Resistin in endocrine pancreas of sheep: Presence and expression related to different diets.

Resistin (RETN), a recently discovered adipokine, is a cysteine-rich and secretory protein produced by adipocytes. RETN has been detected in several tissues, including human and laboratory animals' pancreas, wherein impairs glucose tolerance and insulin (INS) action and causes INS resistance. This study aims to evaluate the presence and expression of RETN in the pancreas of 15 adult female sheep reared on Apennine pastures, which show a decrease in their nutritional value due to the drought stress linked to the increasing summer aridity. The sheep were divided into 3 groups according to the diet they were subjected to: maximum pasture flowering (MxF) group, maximum pasture dryness (MxD) group, and experimental (Exp) group which received a feed supplementation in addition to the MxD group feeding. Immunohistochemistry and immunofluorescence were performed on formalin-fixed and paraffin-embedded sections of the pancreas to detect the RETN presence and to evaluate the co-localization of RETN with both glucagon (GCG)- and INS-producing cells. In addition, the expression of the three molecules was evaluated also in relation to different diets. RETN was observed only in the endocrine pancreas, showing a wide distribution throughout the pancreatic islets with few negative cells and the RETN producing cells colocalized with both α cells and ß cells. No differences in distribution and immunostaining intensity of RETN, GCG and INS were observed among the three groups. Quantitative PCR showed the expression of RETN, GCG and INS in all tested samples. No significant differences were observed for RETN and GCG among all three groups of sheep. Instead, a high statistically significant expression of INS was detected in the MxF group with respect to the Exp and MxD groups. These results highlight the localization of RETN in GCG- and INS-secreting cells involved in glucose homeostasis suggesting a modulatory role for RETN. Furthermore, the RETN expression is not influenced by food supplementation and thus is not affected by diet.

STAT6-induced production of mucus and resistin-like molecules in lung Club cells does not protect against helminth or influenza A virus infection.

Airway epithelial cells contribute to a variety of lung diseases including allergic asthma, where IL-4 and IL-13 promote activation of the transcription factor STAT6. This leads to goblet cell hyperplasia and the secretion of effector molecules by epithelial cells. However, the specific effect of activated STAT6 in lung epithelial cells is only partially understood. Here, we created a mouse strain to selectively investigate the role of constitutively active STAT6 in Club cells, a subpopulation of airway epithelial cells. CCSP-Cre_STAT6vt mice and bronchiolar organoids derived from these show an enhanced expression of the chitinase-like protein Chil4 (Ym2) and resistin-like molecules (Relm-α, -ß, -γ). In addition, goblet cells of these mice spontaneously secrete mucus into the bronchi. However, the activated epithelium resulted neither in impaired lung function nor conferred a protective effect against the migrating helminth Nippostrongylus brasiliensis. Moreover, CCSP-Cre_STAT6vt mice showed similar allergic airway inflammation induced by live conidia of the fungus Aspergillus fumigatus and similar recovery after influenza A virus infection compared to control mice. Together these results highlight that STAT6 signaling in Club cells induces the secretion of Relm proteins and mucus without impairing lung function, but this is not sufficient to confer protection against helminth or viral infections.

Anthropometric measures, predicted visceral adipose tissue and biomarkers of chronic inflammation.

BACKGROUND: Evidence has linked low-grade systemic inflammation and visceral adipose tissue (VAT) with development of chronic conditions. Cytokines and select proteins released by VAT may promote a low-grade inflammatory response. A number of equations have been developed to estimate VAT levels. In this study, we compared predicted VAT equation relationships with biomarkers of inflammation. METHODS: This was a cross-sectional study of 2038 men and women aged 46-73 years. Correlation and linear regression analyses were performed to examine inflammatory biomarker relationships with four commonly assessed anthropometric measures and 10 predicted VAT equations. RESULTS: Compared with anthropometric measures, predicted VAT equations were found to explain a greater proportion of variance in CRP (R2 = .075, p = .001), IL-6 (R2 = .060, p = .001), TNF-α (R2 = .017, p = .005), resistin (R2 = .011, p = .012), monocyte (R2 = .027, p = .001), eosinophil (R2 = .012, p = .01) and basophil (R2 = .015, p = .002) levels in males, and a greater variance in concentrations of C3 (R2 = .175, p = .001), IL-6 (R2 = .090, p = .001), TNF-α (R2 = .036, p = .001), adiponectin (R2 = .121, p = .001), the adiponectin-to-leptin ratio (R2 = .444, p = .001), resistin (R2 = .025, p = .001), white blood cell count (R2 = .057, p = .001), neutrophils (R2 = .061, p = .001) and lymphocytes (R2 = .020, p = .001) in females. CONCLUSION: Equations for assessing VAT levels might be useful to characterise metabolic health. Further studies that examine predicted VAT relationships with disease and mortality outcomes are warranted.

Interaction between Selected Adipokines and Musculoskeletal and Cardiovascular Systems: A Review of Current Knowledge.

Adipokines are substances secreted by adipose tissue that are receiving increasing attention. The approach to adipose tissue has changed in recent years, and it is no longer looked at as just a storage organ but its secretion and how it influences systems in the human body are also looked at. The role of adipokine seems crucial in developing future therapies for pathologies of selected systems. In this study, we look at selected adipokines, leptin, adiponectin, chemerin, resistin, omentin-1, nesfatin, irisin-1, visfatin, apelin, vaspin, heparin-binding EGF-like growth factor (HB-EGF), and TGF-ß2, and how they affect systems in the human body related to physical activity such as the musculoskeletal and cardiovascular systems.

Astaxanthin Supplementation Augments the Benefits of CrossFit Workouts on Semaphorin 3C and Other Adipokines in Males with Obesity.

Regular physical activity and the use of nutritional supplements, including antioxidants, are recognized as efficacious approaches for the prevention and mitigation of obesity-related complications. This study investigated the effects of 12 weeks of CrossFit training combined with astaxanthin (ASX) supplementation on some plasma adipokines in males with obesity. Sixty-eight males with obesity (BMI: 33.6 ± 1.4 kg·m-2) were randomly assigned into four groups: the control group (CG; n = 11), ASX supplementation group (SG; n = 11), CrossFit group (TG; n = 11), and training plus supplement group (TSG; n = 11). Participants underwent 12 weeks of supplementation with ASX or placebo (20 mg/day capsule daily), CrossFit training, or a combination of both interventions. Plasma levels of semaphorin 3C (SEMA3C), apelin, chemerin, omentin1, visfatin, resistin, adiponectin, leptin, vaspin, and RBP4 were measured 72 h before the first training session and after the last training session. The plasma levels of all measured adipokines were significantly altered in SG, TG, and TSG groups (p < 0.05). The reduction of resistin was significantly higher in TSG than in SG (p < 0.05). The plasma levels of omentin1 were significantly higher in both training groups of TG and TSG than SG (p < 0.05), although such a meaningful difference was not observed between both training groups (p > 0.05). Significant differences were found in the reductions of plasma levels of vaspin, visfatin, apelin, RBP4, chemerin, and SEMA3C between the SG and TSG groups (p < 0.05). The study found that a 12-week intervention using ASX supplementation and CrossFit exercises resulted in significant improvements in several adipokines among male individuals with obesity. Notably, the combined approach of supplementation and training had the most pronounced results. The findings presented in this study indicate that the supplementation of ASX and participation in CrossFit exercise have the potential to be effective therapies in mitigating complications associated with obesity and enhancing metabolic health.

Resistin stimulates PC-3 prostate cancer cell growth through stimulation of SOCS3 and SOCS5 genes.

Resistin and suppressors of cytokine signaling (SOCSs) have been reported to regulate prostate cancer (PCa) cell proliferation and survival, respectively. Whether any of the SOCS molecules mediate the mitogenic effect of resistin on PCa cells is unknown. Using PC-3 human PCa cells, we found that resistin upregulates the expression of SOCS3 and SOCS5 mRNA, but not SOCS7 mRNA, in a dose- and time-dependent manner. The resistin-induced increases in SOCS3 and SOCS5 expression and cell proliferation were prevented by pretreatment with specific inhibitors of the TLR4, ERK, p38 MAPK, JNK, PI3K, and JAK2 proteins. However, pretreatment with a TLR2 inhibitor had no effect on resistin-mediated SOCS3 and SOCS5 expression. In addition, the effects of resistin on SOCS3, SOCS5, and SOCS7 mRNA levels were cell type-specific. Overexpression of either SOCS3 or SOCS5 enhanced further resistin-stimulated growth of PC-3 cells, whereas silencing SOCS3 or SOCS5 antagonized resistin-increased cell growth. Further PCa tissue analysis demonstrated higher levels of RETN, TLR4, SOCS3, and SOCS5 mRNAs in cancer tissues than benign prostate hyperplasia and indicated positive correlations among RETN, TLR4, and SOCS5. These data suggest that SOCS5, TLR4, and, to a lesser extent, SOCS3 can mediate the mitogenic effect of resistin on PC-3 PCa cells.

Adipose Tissue and Plasma Markers Associated with HbA1c Pre- and Post-bariatric Surgery: a Cross-sectional and Cohort Study.

PURPOSE: Obesity can be associated with chronic inflammation and dysregulated expression of inflammatory adipokines that contribute to insulin resistance and type 2 diabetes. This may also affect the clinical response to bariatric surgery. Our objective was whether baseline visceral adipose tissue features and plasma adipokine are associated with HbA1c ≥0.06 at the time of Roux-en-Y gastric bypass (RYGB) surgery and with persistently elevated HbA1c at 12 months post-RYGB. METHODS: During the surgery, adipose biopsies and plasma were collected for adipokine/cytokine profile. Clinical and biochemical measurements were also collected at the time of RYGB and, in those with baseline elevated HbA1c, at 12 months post-RYGB. RESULTS: In the cross-sectional study, 109 patients (82.6% female; age 49 years; BMI 46.98 kg/m2) participated. Of those with elevated HbA1c at baseline (n = 61), 47 patients had repeated measurements at 12 months post-RYGB (23% drop-out). Using a multivariate logistic regression model, older age (adjusted odds ratio (aOR), 1.14; 95% confidence interval (CI), 1.06-1.22) and higher plasma resistin (aOR, 5.30; 95% CI, 1.25-22.44) were associated with higher odds of HbA1c ≥ 0.06, whereas higher plasma adiponectin (aOR, 0.993; 95% CI, 0.99-0.996) was associated with lower odds of HbA1c ≥0.06. In addition, baseline higher average adipose cell area (aOR, 1.0017; 95% CI, 1.0002-1.0032) and plasma resistin (aOR, 1.0004; 95% CI, 1.0000-1.0009) were associated with higher odds of having persistently elevated HbA1c at 12 months post-RYGB. CONCLUSION: Our study suggests that baseline plasma adipokine dysregulation, specifically high resistin, and adipocyte hypertrophy may affect the clinical response to RYGB.

Biomarker panel discriminates diabetics with and without periodontitis pre- and post-therapy.

BACKGROUND AND OBJECTIVE: Biological regulators of periodontal inflammation, collagen degradation, and insulin resistance have not been determined in association with severity of periodontitis and response to periodontal treatment in diabetics. Our objective was to determine whether type 2 diabetes (T2DM) patients with periodontal disease present a distinct salivary biomarker profile compared with T2DM patients without periodontal disease and healthy subjects (without diabetes and periodontitis) pre- and post-nonsurgical therapy. METHODS: Clinical parameters of periodontal health and whole unstimulated saliva were collected from 92 participants (31 Not Periodontitis, NP; 32 T2DM without periodontitis, DWoP; and 29 with T2DM with periodontitis, DWP) at baseline. The T2DM groups received scaling and root planning (SRP) and provided saliva at 6-week follow-up. Salivary concentrations of interleukin (IL)-1ß, IL-6, matrix metalloproteinase-8 (MMP-8), and resistin were measured by immunoassay. RESULTS: The DWP group had significantly more disease and higher salivary concentrations at baseline for IL-1ß, MMP-8, and resistin (p's < .01) compared with DWoP and NP. SRP resulted in significant improvement in periodontal parameters for the T2DM groups; however, more disease persisted (p < .001), and IL-1ß, MMP-8, and resistin concentrations remained significantly higher in the DWP than the DWoP group (p < .01) at 6 weeks post-treatment. Principal component analysis demonstrated the DWoP group appeared more biologically similar to the NP group than the DWP group. Concentrations of these salivary biomarkers increased with increasing periodontal disease severity (p < .05) in this study population. CONCLUSION: Salivary concentrations of IL-1ß, MMP-8, and resistin appear to serve as biomarkers of periodontal status pre- and post-treatment, irrespective of diabetes status.

Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats.

Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg) for 4 weeks. Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.

The differential role of resistin on invasive liver cancer cells.

OBJECTIVES: To determine whether inhibition of kinase signaling will suppress resistin-induced liver cancer progression. Resistin is located in monocytes and macrophages of adipose tissue. This adipocytokine is an important link between obesity, inflammation, insulin resistance, and cancer risk. Pathways that resistin is known to be involved include but are not limited to mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases (ERK). The ERK pathway promotes cellular proliferation, migration, survival of cancer cells, and tumor progression. The Akt pathway is known to be up-regulated in many cancers including liver cancer. METHODS: Using an in vitro model, HepG2 and SNU-449 liver cancer cells were exposed to resistin ± ERK, Akt, or both inhibitors. The following physiological parameters were assessed: cellular proliferation, ROS, lipogenesis, invasion, MMP, and lactate dehydrogenase activity. RESULTS: The inhibition of kinase signaling suppressed resistin-induced invasion and lactate dehydrogenase in both cell lines. In addition, in SNU-449 cells, resistin increased proliferation, ROS, and MMP-9 activity. Inhibition of PI3K and ERK decreased phosphorylated Akt and ERK, and pyruvate dehydrogenase. CONCLUSIONS: In this study, we describe the effect of Akt and ERK inhibitors to determine if inhibition suppresses resistin-induced liver cancer progression. Resistin promotes cellular proliferation, ROS, MMP, invasion and LDH activity in SNU-449 liver cancer cells which is differentially mediated by Akt and ERK signaling pathways.

Concentration of Selected Adipokines and Factors Regulating Carbohydrate Metabolism in Patients with Head and Neck Cancer in Respect to Their Body Mass Index.

Head and neck cancers (HNCs) are a group of tumors not common in European populations. So far, not much is known about the role of obesity, adipokines, glucose metabolism, and inflammation in the pathogenesis of HNC. The aim of the study was to determine the concentrations of ghrelin, omentin-1, adipsin, adiponectin, leptin, resistin, visfatin, glucagon, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), plasminogen activator inhibitor-1 (PAI-1), and gastric inhibitory peptide (GIP) in the blood serum of HNC patients depending on their body mass index (BMI). The study included 46 patients divided into two groups according to their BMI values: the normal BMI group (nBMI) included 23 patients with BMI < 25 kg/m2 and the increased BMI group (iBMI) included patients with BMI ≥ 25 kg/m2. A control group (CG) included 23 healthy people (BMI < 25 kg/m2). Statistically significant differences in the levels of adipsin, ghrelin, glucagon, PAI-1, and visfatin were shown between nBMI and CG. In the case of nBMI and iBMI, statistically significant differences were observed in the concentrations of adiponectin, C-peptide, ghrelin, GLP-1, insulin, leptin, omentin-1, PAI-1, resistin, and visfatin. The obtained results indicate a disruption of endocrine function of adipose tissue and impaired glucose metabolism in HNC. Obesity, which is not a typical risk factor for HNC, may aggravate the negative metabolic changes associated with this type of neoplasm. Ghrelin, visfatin, PAI-1, adipsin, and glucagon might be related to head and neck carcinogenesis. They seem to be promising directions for further research.

Analysis of Selected Salivary Adipokines and Cytokines in Patients with Obesity-A Pilot Study.

Obesity is a chronic, progressive and relapsing disease that produces many adverse health, social and economic effects. The aim of the study was to analyse the concentrations of selected proinflammatory parameters in the saliva of obese and normal body weight individuals. The study included 116 people divided into two groups: the study group (n = 75, subjects with obesity) and the control group (n = 41, individuals with normal body weight). Bioelectrical impedance analysis was performed, and saliva samples were collected from all study participants to determine the concentrations of selected proinflammatory adipokines and cytokines. Statistically significantly higher concentrations of MMP-2, MMP-9 and IL-1ß were found in the saliva of obese women compared to women with normal body weight. Furthermore, statistically significantly higher concentrations of MMP-9, IL-6 and resistin were observed in the saliva of obese men compared to men with normal body weight. Higher concentrations of selected proinflammatory cytokines and adipokines were found in the saliva of obese individuals compared to individuals with normal body weight. It is likely that higher concentrations of MMP-2, MMP-9 and IL-1ß can be detected in the saliva of obese women compared to non-obese women, while higher concentrations of MMP-9, IL-6 and resistin can be found in the saliva of obese men compared to non-obese men, which suggests that further research to confirm our observations and determine the mechanisms of development of metabolic complications associated with obesity depending on gender is needed.

Resistin secreted by porcine alveolar macrophages leads to endothelial cell dysfunction during Haemophilus parasuis infection.

Haemophilus parasuis (H. parasuis) causes exudative inflammation, implying endothelial dysfunction during pathogen infection. However, so far, the molecular mechanism of endothelial dysfunction caused by H. parasuis has not been clarified. By using the transwell-based cell co-culture system, we demonstrate that knocking out resistin in porcine alveolar macrophages (PAMs) dramatically attenuated endothelial monolayer damage caused by H. parasuis. The resistin secreted by PAMs inhibited the expression of the tight junction proteins claudin-5 and occludin rather than the adherens junction protein VE-cadherin in co-cultured porcine aortic endothelial cells (PAECs). Furthermore, we demonstrate that resistin regulated claudin-5 and occludin expression and monolayer PAEC permeability in an LKB1/AMPK/mTOR pathway-dependent manner. Additionally, we reveal that the outer membrane lipoprotein gene lppA in H. parasuis induced resistin expression in PAMs, as deleting lppA reduced resistin expression in H. parasuis-infected PAMs, causing a significant change in LKB1/AMPK/mTOR pathway activity in co-cultured PAECs, thereby restoring tight junction protein levels and endothelial monolayer permeability. Thus, we postulate that the H. parasuis lppA gene enhances resistin production in PAMs, disrupting tight junctions in PAECs and causing endothelial barrier dysfunction. These findings elucidate the pathogenic mechanism of exudative inflammation caused by H. parasuis for the first time and provide a more profound angle of acute exudative inflammation caused by bacteria.

The Mef2c/AdipoR1 axis is responsible for myogenic differentiation and is regulated by resistin in skeletal muscles.

Previous studies have shown that accumulated lipid and insulin resistance emerges in skeletal muscle after the onset of obesity and diabetes. We have previously shown that resistin significantly increases lipid contents in C2C12 cells. However, studies evaluating the effects of resistin on skeletal muscle cells and tissues are limited; despite that, an understanding of resistin action and function on lipid alteration in skeletal muscle tissues is critical for understanding obesity-related diseases. In this study, we document that resistin increases lipid deposition both in vitro and in vivo. Further, resistin promotes fiber type transformation, decreases enzyme activities, inhibits myogenic differentiation, and decreases muscle grip and excise endurance. In addition, adiponectin signaling is activated during myocyte differentiation, but it is inhibited at elevated resistin concentrations. Mechanistic investigation revealed that mef2c is responsible for adiponectin signaling pathway inhibition by inhibiting adipoR1 expression at the transcriptional level. In conclusion, this is the first study to document that resistin increases ectopic lipid deposition in skeletal muscles via a mef2c-adipoR1 signaling pathway, which reveals for the first time the presence of crosstalk between resistin and adiponectin in skeletal muscles.

Regulation of cardiovascular health and disease by visceral adipose tissue-derived metabolic hormones.

Visceral adipose tissue (VAT) is a metabolic organ known to regulate fat mass, and glucose and nutrient homeostasis. VAT is an active endocrine gland that synthesizes and secretes numerous bioactive mediators called 'adipocytokines/adipokines' into systemic circulation. These adipocytokines act on organs of metabolic importance like the liver and skeletal muscle. Multiple preclinical and in vitro studies showed strong evidence of the roles of adipocytokines in the regulation of metabolic disorders like diabetes, obesity and insulin resistance. Adipocytokines, such as adiponectin and omentin, are anti-inflammatory and have been shown to prevent atherogenesis by increasing nitric oxide (NO) production by the endothelium, suppressing endothelium-derived inflammation and decreasing foam cell formation. By inhibiting differentiation of vascular smooth muscle cells (VSMC) into osteoblasts, adiponectin and omentin prevent vascular calcification. On the other hand, adipocytokines like leptin and resistin induce inflammation and endothelial dysfunction that leads to vasoconstriction. By promoting VSMC migration and proliferation, extracellular matrix degradation and inflammatory polarization of macrophages, leptin and resistin increase the risk of atherosclerotic plaque vulnerability and rupture. Additionally, the plasma concentrations of these adipocytokines alter in ageing, rendering older humans vulnerable to cardiovascular disease. The disturbances in the normal physiological concentrations of these adipocytokines secreted by VAT under pathological conditions impede the normal functions of various organs and affect cardiovascular health. These adipokines could be used for both diagnostic and therapeutic purposes in cardiovascular disease.

Demethylation of miR-299-5p by aerobic exercise relieves insulin resistance in the vascular endothelium by repressing resistin.

AIMS: Insulin resistance (IR) is a critical marker underlying type 2 diabetes mellitus (T2DM). Exercise is reported to prevent IR, yet the mechanism of which is complicated and largely unknown. Here, the study aimed to ascertain whether and how aerobic exercise mediates IR in T2DM. METHODS: An in vivo model of high-fat diet (HFD)-induced IR and an in vitro model of high-glucose-induced IR were constructed. RESULTS: Aerobic exercise training in mice led to attenuation of IR in the vascular endothelium. microRNA-299-5p (miR-299-5p) expression was deficient in T2MD, which could be restored by aerobic exercise through modulating the DNA methylation modification enzymes. The expression of miR-299-5p enhanced by aerobic exercise consequently resulted in ameliorating the IR in vivo. Furthermore, increased levels of nitric oxide (NO), reduced levels of Angiotensin II (Ang II), vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in response to miR-299-5p elevation suggested the anti-IR role of miR-299-5p in IR-cell model. Dual-luciferase reporter and ChIP assays identified that miR-299-5p could bind to resistin and hence repressed the resistin level. CONCLUSION: The key observation of the study is that aerobic exercise stimulates miR-299-5p-targeted resistin inhibition through demethylation, which underlies the mechanism of reducing IR.

Exercise training-induced changes in exerkine concentrations may be relevant to the metabolic control of type 2 diabetes mellitus patients: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription. METHODS: A systematic search for relevant studies was performed in 3 databases. Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included: adiponectin, apelin, brain-derived neurotrophic factor, fetuin-A, fibroblast growth factor-21, follistatin, ghrelin, interleukin (IL)-6, IL-8, IL-10, IL-15, IL-18, leptin, myostatin, omentin, resistin, retinol-binding protein 4, tumor necrosis factor-α, and visfatin. RESULTS: Forty randomized controlled trials were selected for data extraction (n = 2160). Exercise training induces changes in adiponectin, fetuin-A, fibroblast growth factor-21, IL-6, IL-10, leptin, resistin, and tumor necrosis factor-α levels but has no significant effects on apelin, IL-18, and ghrelin compared to controls. Physical exercise training favored large and positive changes in pooled exerkines (i.e., an overall effect size calculated from several exerkines) (Hedge's g = 1.02, 95% confidence interval (95%CI): 0.76-1.28), which in turn were related to changes in glycated hemoglobin (mean difference (MD) = -0.81%, 95%CI: -0.95% to -0.67%), fasting glucose (MD = -23.43 mg/dL, 95%CI: -30.07 mg/dL to -16.80 mg/dL), waist circumference (MD = -3.04 cm, 95%CI: -4.02 cm to -2.07 cm), and body mass (MD = -1.93 kg, 95%CI: -2.00 kg to -1.86 kg). Slightly stronger effects were observed with aerobic, resistance, or high-intensity interval protocols at moderate- to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session. CONCLUSION: Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.

Resistin impairs mitochondrial homeostasis via cyclase-associated protein 1-mediated fission, leading to obesity-induced metabolic diseases.

OBJECTIVE: One of the suggested mechanisms of obesity-induced insulin resistance is mitochondrial dysfunction in target tissues such as skeletal muscle. In our study, we examined whether resistin, an adipokine associated with obesity-mediated insulin resistance, induced metabolic disorders by impairing mitochondrial homeostasis. METHODS: The morphology and function of mitochondria of skeletal muscle were examined in resistin-knockout and humanized resistin mice that were subjected to high-fat diet for 3 months. Morphology was examined by transmission electron microscopy. Mitochondria bioenergetics of skeletal muscle were evaluated using a Seahorse XF96 analyzer. Human skeletal myoblasts were used for in vitro studies on signaling mechanisms in responses to resistin. RESULTS: A high-fat diet in humanized resistin mice increased fragmented and shorter mitochondria in the skeletal muscle, whereas resistin-knockout mice had healthy normal mitochondria. In vitro studies showed that human resistin treatment impaired mitochondrial homeostasis by inducing mitochondrial fission, leading to a decrease in ATP production and mitochondrial dysfunction. Induction of mitochondrial fission by resistin was accompanied by increased formation of mitochondria-associated ER membranes (MAM). At the same time, resistin induced up-regulation of the protein kinase A (PKA) pathway. This activation of PKA induced phosphorylation of Drp1 at serine 616, leading to Drp1 activation and subsequent induction of mitochondrial fission. The key molecule that mediated human resistin-induced mitochondrial fission was adenylyl cyclase-associated protein 1 (CAP1), which was reported as a bona fide receptor for human resistin. Moreover, our newly developed biomimetic selective blocking peptide could repress human resistin-mediated mitochondrial dysfunction. High-fat diet-fed mice showed lower exercise capacity and higher insulin resistance, which was prevented by a novel peptide to block the binding of resistin to CAP1 or in the CAP1-knockdown mice. CONCLUSIONS: Our study demonstrated that human resistin induces mitochondrial dysfunction by inducing abnormal mitochondrial fission. This result suggests that the resistin-CAP1 complex could be a potential therapeutic target for the treatment of obesity-related metabolic diseases such as diabetes and cardiometabolic diseases.

Self-reported dietary omega-3 polyunsaturated fatty acids are associated with adipose tissue markers and glucose metabolism in apparently healthy subjects.

BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) and resistin are associated with dysfunctional adipose tissue (AT)-related metabolic complications. The role of dietary eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids in this relationship is unknown. AIM: To investigate the association of EPA and DHA with PAI-1 and resistin, as well as the role of this association on the glucose metabolism of apparently healthy subjects. SUBJECTS AND METHODS: Thirty-six healthy individuals were included. Validated food frequency questionnaires were used to analyse dietary habits. Inflammatory and glucose metabolism markers were quantified. Subcutaneous AT samples were obtained, and adipocyte number, area, and macrophage content were assessed. RESULTS: In 36 subjects aged 56 ± 8 years and with a body mass index of 26 ± 4 kg/m2, logEPA, and logDHA showed significant association with logresistin and a marginal association with PAI-1. Adipocyte number, area, and lognumber of macrophages per adipocyte significantly correlated with PAI-1 but not with logresistin. Although logEPA and logDHA were independently associated with loginsulin, loginsulin resistance, and C-Peptide, the addition of logresistin, but not of PAI-1, into the multivariable model, abolished the associations. CONCLUSIONS: EPA and DHA could modulate glucose metabolism across AT functional states. Our data indicate that this association is independent of other metabolic risk factors.

Single-cell RNA sequencing reveals rebalancing of immunological response in patients with periodontitis after non-surgical periodontal therapy.

BACKGROUND: Periodontitis is a major inflammatory disease of the oral mucosa that is not limited to the oral cavity but also has systemic consequences. Although the importance of chronic periodontitis has been emphasized, the systemic immune response induced by periodontitis and its therapeutic effects remain elusive. Here, we report the transcriptomes of peripheral blood mononuclear cells (PBMCs) from patients with periodontitis. METHODS: Using single-cell RNA sequencing, we profiled PBMCs from healthy controls and paired pre- and post-treatment patients with periodontitis. We extracted differentially expressed genes and biological pathways for each cell type and calculated activity scores reflecting cellular characteristics. Intercellular crosstalk was classified into therapy-responsive and -nonresponsive pathways. RESULTS: We analyzed pan-cellular differentially expressed genes caused by periodontitis and found that most cell types showed a significant increase in CRIP1, which was further supported by the increased levels of plasma CRIP1 observed in patients with periodontitis. In addition, activated cell type-specific ligand-receptor interactions, including the BTLA, IFN-γ, and RESISTIN pathways, were prominent in patients with periodontitis. Both the BTLA and IFN-γ pathways returned to similar levels in healthy controls after periodontal therapy, whereas the RESISTIN pathway was still activated even after therapy. CONCLUSION: These data collectively provide insights into the transcriptome changes and molecular interactions that are responsive to periodontal treatment. We identified periodontitis-specific systemic inflammatory indicators and suggest unresolved signals of non-surgical therapy as future therapeutic targets.