Annexin A family: A new perspective on the regulation of bone metabolism.

Osteoblast-mediated bone formation and osteoclast-mediated bone resorption are critical processes in bone metabolism. Annexin A, a calcium-phospholipid binding protein, regulates the proliferation and differentiation of bone cells, including bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts, and has gradually become a marker gene for the diagnosis of osteoporosis. As calcium channel proteins, the annexin A family members are closely associated with mechanical stress, which can target annexins A1, A5, and A6 to promote bone cell differentiation. Despite the significant clinical potential of annexin A family members in bone metabolism, few studies have reported on these mechanisms. Therefore, based on a review of relevant literature, this article elaborates on the specific functions and possible mechanisms of annexin A family members in bone metabolism to provide new ideas for their application in the prevention and treatment of bone diseases, such as osteoporosis.

Roles and mechanisms of optineurin in bone metabolism.

Optineurin (OPTN) is a widely expressed multifunctional articulatory protein that participates in cellular or mitochondrial autophagy, vesicular transport, and endoplasmic reticulum (ER) stress via interactions with various proteins. Skeletal development is a complex biological process that requires the participation of various osteoblasts, such as bone marrow mesenchymal stem cells (BMSCs), and osteogenic, osteoclastic, and chondrogenic cells. OPTN was recently found to be involved in the regulation of osteoblast activity, which affects bone metabolism. OPTN inhibits osteoclastogenesis via signaling pathways, including NF-κB, IFN-ß, and NRF2. OPTN can promote the differentiation of BMSCs toward osteogenesis and inhibit lipogenic differentiation by delaying BMSC senescence and autophagy. These effects are closely related to the development of bone metabolism disorders, such as Paget's disease of bone, rheumatoid arthritis, and osteoporosis. Therefore, this review aims to explore the role and mechanism of OPTN in the regulation of bone metabolism and related bone metabolic diseases. Our findings will provide new targets and strategies for the prevention and treatment of bone metabolic diseases.

Beneficial effects of Apelin-13 on metabolic diseases and exercise.

Apelin, a novel endogenous ligand of the G-protein-coupled receptor APJ, is encoded by the APLN gene and can be hydrolyzed into multiple subtypes, with Apelin-13 being one of the most active subtypes of the Apelin family. Recent studies have revealed that Apelin-13 functions as an adipokine that participates in the regulation of different biological processes, such as oxidative stress, inflammation, apoptosis, and energy metabolism, thereby playing an important role in the prevention and treatment of various metabolic diseases. However, the results of recent studies on the association between Apelin-13 and various metabolic states remain controversial. Furthermore, Apelin-13 is regulated or influenced by various forms of exercise and could therefore be categorized as a new type of exercise-sensitive factor that attenuates metabolic diseases. Thus, in this review, our purpose was to focus on the relationship between Apelin-13 and related metabolic diseases and the regulation of response movements, with particular reference to the establishment of a theoretical basis for improving and treating metabolic diseases.

[Role of NLRP3 inflammasome in diabetes mellitus and exercise intervention].

Chronic inflammatory reaction has been established as an important sign of the occurrence and development of diabetes mellitus (DM), accompanied by the production of a large number of inflammatory factors, thus aggravating the disease progression. As an important non-invasive intervention measure to inhibit inflammation, exercise plays a very important role in the amelioration of DM. NOD-like receptor protein 3 (NLRP3) inflammasome, a regulatory factor of inflammatory response, can induce a variety of inflammatory cascades and cell death, which are closely related to glucose uptake and dyslipidemia regulation. The development of DM can be postponed with exercise. Previous studies have reported the effects of NLRP3 inflammasome on DM, but the crucial role of exercise in this process remains unclear. Therefore, this paper reviews the research progress on the improving effects of exercise intervention on the symptoms of DM by mediating NLRP3 inflammasome, providing a novel theoretical foundation for understanding the prevention and treatment of DM through exercise.

Signaling pathways regulated by natural active ingredients in the fight against exercise fatigue-a review.

Exercise fatigue is a normal protective mechanism of the body. However, long-term fatigue hinders normal metabolism and exercise capacity. The generation and recovery from exercise fatigue involves alterations in multiple signaling pathways, mainly AMPK, PI3K/Akt, Nrf2/ARE, NF-κB, PINK1/Parkin, and BDNF/TrkB, as well as MAPK signaling pathways that mediate energy supply, reduction of metabolites, oxidative stress homeostasis, muscle fiber type switching, and central protective effects. In recent studies, a rich variety of natural active ingredients have been identified in traditional Chinese medicines and plant extracts with anti-fatigue effects, opening up the field of research in new anti-fatigue drugs. In this review we give an overview of the signaling pathways associated with the activity of natural food active ingredients against exercise fatigue. Such a comprehensive review is necessary to understand the potential of these materials as preventive measures and treatments of exercise fatigue. We expect the findings highlighted and discussed here will help guide the development of new health products and provide a theoretical and scientific basis for future research on exercise fatigue.

Signaling metabolite ß-aminoisobutyric acid as a metabolic regulator, biomarker, and potential exercise pill.

Signaling metabolites can effectively regulate the biological functions of many tissues and organs. ß-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism in skeletal muscle, has been reported to participate in the regulation of lipid, glucose, and bone metabolism, as well as in inflammation and oxidative stress. BAIBA is produced during exercise and is involved in the exercise response. No side effect has been observed in human and rat studies, suggesting that BAIBA can be developed as a pill that confers the benefits of exercise to subjects who, for some reason, are unable to do so. Further, BAIBA has been confirmed to participate in the diagnosis and prevention of diseases as an important biological marker of disease. The current review aimed to discuss the roles of BAIBA in multiple physiological processes and the possible pathways of its action, and assess the progress toward the development of BAIBA as an exercise mimic and biomarker with relevance to multiple disease states, in order to provide new ideas and strategies for basic research and disease prevention in related fields.

Role of MOTS-c in the regulation of bone metabolism.

MOTS-c, a mitochondrial-derived peptide (MDP), is an essential regulatory mediator of cell protection and energy metabolism and is involved in the development of specific diseases. Recent studies have revealed that MOTS-c promotes osteoblast proliferation, differentiation, and mineralization. Furthermore, it inhibits osteoclast production and mediates the regulation of bone metabolism and bone remodeling. Exercise effectively upregulates the expression of MOTS-c, but the specific mechanism of MOTS-c regulation in bone by exercise remains unclear. Therefore, this article reviewed the distribution and function of MOTS-c in the tissue, discussed the latest research developments in the regulation of osteoblasts and osteoclasts, and proposed potential molecular mechanisms for the effect of exercise on the regulation of bone metabolism. This review provides a theoretical reference for establishing methods to prevent and treat skeletal metabolic diseases.

Analysis of the role of irisin receptor signaling in regulating osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells.

The study aimed to explore the role of the irisin receptor (integrin αVß5) signaling pathway in obesity-induced osteoporosis and its potential mechanism. The integrin αVß5 gene of bone marrow mesenchymal stem cells (BMSCs) was silenced and overexpressed, and the cells were exposed to irisin treatment and mechanical stretch. Mouse models of obesity were established by feeding mice a high-fat diet, and 8-week caloric restriction/aerobic exercise regimens were implemented. The results showed that after silencing the integrin αVß5, the osteogenic differentiation of BMSCs was significantly reduced. While overexpression of the integrin αVß5 increased the osteogenic differentiation of BMSCs. Besides, mechanical stretch promoted the osteogenic differentiation of BMSCs. Obesity did not affect integrin αVß5 expression in the bone, but it downregulated the expression of irisin and osteogenic factors, upregulated the expression of adipogenic factors, increased bone marrow fat, reduced bone formation, and destroyed the bone microstructure. Caloric restriction, exercise, and a combined regimen reversed these effects and improved obesity-induced osteoporosis, with the combined treatment exhibiting the most potent effect. This study confirms that the irisin receptor signaling pathway has a significant part in transmitting 'mechanical stress' and regulating 'osteogenic/adipogenic differentiation' of BMSCs via recombinant irisin, mechanical stretch, and overexpression/silencing of the integrin αVß5 gene.

[IL-27: a novel cytokine mediating immune related diseases].

Interleukin 27 (IL-27) is a pleiotropic cytokine that is involved in the regulation of the body's innate and adaptive immunity. Previous studies have shown that IL-27 mediates a variety of inflammatory responses in vivo. With the development of animal models and technical tools, several studies have shown that it is also closely associated with autoimmune diseases and other immune related diseases, and is considered as an important candidate for the treatment of viral disease, autoimmune diseases, tumors and obesity. Therefore, this paper reviews recent progress on the role of IL-27 in acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis, tumors and obesity, with the aim of providing new ideas for the treatment of immune related diseases.

Role of SIRT3 in bone homeostasis and its application in preventing and treating bone diseases.

Bone homeostasis refers to the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption and the maintenance of stable bone mass. SIRT3 is a class of mitochondrial protein deacetylase that influences various mitochondrial functions and is involved in the mechanisms underlying resistance to aging; regulation of bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts; and development of osteoporosis, osteoarthritis, and other bone diseases. Moreover, exercise affects bones through SIRT3. Thus, studies on SIRT3 may provide insights for the treatment of bone diseases. Although SIRT3 can exert multiple effects on bone, the specific mechanism by which it regulates bone homeostasis remains unclear. By evaluating the relevant literature, this review discusses the structure and function of SIRT3, reveals the role and associated mechanisms of SIRT3 in regulating bone homeostasis and mediating bone health during exercise, and highlights the potential pharmacological value of SIRT3 in treating bone diseases.

Diet and exercise interventions reduce serum asprosin and the corresponding hypothalamic- pituitary-gonad-axis dysfunction in obese men.

Background: Asprosin (ASP) is a recently discovered adipocyte factor that participates in glucose metabolism and inflammatory reactions. Recent findings suggest that it may be involved in the regulation of sex hormone secretion in the hypothalamic-pituitary-gonad (HPG) axis, but no studies have been reported in related populations. The purpose of this study was to evaluate the changes in serum ASP levels in healthy men and obese men, as well as before and after exercise weight loss, and to investigate male hypogonadism, insulin resistance, inflammatory response, and relationships induced by ASP and obesity. Methods: Thirty-eight young male volunteers were recruited and divided into a normal group (n = 20) and an obese group (n = 18) according to their body mass index. Fourteen of the obese men underwent a 14-week exercise and diet intervention (first 8 weeks of aerobic exercise at 60%-70% HRmax for 30-50 min/4 days a week). Beginning at week 9, the intensity was increased to 75% HRmax. Participants in the obese groups maintained a calorie-restricted diet throughout the study period. Results: Serum ASP levels in the obese group were significantly higher than those in the normal group, and serum gonadotropin-releasing hormone (GnRh), luteinizing hormone (LH), and testosterone (T) levels were decreased. After 14 weeks of exercise and diet intervention, serum ASP decreased significantly, the levels of body weight, lean body weight, body fat rate, fasting insulin (FINS), homeostatic model assessment for insulin resistance, TNF-α, IL-6, and IL-1ß decreased significantly, and the serum GnRH, LH, and T levels increased significantly. ASP was positively correlated with body weight, body fat percentage, FINS, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß and negatively correlated with relative lean body weight and serum LH and T levels. Conclusion: The serum ASP levels were increased in obese men compared with those of normal weight individuals, resulting in a chronic inflammatory reaction, high serum insulin, and HPG axis injury. Fourteen weeks of exercise and diet intervention effectively alleviated this phenomenon. It has been speculated that ASP might regulate male reproductive function by regulating the inflammatory response and insulin sensitivity.

A cross-sectional comparative study on the effects of body mass index and exercise/sedentary on serum asprosin in male college students.

Adipocytes regulate the body's metabolism by secreting adipokines to maintain energy homeostasis. Asprosin is a new type of adipokine, and its relationship with obesity remains controversial. There are a few reports on the effect of long-term exercise on serum asprosin level. This study aimed to investigate the effects of body mass index (BMI) and exercise/sedentary habit on serum asprosin in male college students as well as the relationship between serum asprosin and body composition and related metabolic indicators and provided a basis for further exploration of the biological function of asprosin. Ninety-six male college students were classified into the sedentary habit group (SD; 48) and the special training experience group (ET; 48). Both groups included three subgroups of normal BMI, overweight, and obesity, with 16 people in each subgroup. One-way analysis of variance, analysis of covariance, and Pearson correlation analysis were performed. The results showed that serum asprosin levels in the obesity subgroup were significantly higher than those in the normal and overweight subgroups. Excluding BMI interference, there were no significant differences in serum asprosin between the SD and ET groups; however, there were significant differences in body composition, tumor necrosis factor-α, interleukin-6, and interleukin-10. Asprosin was positively correlated with BMI, body fat percentage, visceral fat area, fasting insulin, insulin resistance homeostasis model, total cholesterol, low-density lipoprotein, tumor necrosis factor-α, interleukin-6, and leptin levels and was negatively correlated with relative lean body mass, relative skeletal muscle mass, high-density lipoprotein, and interleukin-10, and adiponectin levels. In conclusion, serum asprosin is closely related to body weight, body composition, glucose and lipid metabolism, inflammatory response, and fat hormones. Long-term exercise training cannot prevent BMI increase from increasing serum asprosin level. If the influence of BMI is excluded, long-term exercise training does not affect serum asprosin.

Effects of exercise and dietary intervention on muscle, adipose tissue, and blood IRISIN levels in obese male mice and their relationship with the beigeization of white adipose tissue.

Background: Obesity is a growing problem worldwide, and newer therapeutic strategies to combat it are urgently required. This study aimed to analyze the effect of diet and exercise interventions on energy balance in mice and elucidate the mechanism of the peroxisome proliferator-activated receptor-gamma co-activator-1-alpha-IRISIN-uncoupling protein-1 (PGC-1α-IRISIN-UCP-1) pathway in the beigeization of white adipose tissue. Methods: Four-week-old male C57BL/6 mice were randomly divided into normal (NC) and high-fat diet (HFD) groups. After 10 weeks of HFD feeding, obese mice were randomly divided into obesity control (OC), obesity diet control (OD), obesity exercise (OE), and obesity diet control exercise (ODE) groups. Mice in OE and ODE performed moderate-load treadmill exercises: for OD and ODE, the diet constituted 70% of the food intake of the OC group for 8 weeks. Results: Long-term HFD inhibits white adipose tissue beigeization by downregulating PGC-1α-IRISIN-UCP-1 in the adipose tissue and skeletal muscles. Eight weeks of exercise and dietary interventions alleviated obesity-induced skeletal muscle, and adipose tissue PGC-1α-IRISIN-UCP-1 pathway downregulation promoted white adipose tissue beigeization and reduced body adipose tissue. The effects of the combined intervention were better than those of single interventions. Conclusions: Diet and exercise intervention after obesity and obesity itself may affect the beigeization of WAT by downregulating/upregulating the expression/secretion of skeletal muscle and adipose PGC-1α-IRISIN, thereby influencing the regulation of bodyweight. The effects of the combined intervention were better than those of single interventions.

[Effects of aerobic exercise and dietary intervention on testicular oxidative stress in obese mice].

OBJECTIVE: Through aerobic exercise and diet intervention on obese mice, the effects of exercise and diet intervention on testicular oxidative stress and p38MAPK-NF-κB pathway were investigated in obese mice. METHODS: Seventeen C57BL/6J mice were randomly divided into a normal diet group (ND), and 37 mice were divided into a high-fat diet group (HFD), the high-fat diet accounted for 40% of fat. After 12 weeks of feeding, 3 obesity-resistant mice were excluded from the HFD group, and the remaining 34 were successfully modeled. The mice in ND group were then divided into normal diet control group (NC, n=8) and normal diet and exercise group (NE, n=9). The mice in HFD group were divided into obese high-fat diet control group (OC, n=8), obese high-fat diet and exercise group (OE, n=9), obese normal diet group (ONC, n=8), and obese normal diet and exercise group (ONE, n=9). Each group continued to feed for 8 weeks, and the NE, OE and ONE groups performed treadmill exercise for 8 weeks at a speed of 20 m/min, 60 min/d, 6 d/week. Blood and testicular tissue samples were collected 36～40 h after the last exercise. Serum testosterone and testicular oxidative stress (MDA, T-SOD, T-AOC) levels were detected by ELISA, and testicular p38MAPK-NF-κB levels were detected by RT-PCR and Western blot. RESULTS: Compared with the NC group, the body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels in the OC group were increased significantly (P＜0.01), while the levels of testicular SOD, testis coefficient and blood testosterone were decreased significantly (P＜0.01); the body fat parameters of the mice in the NE group were decreased significantly (P＜0.05), and the serum level of testosterone was increased significantly (P＜0.01). Compared with the OC group, the body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels were decreased significantly in the OE group (P＜0.05 or 0.01), and the testicular SOD and blood testosterone levels were increased significantly (P＜0.01); Body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels were decreased significantly in ONC group (P＜0.01), while testicular SOD level and testis coefficient were increased significantly (P＜0.05); Body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels of mice in ONE group were decreased significantly (P＜0.01), while testicular SOD, testis coefficient and blood testosterone levels were increased significantly (P＜0.01). CONCLUSION: Obesity induces oxidative stress in the testis of mice, up-regulates the level of p38MAPK-NF-κB, and reduces the level of blood testosterone; exercise, diet and exercise*diet interventions can reduce testicular oxidative stress and down-regulate testicular p38MAPK-NF-κB levels by reducing body fat.

[Effects of exercise intervention on mitochondrial-derived peptide MOTS-c in the germ cells of obese men].

Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a newly discovered mitochondrial-derived peptide with the main functions of promoting glucose metabolism and reducing adipose tissue. MOTS-c was found to be a substance that can mimic the motor effect and improve the motor ability. It is sex-related and the circulating MOTS-c level is decreased in obese males. Obesity can cause male reproductive dysfunction, while exercise can improve obesity-induced reduction of male reproductive function. This article discusses the effect of exercise intervention on the mitochondrial-derived peptide MOTS-c in the germ cells of obese men.

Regular aerobic exercise activates PDGF-BB/PDGFR-ß signaling and modulates the inflammatory-anti-inflammatory balance in diet-induced obese mice.

OBJECTIVE: Regular aerobic exercise induces cardioprotection by counteracting the obesity-associated inflammatory response, dyslipidemia. PDGF-BB/PDGFR-ß signaling is established as a crucial mechanism of endothelial cell-cardiomyocyte communication and cardioprotection, but its physiological roles in response to obesity and regular aerobic exercise are unknown. METHODS: Thirty C57BL/6 mice were divided into three groups: a normal diet group, a high-fat diet group, and a high-fat diet plus aerobic exercise group. Glucose metabolic parameters, inflammation-related indicators, and blood lipids indicators were detected. In addition, gene expression levels of the inflammatory factors, PDGF-BB, PDGFR-ß, PI3K, Akt, eNOS, and P53 in cardiac tissue were quantified. Morphological analysis was also used to quantify the magnitude of inflammation. RESULTS: High-fat diet (HFD) feeding resulted in adiposity, dyslipidemia, and low levels of cardioprotective factors such as APN and eNOS (P < 0.05), which were improved significantly by 8 weeks of aerobic exercise (P < 0.05). HFD feeding increased the gene expression levels of proinflammatory cytokines and decreased the gene expression levels of anti-inflammatory cytokines in cardiac tissue (P < 0.05), which was reversed by regular aerobic exercise (P < 0.05). In addition, HFD feeding suppressed the levels of the cardioprotective factors PDGF-BB and eNOS through PDGF-BB/PDGFR-ß/PI3K/Akt/eNOS signaling in cardiac tissue, while regular aerobic exercise activated PDGF-BB/PDGFR-ß/PI3K/Akt/eNOS signaling. CONCLUSION: Regular aerobic exercise improved adiposity, dyslipidemia induced by HFD feeding. Regular aerobic exercise exerted a prominent role in modulating the inflammatory-anti-inflammatory balance and activating the levels of the cardioprotective factors eNOS and PDGF-BB through PDGF-BB/PDGFR-ß signaling.

MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway.

Mitochondrial-derived peptide (MOTS-c) has gained increasing attention as a promising therapeutic or prevention strategy for obesity and diabetes mellitus. MOTS-c targets the folate cycle, leading to an accumulation of 5-aminomidazole-4-carboxamide ribonucleotide (AICAR) as well as AMPK activation. AMPK is a well-known upstream regulator of the proliferation-activated receptor co-activator 1 (PGC-1α), which can improve mitochondrial biogenesis via co-transcriptional modifications. We hypothesized that AMPK can induce the expression of MOTS-c through PGC-1α. Our study aimed to explore whether MOTS-c and/or exercise can regulate MOTS-c expression, attenuate insulin resistance and enhance glucose metabolism both in vitro and in vivo. It was found that C2C12 myotubes exposed to Compound C (an AMPK inhibitor) had deceases in the protein and mRNA expressions of PGC-1α and MOTS-c. PGC-1α knockdown downregulated the protein and mRNA expressions of MOTS-c in C2C12 myotubes, whereas both PGC-1α overexpression and recombinant MOTS-c supplementation upregulated the protein and mRNA expressions of MOTS-c in C2C12 myotubes. Furthermore, the skeletal muscle and plasma levels of MOTS-c were markedly reduced in high-fat diet-induced obese mice. Treadmill training remarkably upregulated the protein levels of MOTS-c, PGC-1α and GLUT4, along with the phosphorylation levels of AMPK and ACC. Altogether, these results indicate that AMPK/PGC-1α pathway can mediate the secretion and/or production of MOTS-c in skeletal muscle, implying the possible roles of exercise intervention and recombinant MOTS-c in treating obesity and diabetes mellitus.

Leptin and inflammatory factors play a synergistic role in the regulation of reproduction in male mice through hypothalamic kisspeptin-mediated energy balance.

BACKGROUND: Energy balance is closely related to reproductive function, wherein hypothalamic kisspeptin mediates regulation of the energy balance. However, the central mechanism of kisspeptin in the regulation of male reproductive function under different energy balance states is unclear. Here, high-fat diet (HFD) and exercise were used to change the energy balance to explore the role of leptin and inflammation in the regulation of kisspeptin and the hypothalamic-pituitary-testis (HPT) axis. METHODS: Four-week-old male C57BL/6 J mice were randomly assigned to a normal control group (n = 16) or an HFD (n = 49) group. After 10 weeks of HFD feeding, obese mice were randomly divided into obesity control (n = 16), obesity moderate-load exercise (n = 16), or obesity high-load exercise (n = 17) groups. The obesity moderate-load exercise and obesity high-load exercise groups performed exercise (swimming) for 120 min/day and 120 min × 2 times/day (6 h interval), 5 days/week for 8 weeks, respectively. RESULTS: Compared to the mice in the normal group, in obese mice, the mRNA and protein expression of the leptin receptor, kiss, interleukin-10 (IL-10), and gonadotropin-releasing hormone (GnRH) decreased in the hypothalamus; serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels and sperm quality decreased; and serum leptin, estradiol, and tumor necrosis factor-α (TNF-α) levels and sperm apoptosis increased. Moderate- and high-load exercise effectively reduced body fat and serum leptin levels but had the opposite effects on the hypothalamus and serum IL-10 and TNF-α levels. Moderate-load exercise had anti-inflammatory effects accompanied by increased mRNA and protein expression of kiss and GnRH in the hypothalamus and increased serum FSH, LH, and testosterone levels and improved sperm quality. High-load exercise also promoted inflammation, with no significant effect on the mRNA and protein expression of kiss and GnRH in the hypothalamus, serum sex hormone level, or sperm quality. Moderate-load exercise improved leptin resistance and inflammation and reduced the inhibition of kisspeptin and the HPT axis in obese mice. The inflammatory response induced by high-load exercise may counteract the positive effect of improving leptin resistance on kisspeptin and HPT. CONCLUSION: During changes in energy balance, leptin and inflammation jointly regulate kisspeptin expression on the HPT axis.

Aerobic Exercise Improves Pulmonary Fibrosis by Improving Insulin Resistance and Inflammation in Obese Mice.

BACKGROUND: Previous studies have demonstrated that obesity is associated with pulmonary fibrosis. We attempted to identify whether regular aerobic exercise (AE) can protect against high-fat diet (HFD)-associated pulmonary fibrosis. METHODS: Forty-eight C57BL/6 mice were randomly assigned to four groups: chow group (Ch), chow plus exercise group (CE), obesity group (Ob), and obesity plus exercise group (OE). The mice were fed either an HFD or a chow diet for 16 weeks, and low-intensity aerobic exercise (AE) was performed in the last 8 weeks. We measured the degree of pulmonary fibrosis; pulmonary inflammation; oxidative stress parameters; insulin resistance-related indicators; the number of inflammatory cells in bronchoalveolar lavage fluid (BALF); the mRNA expression levels of IL-10, IL-1ß, TGF-ß, TNF-α, CXCL-1, IL-17, MMP-9, MPO, NE, and sirt-1; and the BALF levels of CXCL-1, IL-17, TGF-ß, IL-10, IL-1ß, and TNF-α in lung tissue. RESULTS: AE in obese mice protected against obesity-associated pulmonary fibrosis, chronic inflammation, pro-oxidative/antioxidative imbalance, and insulin resistance. AE ameliorated the HFD-induced inflammatory response and neutrophil infiltration in the lung. AE downregulated BALF levels of CXCL-1, IL-1ß, TNF-α IL-17, and TGF-ß but upregulated BALF levels of IL-10. AE decreased IL-1ß, TGF-ß, TNF-α, CXCL-1, IL-17, MMP-9, MPO, and NE mRNA expression levels but upregulated IL-10 and sirt-1 mRNA expression levels in the lung. CONCLUSIONS: AE protects against HFD-induced pulmonary fibrosis by improving obesity-associated insulin resistance, chronic low-grade inflammation, and pro-oxidative/antioxidative imbalance. AE improved HFD-induced pulmonary fibrosis by suppressing IL-17, TGF-ß, NE, and MMP-9 expression and activating IL-10 and sirt-1 expression.

Adiponectin treatment improves insulin resistance in mice by regulating the expression of the mitochondrial-derived peptide MOTS-c and its response to exercise via APPL1-SIRT1-PGC-1α.

AIMS/HYPOTHESIS: Adiponectin stimulates mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a major regulator of mitochondrial biogenesis. MOTS-c (mitochondrial open reading frame of the 12S rRNA) is a biologically active mitochondrial-derived peptide encoded by mitochondrial DNA. It influences the mechanisms of obesity and diabetes. We hypothesised that the adiponectin pathway may regulate the production and/or secretion of MOTS-c in skeletal muscle. We aimed to determine whether exercise and adiponectin affect MOTS-c to improve insulin resistance in mice. METHODS: To investigate this hypothesis, we used wild-type C57BL/6 mice subjected to high-fat diet, an exercise regimen, and i.p. injection of recombinant mouse adiponectin (Acrp30) or MOTS-c, and adiponectin knockout (Adipoq-/-) mice (C57BL/6 background) subjected to i.p. injection of Acrp30. C2C12 myotubes were also treated with sirtuin 1 (SIRT1) inhibitor, PGC-1α inhibitor, SIRT1 activator, plasmid-expressed active APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper), pcDNA-SIRT1, or siRNA against APPL1, SIRT1 or PGC-1α. RESULTS: In Adipoq-/- mice, MOTS-c levels in the plasma and skeletal muscle were downregulated. In C2C12 myotubes, adiponectin increased the mRNA expression of MOTS-c. APPL1 protein level following adiponectin treatment positively correlated with MOTS-c protein and mRNA levels in C2C12 myotubes. SIRT1 overexpression increased the adiponectin-induced mRNA and protein expression of MOTS-c, SIRT1 and PGC-1α. Pharmacologic and genetic inhibition of PGC-1α suppressed the increases in MOTS-c mRNA and protein levels induced by SIRT1 overexpression. In mice, plasma and skeletal muscle MOTS-c levels were significantly downregulated following high-fat-diet. Exercise and i.p. Acrp30 or MOTS-c increased MOTS-c levels and adiponectin mRNA and protein expression in the plasma and skeletal muscle. CONCLUSIONS/INTERPRETATION: Our findings showed that the APPL1-SIRT1-PGC-1α pathway regulates the production and/or secretion of skeletal muscle MOTS-c by mediating adiponectin signalling. Our study provides an insight into the cellular and molecular pathways underlying the pathogenesis of diabetes and shows that MOTS-c is a potential novel therapeutic target in the treatment of diabetes. Graphical abstract.