Resveratrol and Dulaglutide ameliorate adiposity and liver dysfunction in rats with diet-induced metabolic syndrome: Role of SIRT-1 / adipokines / PPARγ and IGF-1.

BACKGROUND: Adiposity and non-alcoholic fatty liver disease (NAFLD) are common characteristics of metabolic syndrome (MS). Understanding the underlying pathogenesis is crucial for the development of new remedies. Resveratrol controls obesity and glycemic disorders in patients with MS. OBJECTIVES: This study aimed to evaluate the effect of resveratrol and dulaglutide on adipose tissues and liver in rats with MS, declaring their possible mechanisms. METHODS: Rats allocated as Control, MS (induced by a high fat/ high sucrose diet for eight weeks), MS + Resveratrol (30 mg/kg/day orally), and MS + Dulaglutide (0.6 mg/kg twice weekly SC); drugs administration was in the last four weeks. Serum biochemical measurements were done. Liver and visceral fat were processed for biochemistry, histopathology, and immunohistochemistry. RESULTS: MS results demonstrated significantly increased systolic and diastolic blood pressure, anthropometric measurements, serum levels of alanine aminotransferase (ALT), glycemic indices, and lipids with decreased HDL-C. Tissue levels of leptin, malondialdehyde (MDA), and TNF-α reactivity significantly increased. Expression of adiponectin, PPARγ, and insulin growth factor-1 (IGF-1) decreased. Also, Western blotting mRNA gene expression of liver SIRT-1 was down-regulated. Resveratrol and dulaglutide significantly and effectively reversed MS complexity, ameliorating all findings, particularly NAFLD and adiposity-induced inflammation. Resveratrol significantly appears superior to dulaglutide regarding the effects on hemodynamics, lipids, adipokines, IGF-1 levels, and adipocyte size. Parallel, dulaglutide has more influence on glycemic control. CONCLUSION: Protective effects of the drugs may be through correlations between SIRT-1/adipokines/IGF-1 and PPARγ, improving the cross-talk between insulin resistance, obesity markers, liver dysfunction, and TNF-α. Promising multi-beneficial therapies of resveratrol or dulaglutide in MS are recommended clinically for this purpose. Showing the Experimental Design.

Effect of Dietary Intervention, with or without Cointerventions, on Inflammatory Markers in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease from simple steatosis to nonalcoholic steatohepatitis, with inflammatory cytokines and adipokines identified as drivers of disease progression. Poor dietary patterns are known to promote an inflammatory milieu, although the effects of specific diets remain largely unknown. This review aimed to gather and summarize new and existing evidence on the effect of dietary intervention on inflammatory markers in patients with NAFLD. The electronic databases MEDLINE, EMBASE, CINAHL, and Cochrane were searched for clinical trials which investigated outcomes of inflammatory cytokines and adipokines. Eligible studies included adults >18 y with NAFLD, which compared a dietary intervention with an alternative diet or control (no intervention) group or were accompanied by supplementation or other lifestyle interventions. Outcomes for inflammatory markers were grouped and pooled for meta-analysis where heterogeneity was allowed. Methodological quality and risk of bias were assessed using the Academy of Nutrition and Dietetics Criteria. Overall, 44 studies with a total of 2579 participants were included. Meta-analyses indicated intervention with an isocaloric diet plus supplement was more effective in reducing C-reactive protein (CRP) [standard mean difference (SMD): 0.44; 95% CI: 0.20, 0.68; P = 0.0003] and tumor necrosis factor-alpha (TNF-α) (SMD: 0.74; 95% CI: 0.02, 1.46; P = 0.03) than an isocaloric diet alone. No significant weighting was shown between a hypocaloric diet with or without supplementation for CRP (SMD: 0.30; 95% CI: -0.84, 1.44; P = 0.60) and TNF-α (SMD: 0.01; 95% CI: -0.43, 0.45; P = 0.97). In conclusion, hypocaloric and energy-restricted diets alone or with supplementation, and isocaloric diets with supplementation were shown to be most effective in improving the inflammatory profile of patients with NAFLD. To better determine the effectiveness of dietary intervention alone on a NAFLD population, further investigations of longer durations, with larger sample sizes are required.

Changes in adipokine concentrations in antidepressant-resistant bipolar depression after ketamine infusion and electroconvulsive therapy.

OBJECTIVES: This study attempts to assess the concentration of two opposite-acting adipokines (anti-inflammatory adiponectin and pro-inflammatory resistin) in antidepressant-resistant patients undergoing ketamine infusion (KI) and electroconvulsive therapy (ECT). METHODS: The study group comprised 52 patients hospitalised due to episodes of depression in the course of bipolar disorders. The Hamilton depression scale was used to assess the intensity of the depression symptoms before starting therapy and one day after its completion. The serum concentration of adipokines was determined before and after the therapeutic intervention using an ELISA method. RESULTS: Baseline adipokine levels differed between patients receiving KI and ECT therapy. Regardless of the procedure used, these levels changed after treatment, with the nature of these changes being different. In the case of KI, the adiponectin levels increased, and resistin levels decreased. In contrast, after ECT, the concentrations of both adipokines decreased. Changes in adipokine concentrations correlated with improvement in mental status, as assessed by the Hamilton Rating Scale, type of bipolar disorder, and gender. CONCLUSIONS: Adipokines remain interesting candidate biomarkers in assessing the state and course of the disease depending on the therapeutic procedure applied. However, the relatively small study group and limited original research available for discussion justify further investigation.

Isolated vitamin D supplementation improves the adipokine profile of postmenopausal women: a randomized clinical trial.

OBJECTIVE: The aim of the study is to evaluate the effect of vitamin D supplementation alone on the adipokine profile of postmenopausal women. METHODS: In this randomized clinical trial, 160 women were randomized to 2 groups: oral supplementation with 1,000 IU cholecalciferol/d (vitamin D, n = 80) or placebo (PL, n = 80). Women with amenorrhea 12 months or more and aged 50 to 65 years were included. Women with established cardiovascular disease, insulin-dependent diabetes, renal failure, liver diseases, and previous use of menopausal hormone therapy and vitamin D were excluded. The intervention lasted 9 months and serum adiponectin, resistin, and adipsin levels were determined at the start and end of treatment. Intention to treat was adopted as the statistical method using a repeated measures design, followed by Wald's multiple comparison test adjusted for group × time interaction. RESULTS: After 9 months, 25-hydroxyvitamin D concentrations increased from 15.0 ± 7.5 to 27.5 ± 10.4 ng/mL (+45.4%) in the vitamin D group and decreased from 16.9 ± 6. to 13.8 ± 6.0 ng/mL (-18.5%) in the PL group ( P < 0.001). In the vitamin D group, there was an increase in adiponectin (+18.6%) and a decrease in resistin (-32.4%, P < 0.05). At the end point, a difference was observed between the PL and vitamin D groups in mean adiponectin and resistin levels (11.5 ± 5.5 vs 18.5 ± 21.8 ng/mL, P = 0.047, and 16.5 ± 3.5 vs 11.7 ± 3.3 ng/mL, P = 0.027, respectively). There were no significant intervention effects on serum adipsin levels. CONCLUSIONS: Daily supplementation with 1,000 IU of vitamin D alone was associated with an increase in adiponectin and a decrease in resistin, suggesting a beneficial effect on the adipokine profile of postmenopausal women with vitamin D deficiency.

The Role of Adipokines in the Establishment and Progression of Head and Neck Neoplasms.

Adipokines constitute a family of protein factors secreted by white adipose tissue (WAT), that regulate the functions of WAT and other sites. Leptin, adiponectin and resistin, are the main adipokines present in serum and saliva, targeting several tissues and organs, including vessels, muscles, liver and pancreas. Besides body mass regulation, adipokines affect glucose homeostasis, inflammation, angiogenesis, cell proliferation and apoptosis, and other crucial cell procedures. Their involvement in tumor formation and growth is well established and deregulation of adipokine and adipokine receptors' expression is observed in several malignancies including those located in the head and neck region. Intracellular effects of adipokines are mediated by a plethora of receptors that activate several signaling cascades including Janus kinase/ Signal transducer and activator of transcription (JAK/ STAT pathway), Phospatidylinositol kinase (PI3/ Akt/ mTOR) and Peroxisome proliferator-activated receptor (PPAR). The present review summarizes the current knowledge on the role of adipokines family members in carcinogenesis of the head and neck region. The diagnostic and prognostic significance of adipokines and their potential role as serum and saliva biomarkers are also discussed.

Neuroprotective nature of adipokine resistin in the early stages of focal cerebral ischemia in a stroke mouse model.

New evidence suggests that resistin may have a therapeutic potential effect in management of neurodegenerative disease; but its role in the pathophysiology of stroke-induced injuries is not understood. However, further investigations are required to elucidate the effect of resistin and explore its possible molecular mechanisms on the ischemic reperfusion injury. Transient focal cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) in mice. Animal treated with resistin at doses of 25, 50, 100, 200, and 400 ng/mouse, on the MCAO commencement. Neurological function, infarct size, brain edema and Blood-brain barrier (BBB) disruption were measured. Additionally, content of malondialdehyde (MDA), TUNEL-positive cells and apoptosis-related proteins were assessed by immunohistochemistry and western blot techniques. Resistin mRNA was detected at 3 h, 6 h, 12 h and 24 h after MCAO using real-time QRT-PCR method. Central administration of resistin only at doses of 200 and 400 ng/mouse considerably reduced the infarct size and promoted neurological function (p < 0.001). In addition, resistin (400 ng/mouse) significantly decreased brain edema (p < 0.001), evans blue (EB) leakage (p < 0.05), MDA content (p < 0.005), apoptotic cells and apoptosis-related proteins (p < 0.001). Resistin mRNA expression markedly increased at 12-h time point and then returned to basal level at 24 h after MCAO. Our findings revealed that treatment with resistin could attenuate ischemic damage in a dose-dependent approach via suppressing apoptosis and oxidative stress. Application of resistin in clinical settings to treat stroke and brain ischemia warrants further research.

Adipokines and Myokines: A Pivotal Role in Metabolic and Cardiovascular Disorders.

Obesity induces an imbalance in the expression and secretion of several cytokines, which contributes to the development of metabolic and cardiovascular disorders. On the contrary, skeletal muscle is known to have a role in reversing the detrimental impact of obesity. It has been established that adipose tissue acts as an endocrine organ that secretes proinflammatory and anti-inflammatory adipokines. Similarly, skeletal muscle produces secretory molecules, called myokines, from contracting muscle fibers. Myokines were recently recognized as beneficial modulators of obesity, metabolic syndrome, and type 2 diabetes. Furthermore, adipokines and myokines play a crucial role in the communication between adipose tissue, skeletal muscle and other organs. It could be beneficial to find novel adipokines and myokines, and to explore their signaling pathways to identify targets for the treatment and prevention of cardiometabolic disorders. In this review, we summarize recent studies on cross-talk between skeletal muscle and adipose tissue. In particular, we concentrate on the major action mechanisms of adipokines and myokines, such as adiponectin, adipocyte fatty acid binding protein, C1q/TNF-related proteins, interleukin- 6, irisin, and fibroblast growth factor 21.

Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system.

Obesity is a risk factor of cardiovascular diseases. However, in the case of heart failure, obese and overweight patients have a more favourable prognosis compared to patients who have a normal body weight. This phenomenon is referred to as the "obesity paradox," and it is explained by, among others, a positive effect of adipokines produced by adipose tissue, particularly by the tissue located in the direct vicinity of the heart and blood vessels. The favourable effect on the cardiovascular system is mostly associated with adiponectin and omentin, but the levels of these substances are reduced in obese patients. Among the adipokines which levels are positively correlated with the adipose tissue content, favourable activity is demonstrated by apelin, progranulin, chemerin, TNF-α (tumour necrosis factor-)α, CTRP-3 (C1q/tumour necrosis factor (TNF) related protein), leptin, visfatin and vaspin. This activity is associated with the promotion of regeneration processes in the damaged myocardium, formation of new blood vessels, reduction of the afterload, improvement of metabolic processes in cardiomyocytes and myocardial contractile function, inhibition of apoptosis and fibrosis of the myocardium, as well as anti-inflammatory and anti-atheromatous effects. The potential use of these properties in the treatment of heart failure and ischaemic heart disease, as well as in pulmonary hypertension, arterial hypertension and the limitation of the loss of cardiomyocytes during cardioplegia-requiring cardiosurgical procedures, is studied. The most advanced studies focus on analogues of apelin and progranulin.

Targeted delivery of adipocytokines into the heart by induced adipocyte cell-sheet transplantation yields immune tolerance and functional recovery in autoimmune-associated myocarditis in rats.

BACKGROUND: Clinical prognosis is critically poor in fulminant myocarditis, while it's initiation or progression is fated, in part, by T cell-mediated autoimmunity. Adiponectin (APN) and associated adipokines were shown to be immune tolerance inducers, although the clinically relevant delivery method into target pathologies is under debate. Whether the cell sheet-based delivery system of adipokines might induce immune tolerance and functional recovery in experimental autoimmune myocarditis (EAM) was tested. METHODS AND RESULTS: Scaffold-free-induced adipocyte cell-sheet (iACS) was generated by differentiating adipose tissue-derived syngeneic stromal vascular-fraction cells into adipocytes on temperature-responsive dishes. Rats with EAM underwent iACS implantation or sham operation. Supernatants of iACS contained a high level of APN and hepatocyte growth factor (HGF), and reduced proliferation of CD4-positive T cells in vitro. Immunohistolabelling showed that the iACS implantation elevated the levels of APN and HGF in the myocardium compared to the sham operation, which attenuated the immunological response by inhibiting CD68-positive macropharges and CD4-positive T-cells and activating Foxp3-positive regulatory T cells. Consequently, left ventricular ejection fraction was significantly greater after the iACS implantation than after the sham operation, in association with less collagen accumulation. CONCLUSIONS: The targeted delivery of adipokines using tissue-engineered iACS ameliorated cardiac performance of the EAM rat model via effector T cell suppression and induction of immune tolerance. These findings might suggest a potential of this tissue-engineered drug delivery system in treating fulminant myocarditis in the clinical setting.

C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart.

BACKGROUND: Obesity and diabetes mellitus adversely affect postischemic heart remodeling via incompletely understood mechanisms. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation, similar to adiponectin. The aim of the present study was to determine whether CTRP3 may regulate postischemic cardiac remodeling and cardiac dysfunction, and, if so, to elucidate the underlying mechanisms. METHODS AND RESULTS: Male adult mice were subjected to myocardial infarction (MI) via left anterior descending coronary artery occlusion. Both the effect of MI on endogenous CTRP3 expression/production and the effect of exogenous CTRP3 (adenovirus or recombinant CTRP3) replenishment on MI injury were investigated. MI significantly inhibited adipocyte CTRP3 expression and reduced the plasma CTRP3 level, reaching a nadir 3 days after MI. CTRP3 replenishment improved survival rate (P<0.05), restored cardiac function, attenuated cardiomyocyte apoptosis, increased revascularization, and dramatically reduced interstitial fibrosis (all P<0.01). CTRP3 replenishment had no significant effect on cardiac AMP-activated protein kinase phosphorylation but significantly increased Akt phosphorylation and expression of hypoxia inducing factor-1α and vascular endothelial growth factor. Surprisingly, treatment of human umbilical vascular endothelial cells with CTRP3 did not directly affect nitric oxide production or tube formation. However, preconditioned medium from CTRP3-treated cardiomyocytes significantly enhanced human umbilical vascular endothelial cell tube formation, an effect blocked by either pretreatment of cardiomyocytes with a PI3K inhibitor or pretreatment of human umbilical vascular endothelial cells with a vascular endothelial growth factor inhibitor. Finally, the protective effect of adipocyte-conditioned medium against hypoxia-induced cardiomyocyte injury is significantly blunted when CTRP3 is knocked down. CONCLUSION: CTRP3 is a novel antiapoptotic, proangiogenic, and cardioprotective adipokine, the expression of which is significantly inhibited after MI.

Physiological, pathological and potential therapeutic roles of adipokines.

Formerly regarded purely as passive energy storage, adipose tissue is now recognized as a vital endocrine organ. Adipocytes secrete diverse peptide hormones named adipokines, which act in a autocrine, paracrine or endocrine way to influence several biological functions. Adipokines comprise diverse bioactive substances, including cytokines, growth, and complement factors, which perform essential regulatory functions related to energy balance, satiety and immunity. Presently adipokines have been widely implicated in obesity, diabetes, hypertension and cardiovascular diseases. In this article we aim to present a brief description of the roles and potential therapeutic modulation of adipokines, such as leptin, resistin, adiponectin, apelin, visfatin, FABP-4, tumor necrosis factor-α (TNF-α), interleukin-6 and plasminogen activator inhibitor-1 (PAI-1).

Targeting adipocyte apoptosis: a novel strategy for obesity therapy.

Obesity is an increasing world problem that may cause several metabolic complications including insulin resistance, hyperlipidemia, hypertension, and atherosclerosis. Development of therapeutic drugs for obesity has been proven difficult. Current strategies for weight reduction are inhibition of food intake through the central nervous system or blocking the absorption of lipids in the gut. These therapies have many side effects, so new treatments are urgently needed. Fat loss could also be achieved through a decrease in the size and number of adipocytes through apoptosis. Apoptosis is a normal phenomenon of cell death for the purpose of maintaining homeostasis. Induction of apoptosis is a reasonable way to remove adipocytes in obese patients. It is reported that several adipokines and natural products play roles in induction of adipocyte apoptosis. Here we review the recent progress of the roles and mechanisms of adipocyte apoptosis induced by leptin, tumor necrosis factor-α (TNF-α), and natural compounds.

Resistin, an adipocytokine, offers protection against acute myocardial infarction.

Resistin, an adipocyte-derived hormone, is thought to represent a link between obesity and insulin-resistant diabetes. The potential role of resistin as a cardioprotective agent has not been explored. Our hypothesis is that resistin has a cardioprotective effect that is mediated by the resistin receptor-coupled activation of PI3K/Akt/PKC/K(ATP) dependent pathways. Our studies demonstrated that pretreatment of mouse hearts with 10 nM resistin for 5 min protected the heart against I/R injury in a mouse heart perfusion model. When mouse hearts were subjected to 60 min of LAD ligation followed by 4 h of reperfusion, resistin pretreatment (33 microg/kg) for 30 min or 24 h before ligation was able to significantly reduce the infarct size/risk area. The protective effect of resistin was abolished by wortmannin, as well as by an Akt inhibitor, triciribine. Resistin's protective effect was absent in Akt kinase-deficient mutant mice. The protective effect was also blocked by chelerythrine, a PKC inhibitor, and epsilonV1-2, a PKCepsilon inhibitor. Finally, the protective effect was blocked by 5-hydroxydecanoate, which blocks the opening of mitoK(ATP) channels. Resistin-induced Akt phosphorylation in HL-1 cells was inhibited by wortmannin and triciribine. Resistin also induced PKCepsilon phosphorylation, which was blocked by triciribine. These studies demonstrate that resistin's cardioprotective effect is mediated by PI3K/Akt/PKC dependent pathways. In addition to cardiomyocytes, resistin also induced Akt phosphorylation in endothelial cells and smooth muscle cells, suggesting that resistin receptors are present in these cells. The effect of resistin on apoptosis was assessed in hearts subjected to 30 min of ischemia and 3 h of reperfusion. There were significantly fewer in situ oligo ligation-positive myocyte nuclei in mice treated with resistin. Our results show that resistin can dramatically reduce apoptosis and infarct size, thus protecting the heart against I/R injury.