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.

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.

The Role of Adipokines between Genders in the Pathogenesis of Osteoarthritis.

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability-in particular, between genders. Recent research has increasingly focused on the role of adipokines-especially leptin, adiponectin, and resistin-in the development of OA. Adipokines, peptide hormones primarily secreted by adipose tissue, are involved in crucial physiological processes related to metabolism and immunity. They can also impact bone and cartilage turnover by interacting with joint cells such as osteoblasts, osteoclasts, chondrocytes, and mesenchymal stem cells, thereby linking inflammation with bone cartilage homeostasis. This review aims to elucidate the structure and functions of various adipokines, their serum and synovial levels, and their association with clinical presentation and radiographic progression in OA patients, with a focus on differences between sexes. A narrative literature review was conducted using three databases specifically analyzing sex differences. OA patients generally show elevated serum and synovial levels of leptin, chemerin, and visfatin, as well as high plasma levels of resistin and visfatin. In contrast, synovial levels of adiponectin and omentin are reduced in OA patients compared to healthy individuals, with an inverse relationship to disease severity, suggesting a potential protective role. Resistin and leptin were positively correlated with pain severity and radiographic progression, while adiponectin's role in OA remains controversial. Regarding sex differences, male OA patients exhibited higher serum levels of leptin, chemerin, and omentin compared to healthy controls, with a positive correlation to the BMI and estrogen levels, potentially explaining the sexual dimorphism observed in this condition. Studies on visfatin and lipocalin did not reveal significant differences in synovial or serum levels between the sexes. The role of resistin remains controversial. Adipokines influence the joint microenvironment and contribute to the progression of osteoarthritis (OA). However, the precise biological mechanisms are not yet fully understood due to the complex interactions between the metabolic, mechanical, and immune systems. Further research is needed to clarify their roles in OA and to identify targeted therapies for managing this degenerative disease.

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.

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.

Adipocytes promote breast tumorigenesis through TAZ-dependent secretion of Resistin.

Adipocytes have been implicated in breast tumor growth and stemness maintenance through secreted factors. However, the mechanisms by which these cytokines are regulated during diet-induced obesity and contribute to breast tumorigenesis remain largely unknown. Here we show that transcription cofactor TAZ in adipocytes is directly up-regulated by the free fatty acid/PPARγ axis upon dietary fat stimulation. TAZ knockdown alters the expression profile of a series of secreted proteins and attenuates the tumor-supporting function of adipocytes. Moreover, we identify Resistin, an adipose-derived hormone, as a functional downstream target of TAZ, which facilitates tumorigenesis, and its expression correlated with adipocyitc TAZ in triple-negative breast cancer samples. Further, Adiponectin-cre-mediated TAZ knockout in adipocytes mitigates breast tumor growth. Taken together, our findings highlight how diet-induced TAZ expression in adipocytes promotes tumorigenesis, suggesting promising cancer therapeutic targets.

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.

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.

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.

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.

A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

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.

Toll-like Receptor 7 (TLR7) Is Expressed in Adipocytes and the Pharmacological TLR7 Agonist Imiquimod and Adipocyte-Derived Cell-Free Nucleic Acids (cfDNA) Regulate Adipocyte Function.

Endosome-localized Toll-like receptors (TLRs) 3 and 9 are expressed and functionally active in adipocytes. The functionality and role of TLR7 in adipocyte biology and innate immunity of adipose tissue (AT) is poorly characterized. We analyzed TLR7 mRNA and protein expression in murine 3T3-L1 and primary adipocytes, in co-cultures of 3T3-L1 adipocytes with murine J774A.1 monocytes and in human AT. The effects of TLR7 agonists imiquimod (IMQ) and cell-free nucleic acids (cfDNA) on adipokine concentration in cell-culture supernatants and gene expression profile were investigated. We found that TLR7 expression is strongly induced during adipocyte differentiation. TLR7 gene expression in adipocytes and AT stroma-vascular cells (SVC) seems to be independent of TLR9. IMQ downregulates resistin concentration in adipocyte cell-culture supernatants and modulates gene expression of glucose transporter Glut4. Adipocyte-derived cfDNA reduces adiponectin and resistin in cell-culture supernatants and potentially inhibits Glut4 gene expression. The responsiveness of 3T3-L1 adipocytes to imiquimod is preserved in co-culture with J774A.1 monocytes. Obesity-related, adipocyte-derived cfDNA engages adipocytic pattern recognition receptors (PRRs), modulating AT immune and metabolic homeostasis during adipose inflammation.

The Levels of Ghrelin, Glucagon, Visfatin and Glp-1 Are Decreased in the Peritoneal Fluid of Women with Endometriosis along with the Increased Expression of the CD10 Protease by the Macrophages.

The aim of this study was to evaluate the levels of ten energy metabolism factors: C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1 (total), resistin, and visfatin, and to determine the expression of GLP1R receptors, CD10, CD26 proteases, and pro-inflammatory marker CD86 by macrophages in the peritoneal fluid (PF) in patients with endometriosis. The study included 54 women with endometriosis and a control group of 30 women with uterine myoma without signs of endometriosis. The levels of factors in PF were assessed by a multiplex method. Expression of GLP1R receptors, CD10, CD26 proteases, and CD86 by macrophages was evaluated using flow cytometry. It was found that in women with endometriosis, the concentrations of ghrelin, GLP-1, glucagon, and visfatin in PF were reduced (p = 0.007, p = 0.009, p = 0.002, p = 0.008, respectively). At the same time, there was a noted increase in the CD10 protease expression by peritoneal macrophages (p = 0.044). Correlation analysis showed a positive correlation of ghrelin and GLP-1 levels with CD86 macrophage expression (p = 0.044, p = 0.022, respectively) in the study group; a positive correlation was also found between the levels of GLP-1, glucagon, and visfatin with CD26 macrophage expression (p = 0.041, p = 0.048, p = 0.015, respectively) in PF. No correlations were found in the control group. These results indicate that a decrease in the levels of ghrelin, GLP-1, glucagon, and visfatin in PF may contribute to endometriosis development through their impact on the expression of pro-inflammatory markers of PF macrophages.

Exosomal MALAT1 Derived from High Glucose-Treated Macrophages Up-Regulates Resistin Expression via miR-150-5p Downregulation.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in the pathophysiological process associated with diabetes-related complications. The effect of high glucose levels on macrophage-derived exosomal MALAT1 is unknown. Therefore, we investigated the molecular regulatory mechanisms controlling exosomal MALAT1 in macrophages under high glucose treatment and the therapeutic target of macrophage-derived exosomal MALAT1 using a balloon injury model of vascular disease in diabetic rats. High glucose (25 mM) significantly increased MALAT1 expression in macrophage-derived exosomes. MALAT1 suppressed miR-150-5p expression in macrophage-derived exosomes under high-glucose conditions. Silencing MALAT1 using MALAT1 siRNA significantly reversed miR-150-5p expression induced by macrophage-derived exosomes. Macrophage-derived exosomes under high-glucose treatment significantly increased resistin expression in macrophages. Silencing MALAT1 and overexpression of miR-150-5p significantly decreased resistin expression induced by macrophage-derived exosomes. Overexpression of miR-150-5p significantly decreased resistin luciferase activity induced by macrophage-derived exosomes. Macrophage-derived exosome significantly decreased glucose uptake in macrophages and silencing MALAT1, resistin or overexpression of miR-150-5p significantly reversed glucose uptake. Balloon injury to the carotid artery significantly increased MALAT1 and resistin expression and significantly decreased miR-150-5p expression in arterial tissue. Silencing MALAT1 significantly reversed miR-150-5p expression in arterial tissue after balloon injury. Silencing MALAT1 or overexpression of miR-150-5p significantly reduced resistin expression after balloon injury. In conclusion, high glucose up-regulates MALAT1 to suppress miR-150-5p expression and counteracts the inhibitory effect of miR-150-5p on resistin expression in macrophages to promote vascular disease. Macrophage-derived exosomes containing MALAT1 may serve as a novel cell-free approach for the treatment of vascular disease in diabetes mellitus.

Resistin is co-secreted with adiponectin in white mouse adipocytes.

In the current work we have investigated the cellular and molecular regulation of resistin secretion in cultured and primary mouse adipocytes. Resistin is an adipose tissue hormone proposed to contribute to metabolic disease. In rodents, resistin is secreted from white adipocytes whereas it is in humans synthesised and released from other cell types within white adipose tissue. The metabolic importance of resistin has been studied in both mouse and man, but the regulation of its release remains poorly investigated. Here we define that, in mouse adipocytes, resistin secretion is triggered by an intracellular elevation of cAMP and/or Ca2+. Resistin release is stimulated via activation of beta 3 adrenergic receptors (ß3ARs) and the downstream signalling protein exchange protein activated by cAMP (Epac). The secretion of resistin is markedly abrogated in adipocytes isolated from obese and diabetic mice. Immunocytochemical staining demonstrates a significant overlap between signals for resistin and the adipocyte hormone adiponectin. Our data propose that resistin and adiponectin are contained within the same vesicles in mouse adipocytes and that the two hormones are co-secreted in response to the same exocytosis-triggering signals.

Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3.

In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.

Resistin mitigates stemness and metabolic profile of human adipose-derived mesenchymal stem cells via insulin resistance.

During obesity adipose tissue abundantly secrete pro-inflammatory adipokines like Tumour Necrosis factor-alpha (TNFα), resistin, leptin, etc. but reduced anti-inflammatory adipokines like adiponectin, interleukin (IL)-10, and IL-4. In our recent clinical study, it was observed that both gene expressions and stored levels of resistin were elevated in adipose tissue of metabolically obese Indians. Resistin profoundly increases obesity, mitigates lipid metabolism, and causes peripheral insulin resistance. It dysregulates the metabolism of human adipocytes but, its effects on human adipose-derived mesenchymal stem cells (hADSC) are sparsely explored. Therefore, the present study was designed to explore the repercussion of resistin on stemness and metabolic profile of hADSC. hADSC were isolated from a healthy individual followed by immunophenotyping. Purified cells were treated with resistin and proliferation was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Cell Cycle experiments. Gene expressions of pluripotent markers, inflammatory mediators, and lipogenic genes were scrutinized. Insulin sensitivity was examined by western blot and glucose uptake assay. Further, consequences of resistin on differentiation potentials of hADSC were examined by temporal expressions of phospho (p)SMAD1/5/8 protein complex, non-phosphorylated beta (ß) catenin, and their dependent adipogenic transcription factors (ATF) and osteogenic transcription factors (OTF). MTT and cell cycle analysis revealed that resistin hampered proliferation of hADSC. Expressions of inflammatory markers and lipogenic genes were elevated. Resistin impaired insulin sensitivity and thus embarked insulin resistance in hADSC. Resistin increased adipogenesis and osteogenesis by altering expressions of activated pSMAD1/5/8 complex, activated ß catenin, ATF and OTF temporally. Downregulation of CCAAT/enhancer-binding proteins (C/EBP)α and adiponectin in adipocytes and Sirtuin (SIRT)1 in osteocytes denote that resistin induces immaturity and insulin resistance in adipocytes and osteocytes. This is the first study which, reports that resistin mitigates the stemness of hADSC by reducing proliferation, inducing insulin resistance, and hampering maturation of adipocyte and osteocyte which could lead to metabolic disorders.

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.