Adipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV.

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.

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.

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.

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.

Regulatory Networks, Management Approaches, and Emerging Treatments of Nonalcoholic Fatty Liver Disease.

The pathogenesis of NAFLD is complex and diverse, involving multiple signaling pathways and cytokines from various organs. Hepatokines, stellakines, adipokines, and myokines secreted by hepatocytes, hepatic stellate cells, adipose tissue, and myocytes play an important role in the occurrence and development of nonalcoholic fatty liver disease (NAFLD). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributes to the progression of NAFLD by mediating liver inflammation, immune response, hepatocyte death, and later compensatory proliferation. In this review, we first discuss the crosstalk and interaction between hepatokines, stellakines, adipokines, and myokines and NF-κB in NAFLD. The characterization of the crosstalk of NF-κB with these factors will provide a better understanding of the molecular mechanisms involved in the progression of NAFLD. In addition, we examine new expert management opinions for NAFLD and explore the therapeutic potential of silymarin in NAFLD/NASH.

Periodontal status and whole salivary adipokines after scaling and root planing with and without adjunct antimicrobial photodynamic therapy in obese patients with periodontitis.

OBJECTIVE: Whole-salivary (WS) adiponectin and leptin levels after scaling and root planing (SRP) with and without antimicrobial-photodynamic-therapy (aPDT) in obese and normal-weight individuals with periodontitis remain uninvestigated. This study compared the effect of SRP without and with adjuvant aPDT on periodontal status and WS leptin and adiponectin levels (LAL) in obese patients with periodontitis. METHODS: Groups 1 and 2 entailed obese patients without and with periodontitis. Groups 3 and 4 had normal weight individuals without and with periodontitis. Therapeutically, individuals with periodontitis were categorized into test- (SRP+aPDT) and control- (SRP alone) subgroups. All patients without periodontitis underwent routine dental prophylaxis. Clinical attachment loss (AL), gingival and plaque index (GI and PI), probing depth (PD), missing teeth (MT) and WS LAL were measured at baseline and at three months of follow-up. P<5% were graded statistically significant. RESULTS: At baseline, clinicoradiographic variables were significantly higher among patients in test- and control-groups in groups 1 (P<0.01) and 3 (P<0.01) versus 2 and 4. In group 2 and 3, LL were significantly high at baseline compared with follow-up (P<0.01). There was no difference in periodontal parameters and WS adiponectin and LL in the test and control-groups at of follow-up. No correlation existed between salivary LAL and clinical periodontal parameters (PI, GI, PD and clinical AL). No correlation existed between age, gender and BMI and WS LAL. CONCLUSION: In the short-term, SRP with or without aPDT is ineffective in the treatment of periodontitis in obese patients with periodontitis.

Adipocytokines and achievement of low disease activity in rheumatoid arthritis.

PURPOSE: To determine if adipocytokines are independently associated with the achievement of low disease activity (LDA) over long-term follow-up in a large rheumatoid arthritis (RA) registry. METHODS: This cohort study evaluated adults with RA from the Veteran's Affairs RA Registry. Adipocytokines (adiponectin, leptin, and fibroblast growth factor [FGF]-21) and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum from enrollment. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox proportional hazard models evaluated associations between adipocytokines and rates of 1) DAS28 LDA and remission, 2) individual Boolean remission criteria and 3) initiation of a new bDMARD or tsDMARD. RESULTS: There were 1,276 participants with a DAS28 >3.2 at enrollment. Of these, 827 achieved LDA and 598 achieved remission over 2,287 and 4,096 person-years, respectively. Patients in the highest quartile of adiponectin had lower rates LDA before and after adjustment [aHR Q4: 0.68 (0.53,0.87) p<0.001]. Those in the highest quartile of leptin and FGF-21 also had lower rates of LDA. Higher quartiles of adipocytokines were also associated with lower rates of achieving a low patient/evaluator global scores and low tender joint counts. Among 1,236 biologic-naïve participants, values above the median for adiponectin [HR: 1.67 (1.23,1.26) p = 0.001] and FGF-21 [HR: 1.27 (1.09,1.47) p = 0.002] were associated with a greater likelihood of initiating a b/tsDMARD. CONCLUSIONS: Adipocytokines may serve as prognostic biomarkers of a more severe RA disease course. Additional study is needed to determine whether adipocytokines are phenotypic markers or whether they actively promote disease progression.

[Changes in adipokines in the blood of patients with the first episode of schizophrenia during treatment with haloperidol and risperidone]. / Izmenenie soderzhaniya adipokinov krovi u bol'nykh s pervym epizodom shizofrenii v protsesse terapii galoperidolom i risperidonom.

OBJECTIVE: To study plasma adipokines (adiponectin, leptin, adipsin) in patients with the first episode of schizophrenia treated with haloperidol and risperidone. MATERIAL AND METHODS: Two hundred and twelve patients with the first episode of paranoid schizophrenia (F20.09) were examined. Patients were divided into the haloperidol group (n=107) and the risperidone group (n=105). The control group included 132 healthy people. Body mass index was recorded at baseline and in 2, 4, 6, 8 week of treatment. Adiponectin, adipsin and leptin were determined by the multiplex analysis. Blood test was conducted prior to therapy and after 8 weeks of treatment. RESULTS: An increase in body mass index is recorded in both clinical groups, with no statistically significant differences between groups. Before treatment with antipsychotics, the levels of adiponectin and adipsin increase in both clinical groups. In the course of therapy, the levels of adiponectin and adipsin significantly increase in the haloperidol group and the levels of adiponectin and leptin in the risperidone group. CONCLUSION: The increase in body weight is not the only mechanism of changes in adipokines in blood during treatment with antipsychotics. Further studies on the relationship between the levels of adipokines and pharmacogenic metabolic disorders are required.

Zinc-α2-glycoprotein relieved seizure-Induced neuronal glucose uptake impairment via insulin-like growth factor 1 receptor-regulated glucose transporter 3 expression.

Glucose hypometabolism is observed in epilepsy and promotes epileptogenesis. Glucose hypometabolism in epilepsy may be attributed to decreased neuronal glucose uptake, but its molecular mechanism remains unclear. Zinc-α2-glycoprotein (ZAG) is related to glucose metabolism and is reported to suppress seizures. The anti-epileptic effect of ZAG may be attributed to its regulation of neuronal glucose metabolism. This study explored the effect of ZAG on neuronal glucose uptake and its molecular mechanism via insulin-like growth factor 1 receptor (IGF1R)-regulated glucose transporter 3 (GLUT-3) expression. The ZAG level was modulated by lentivirus in primary culture neurons. Neuronal seizure models were induced by Mg2+ -free artificial cerebrospinal fluid. We assessed neuronal glucose uptake by the 2-NBDG method and Glucose Uptake Colorimetric Assay Kit. IGF1R was activated by IGF1 and blocked by AXL1717. The expression and distribution of IGF1R and GLUT-3, together with IGF1R phosphorylation, were measured by western blot. The binding between ZAG and IGF1R was determined by coimmunoprecipitation. Neuronal glucose uptake and GLUT-3 expression were significantly decreased by seizure or ZAG knockdown, whereas ZAG over-expression or IGF1 treatment reversed this decrease. The effect of ZAG on neuronal glucose uptake and GLUT-3 expression was blocked by AXL1717. ZAG increased IGF1R distribution and phosphorylation possibly by binding. Additionally, IGF1R increased GLUT-3 activity by increasing GLUT-3 expression. In epilepsy/seizure, neuronal glucose uptake suppression may be attributed to a decrease in ZAG, which suppresses neuronal GLUT-3 expression by regulating the activity of IGF1R. ZAG, IGF1R, and GLUT-3 may be novel potential therapeutic targets of glucose hypometabolism in epilepsy and seizures.

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.

The potential of adipokines as therapeutic agents for cardiovascular disease.

Adipose tissue functions as an endocrine organ by producing bioactive secretory proteins, also known as adipokines, that can directly act on nearby or remote organs. Most of the adipokines are upregulated by obese conditions, and typically promote obese complications. In contrast, some adipokines, such as adiponectin, CTRP9 and omentin, are downregulated in obese states. These factors exert salutary actions on obesity-linked cardiovascular disorders. In this review, we focus on the significance of adiponectin, CTRP9 and omentin as therapeutic agents for cardiovascular disease.

The chemerin receptor 23 agonist, chemerin, attenuates monosynaptic C-fibre input to lamina I neurokinin 1 receptor expressing rat spinal cord neurons in inflammatory pain.

BACKGROUND: Recent evidence has shown that the chemerin receptor 23 (ChemR23) represents a novel inflammatory pain target, whereby the ChemR23 agonists, resolvin E1 and chemerin, can inhibit inflammatory pain hypersensitivity, by a mechanism that involves normalisation of potentiated spinal cord responses. This study has examined the ability of the ChemR23 agonist, chemerin, to modulate synaptic input to lamina I neurokinin 1 receptor expressing (NK1R+) dorsal horn neurons, which are known to be crucial for the manifestation of inflammatory pain. RESULTS: Whole-cell patch-clamp recordings from pre-identified lamina I NK1R+ neurons, in rat spinal cord slices, revealed that chemerin significantly attenuates capsaicin potentiation of miniature excitatory postsynaptic current (mEPSC) frequency, but is without effect in non-potentiated conditions. In tissue isolated from complete Freund's adjuvant (CFA) treated rats, chemerin significantly reduced the peak amplitude of monosynaptic C-fibre evoked excitatory postsynaptic currents (eEPSCs) in a subset of lamina I NK1R+ neurons, termed chemerin responders. However, chemerin did not alter the peak amplitude of monosynaptic C-fibre eEPSCs in control tissue. Furthermore, paired-pulse recordings in CFA tissue demonstrated that chemerin significantly reduced paired-pulse depression in the subset of neurons classified as chemerin responders, but was without effect in non-responders, indicating that chemerin acts presynaptically to attenuate monosynaptic C-fibre input to a subset of lamina I NK1R+ neurons. CONCLUSIONS: These results suggest that the reported ability of ChemR23 agonists to attenuate inflammatory pain hypersensitivity may in part be due to a presynaptic inhibition of monosynaptic C-fibre input to lamina I NK1R+ neurons and provides further evidence that ChemR23 represents a promising inflammatory pain target.

Adipose tissue, hormones, and treatment of type 1 diabetes.

Type 1 diabetes (T1D) is a serious disease with increasing incidence worldwide, with fatal consequences if untreated. Traditional therapies require direct or indirect insulin replacement, which involves numerous limitations and complications. While insulin is the major regulator of blood glucose, recent reports demonstrate the ability of several extra-pancreatic hormones to decrease blood glucose and improve metabolic homeostasis. Such hormones mainly include adipokines originating from adipose tissue (AT), while specific factors from the gut and liver also contribute to glucose homeostasis. Correction of T1D with adipokines is progressively becoming a realistic option, with the potential to overcome many problems associated with insulin replacement. Several recent studies demonstrate insulin-independent reversal or amelioration of T1D through administration of specific adipokines. Our recent work demonstrates the ability of healthy AT to compensate for the function of endocrine pancreas in long-term correction of T1D. This review discusses the potential of AT-related therapies for T1D as viable alternatives to insulin replacement.

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.