 mM) till the end of recording, when Fura-2 indicated that Ca(2+) transients recovered partly and even disappeared. Importantly, nitric oxide synthase (NOS) inhibitor (L-NAME) suppressed caffeine-induced mtDNA biogenesis, whereas NO donor (DETA-NO) increased mtDNA content. These data strongly suggest that caffeine-induced mtDNA biogenesis is dose-sensitive and dependent on a certain level of stress. Further, an increasing level of NO following Ca(2+) transients is required for caffeine-induced mtDNA biogenesis. Additionally, Ca(2+) transients, a usual and first response to caffeine, was either suppressed or attenuated by L-NAME, DETA-NO, AICAR and U0126, suggesting an inability to control [Ca(2+)](i) in these treated cells. There may be an important interplay between NO and Ca(2+) transients in intracellular signaling system involving NOS, AMPK and MEK.

Increased insulin sensitivity and distorted mitochondrial adaptations during muscle unloading.

We aimed to further investigate mitochondrial adaptations to muscle disuse and the consequent metabolic disorders. Male rats were submitted to hindlimb unloading (HU) for three weeks. Interestingly, HU increased insulin sensitivity index (ISI) and decreased blood level of triglyceride and insulin. In skeletal muscle, HU decreased expression of pyruvate dehydrogenase kinase 4 (PDK4) and its protein level in mitochondria. HU decreased mtDNA content and mitochondrial biogenesis biomarkers. Dynamin-related protein (Drp1) in mitochondria and Mfn2 mRNA level were decreased significantly by HU. Our findings provide more extensive insight into mitochondrial adaptations to muscle disuse, involving the shift of fuel utilization towards glucose, the decreased mitochondrial biogenesis and the distorted mitochondrial dynamics.

Compared with High-intensity Interval Exercise, Moderate Intensity Constant Load Exercise is more effective in curbing the Growth and Metastasis of Lung Cancer.

The morbidity and mortality of lung cancer are among the forefront of various cancers, and it is one of the major cancers that seriously threaten human life and health. It is well known that the abundant angiogenesis and lymphangiogenesis in tumor tissues play an important role in tumor growth and metastasis. In addition, The epithelial-mesenchymal transition (EMT), which facilitates the tumor cell metastasis and invasion, is triggered by many stimuli, such as matrix metalloproteinases 2 (MMP2), MMP9, and transforming growth factor-ß1 (TGF-ß1). At present, various studies have confirmed that both moderate intensity constant load exercise (MICE) and high-intensity interval exercise (HIIE) have a positive therapeutic effect on the treatment of lung cancer, delaying the progression of lung cancer. However, little is currently known regarding whether its specific treatment mechanism is related to blood vessels, lymphatic vessels, and EMT. Indeed, we found an increase in angiogenesis and lymphangiogenesis in lung cancer tissues. However, compared to high-intensity interval exercise, moderate intensity constant load exercise can significantly reduce tumor growth in the lung independent of blood vessels and lymphatic vessels. It is worth noting that moderate intensity constant load exercise can also reduce the level of MMP9 in lung cancer tissues, which may control tumor metastasis to a certain extent. In addition, high-intensity interval exercise reduces the expression of MMP2, but it tends to enhance EMT and activate TGF-ß1. Taken together, our findings suggest that, whether it is tumor growth or metastasis, moderate intensity constant load exercise has a better therapeutic effect on lung cancer than high-intensity interval exercise.

Exercise modulates polarization of TAMs and expression of related immune checkpoints in mice with lung cancer.

Purpose: Many studies have found that both endurance exercise (EX) and high-intensity interval training (HIIT) have a positive therapeutic effect on the treatment of lung cancer patients, but the specific mechanism is unclear. Therefore, we investigated whether EX and HIIT could delay the progression of lung cancer by affecting the infiltration of tumor-associated macrophages (TAMs) and restoring the tumor phagocytic activity of TAMs in lung cancer tissue. Methods: BALB/c mice were divided into 4 groups. The mice were given saline as the saline group (Saline), and the mice were given urethane as the lung cancer mice. The lung cancer mice were randomly divided into the control group (CON), EX group, and HIIT group. After exercise, the cancer tissues were collected for RT-PCR, immunofluorescence staining, and Wes automated western blotting system analysis. Results: Compared with the Saline group, the mRNA levels of TAMs M1 markers IL-6, TNF-α, iNOS, and M2 markers CD206, IL-10, and Arg-1 in the CON group were significantly increased (P<0.05). There was no significant difference in the percentage of F4/80 positive cells among the groups. Compared with the CON group, the percentage of CD86-positive cells in TAMs in the EX group was significantly decreased (P<0.05). From the protein expression level, compared with the CON group, the expression of SIRPα in the EX group was significantly increased (P<0.0001) and the expression of PD-L1 had a tendency to increase (P=0.06). Compared with the CON group, the expressions of IL-10, IL-12, CD47, and CD24 in the HIIT group were significantly increased (P<0.05). In addition, compared with the CON group, plasma IFN-γ in the EX group and HIIT group was significantly increased (P<0.05). Conclusion: Lung cancer tissue presents an inflammatory tumor microenvironment. The therapeutic effect of exercise on lung cancer is independent of the infiltration of TAMs in lung cancer tissue. In addition, endurance exercise can reduce the proportion of M1-type TAMs in lung cancer tissues, while HIIT antagonistically regulates M1 and M2 polarization of TAMs by increasing the levels of IL-10 and IL-12 in lung cancer tissues and circulating IFN-γ. Finally, endurance exercise and HIIT can modulate the expression of some immune checkpoints in lung cancer tissues.

Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases.

Mitochondria play a pivotal role in energy generation and cellular physiological processes. These organelles are highly dynamic, constantly changing their morphology, cellular location, and distribution in response to cellular stress. In recent years, the phenomenon of mitochondrial transfer has attracted significant attention and interest from biologists and medical investigators. Intercellular mitochondrial transfer occurs in different ways, including tunnelling nanotubes (TNTs), extracellular vesicles (EVs), and gap junction channels (GJCs). According to research on intercellular mitochondrial transfer in physiological and pathological environments, mitochondrial transfer hold great potential for maintaining body homeostasis and regulating pathological processes. Multiple research groups have developed artificial mitochondrial transfer/transplantation (AMT/T) methods that transfer healthy mitochondria into damaged cells and recover cellular function. This paper reviews intercellular spontaneous mitochondrial transfer modes, mechanisms, and the latest methods of AMT/T. Furthermore, potential application value and mechanism of AMT/T in disease treatment are also discussed.

Gene expression profile associated with Asmt knockout-induced depression-like behaviors and exercise effects in mouse hypothalamus.

Sleep disorder caused by abnormal circadian rhythm is one of the main symptoms and risk factors of depression. As a known hormone regulating circadian rhythms, melatonin (MT) is also namely N-acetyl-5-methoxytryptamine. N-acetylserotonin methyltransferase (Asmt) is the key rate-limiting enzyme of MT synthesis and has been reportedly associated with depression. Although 50-90% of patients with depression have sleep disorders, there are no effective treatment ways in the clinic. Exercise can regulate circadian rhythm and play an important role in depression treatment. In the present study, we showed that Asmt knockout induced depression-like behaviors, which were ameliorated by swimming exercise. Moreover, swimming exercise increased serum levels of MT and 5-hydroxytryptamine (5-HT) in Asmt knockout mice. In addition, the microarray data identified 10 differentially expressed genes (DEGs) in KO mice compared with WT mice and 29 DEGs in KO mice after swimming exercise. Among the DEGs, the direction and magnitude of change in epidermal growth factor receptor pathway substrate 8-like 1 (Eps8l1) and phospholipase C-ß 2 (Plcb2) were confirmed by qRT-PCR partly. Subsequent bioinformatic analysis showed that these DEGs were enriched significantly in the p53 signaling pathway, long-term depression and estrogen signaling pathway. In the protein-protein interaction (PPI) networks, membrane palmitoylated protein 1 (Mpp1) and p53-induced death domain protein 1 (Pidd1) were hub genes to participate in the pathological mechanisms of depression and exercise intervention. These findings may provide new targets for the treatment of depression.

Adeno-Associated Virus-Mediated Knockdown of SLC16A11 Improves Glucose Tolerance and Hepatic Insulin Signaling in High Fat Diet-Fed Mice.

BACKGROUND: SLC16A11, a member of the SLC16 family, is associated with lipid metabolism, causing increased intracellular triacylglycerol (TAG) levels. In the current study, our primary goal was to determine if an SLC16A11 knockdown would improve glucose tolerance and hepatic insulin signaling in high fat diet (HFD)-fed mice. Additionally, the mechanism for exercise-improved insulin sensitivity remains unclear, and there is no mechanistic insight into SLC16A11's role in insulin sensitivity under exercise stress. Therefore, we also examined the impact of endurance exercise on the abundance of SLC16A11. METHODS: C57BL/6 J male mice were fed either regular chow (Control) or HFD for 8 weeks and then injected with adeno-associated virus (AAV). Plasma parameters, tissue lipid contents, glucose tolerance, and expression profiles of hepatic insulin signaling were detected. Also, other mice were divided randomly into sedentary and exercise groups. We assessed hepatic expression of SLC16A11 after 8 weeks of endurance exercise. RESULTS: 1) Hepatic SLC16A11 expression was greater in HFD-fed mice compared to Control mice. 2) AAV-mediated knockdown of SLC16A11 improved glucose tolerance, prevented TAG accumulation in serum and liver, and increased phosphorylation of protein kinase B (Akt) and glycogen synthesis kinase-3ß (GSK3ß) in HFD-fed mice. 3) Endurance exercise decreased hepatic SLC16A11 expression. CONCLUSIONS: Inactivation of SLC16A11, which is robustly induced by HFD, improved glucose tolerance and hepatic insulin signaling, independent of body weight, but related to TAG. Additionally, SLC16A11 might mediate the health benefits of endurance exercise.

Endurance training but not high-intensity interval training reduces liver carcinogenesis in mice with hepatocellular carcinogen diethylnitrosamine.

Physical activity may reduce cancer initiation. High-intensity interval training (HIT) has been reported to be superior to moderate continuous endurance training (ET) for maximizing health outcomes in cardiovascular disease, obesity and type 2 diabetes. However, the role of HIT vs. ET in the prevention of liver cancer is poorly understood. This study aimed to determine how HIT vs. ET affects cancer initiation in mice with the hepatocellular carcinogen diethylnitrosamine (DEN). C57BL/6 mice were treated with DEN at 3-12 weeks of age and, from 8 to 26 weeks of age, treated with either of exercise modes on treadmill: HIT (85-90% VO2max with intervals) and ET (65-75% VO2max without intervals). We found that mice treated with ET had lower cancer initiation but higher fat mass compared to control DEN-injected mice. In contrast, HIT could not significantly reduce cancer initiation and tumor volumes. Metabolomic analysis in the liver indicated marked differences in cholesterol, palmitic acid, stearic acid, uracil, hydroxypyridine and maltose between HIT- and ET-treated mice, and demonstrated good and obvious separation between ET and DEN control group. Furthermore, mice treated with ET had lower expression of pro-inflammatory cytokines and pro-proliferation genes in liver compared to DEN control group. ET protocol reduced the accumulation of toxic metabolite carbamate, increased the protein level of caspase-1, and reduced JNK phosphorylation in liver. These data indicates that moderate-intensity endurance training may be superior to high-intensity interval training for reducing liver cancer initiation in mice.