Resistin-like molecules: a marker, mediator and therapeutic target for multiple diseases.

Resistin-like molecules (RELMs) are highly cysteine-rich proteins, including RELMα, RELMß, Resistin, and RELMγ. However, RELMs exhibit significant differences in structure, distribution, and function. The expression of RELMs is regulated by various signaling molecules, such as IL-4, IL-13, and their receptors. In addition, RELMs can mediate numerous signaling pathways, including HMGB1/RAGE, IL-4/IL-4Rα, PI3K/Akt/mTOR signaling pathways, and so on. RELMs proteins are involved in wide range of physiological and pathological processes, including inflammatory response, cell proliferation, glucose metabolism, barrier defense, etc., and participate in the progression of numerous diseases such as lung diseases, intestinal diseases, cardiovascular diseases, and cancers. Meanwhile, RELMs can serve as biomarkers, risk predictors, and therapeutic targets for these diseases. An in-depth understanding of the role of RELMs may provide novel targets or strategies for the treatment and prevention of related diseases. Video abstract.

Resistin and Cardiovascular Disease: A Review of the Current Literature Regarding Clinical and Pathological Relationships.

Serum resistin, mainly secreted by the bone marrow, monocytes, and macrophages, contributes to many processes, including endothelial dysfunction, Vascular Smooth Muscle Cell (VSMC) proliferation, and atherothrombosis demonstrating effects on the development of hypertension and Coronary Artery Disease (CAD). Previously published clinical studies have shown that plasma resistin levels are significantly associated with cardiovascular disease risk factors and adverse clinical outcomes associated with the condition. Resistin is associated with vascular smooth muscle cell dysfunction in vitro, most plausibly due to its relationship with oxidative stress in advanced atherosclerosis whereas in vivo studies have shown resistin to be associated with intimal hyperplasia. We aimed to summarize the role of resistin on cardiovascular disease (CVD), as we could not find any review focused on the role of resistin on CVD.

Adipocytokine Profile Reveals Resistin Forming a Prognostic-Related Cytokine Network in the Acute Phase of Sepsis.

INTRODUCTION: Cytokines compose a network and play crucial roles in the pathogenesis and prognosis of sepsis. Adipose tissue is an important immune endocrine organ that releases adipocytokines. This study aimed to evaluate adipocytokines in sepsis from a network perspective. MATERIALS AND METHODS: This retrospective study of 37 patients with sepsis and 12 healthy controls was conducted from February 2014 to July 2015. Blood samples were collected from patients on days 1 (within 24 h of diagnosis), 2, 4, 6, 8, 11, and 15 and from healthy controls. Adipocytokines (adiponectin, leptin, resistin, chemerin, visfatin, vaspin, CXCL-12/SDF-1, angiotensinogen), inflammatory cytokines (IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12/IL-23p40, TNF-α, monocyte chemotactic protein [MCP-1]), and plasminogen activator inhibitor-1 were measured. Acute Physiology and Chronic Health Evaluation II score was evaluated on day 1, and Sequential Organ Failure Assessment (SOFA) score and Japanese Association for Acute Medicine (JAAM) and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation (DIC) scores were assessed at the times of blood sampling. RESULTS: Hierarchical clustering analysis showed the cluster formed by resistin, IL-6, IL-8, MCP-1, and IL-10 on days 1, 2, and 4 represented the cytokine network throughout the acute phase of sepsis. Each cytokine in this network was significantly associated with SOFA and JAAM DIC scores over the acute phase. A Cox proportional hazards model focusing on the acute phase showed a significant relation of these five cytokines with patient prognosis. CONCLUSIONS: Adipocytokines and an inflammatory cytokine profile assessed over time in sepsis patients showed that resistin was involved in an inflammatory cytokine network including IL-6, IL-8, IL-10, and MCP-1 in the acute phase of sepsis, and this network was associated with severity and prognosis of sepsis.

The role of visfatin and resistin in an in vitro model of obesity-induced invasive liver cancer.

Obesity is associated with the development of liver disease and its progression to hepatocellular carcinoma. This link may be attributed to adipocytokines such as visfatin and resistin which have been shown to promote liver cancer incidence and progression. Studies have yet to determine the role of visfatin and resistin in liver cancer, specifically in the context of obesity. The objective of this study was to investigate the effect of neutralizing visfatin and resistin in obese (OB) or normal weight (NW) sera to determine the contribution of these proteins in obesity-induced invasive liver cancer. Sera from OB or NW males was used to determine the efficacy of neutralizing visfatin and resistin to reduce the obesity-induced liver cancer phenotype. HepG2 and SNU-449 cells were exposed to OB and NW sera ± antibodies for visfatin or resistin. The neutralizing antibodies differentially suppressed invasion, reactive oxygen species production, and matrix metalloproteinase-9 secretion. These changes corresponded with a decrease in phosphorylated extracellular signal-regulated kinases and protein kinase B in HepG2 cells, but differences were not observed in CAP1 or ß-catenin. In conclusion, visfatin and resistin have differential roles in obesity-associated liver cancer and may be potential targets to reverse the impact of obesity on liver cancer progression.

Inotropic and lusitropic, but not arrhythmogenic, effects of adipocytokine resistin on human atrial myocardium.

The adipocytokine resistin is released from epicardial adipose tissue (EAT). Plasma resistin and EAT deposition are independently associated with atrial fibrillation. The EAT secretome enhances arrhythmia susceptibility and inotropy of human myocardium. Therefore, we aimed to determine the effect of resistin on the function of human myocardium and how resistin contributes to the proarrhythmic effect of EAT. EAT biopsies were obtained from 25 cardiac surgery patients. Resistin levels were measured by ELISA in 24-h EAT culture media (n = 8). The secretome resistin concentrations increased over the culture period to a maximal level of 5.9 ± 1.2 ng/mL. Coculture with ß-adrenergic agonists isoproterenol (n = 4) and BRL37344 (n = 13) had no effect on EAT resistin release. Addition of resistin (7, 12, 20 ng/mL) did not significantly increase the spontaneous contraction propensity of human atrial trabeculae (n = 10) when given alone or in combination with isoproterenol. Resistin dose-dependently increased trabecula-developed force (maximal 2.9-fold increase, P < 0.0001), as well as the maximal rates of contraction (2.6-fold increase, P = 0.002) and relaxation (1.8-fold increase, P = 0.007). Additionally, the postrest potentiation capacity of human trabeculae was reduced at all resistin doses, suggesting that the inotropic effect induced by resistin might be due to altered sarcoplasmic reticulum Ca2+ handling. EAT resistin release is not modulated by common arrhythmia triggers. Furthermore, exogenous resistin does not promote arrhythmic behavior in human atrial trabeculae. Resistin does, however, induce an acute dose-dependent positive inotropic and lusitropic effect.

Resistin enhances angiogenesis in osteosarcoma via the MAPK signaling pathway.

Over the last two decades, there have been no significant changes in patient outcomes in relation to the treatment of osteosarcoma, an aggressive malignant neoplasm. It is known that vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and in osteosarcoma. Moreover, VEGF-A expression correlates with clinical stages of osteosarcoma. The adipokine resistin exhibits proinflammatory, proangiogenic and metastatic properties, and evidence suggests that resistin may serve as a prognostic biomarker linking obesity and inflammation to cancer. However, whether resistin has a role in osteosarcoma angiogenesis is unclear. This investigation shows that resistin promotes VEGF-A expression in human osteosarcoma cells and activates the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 signaling pathways, while ERK, JNK, and p38 inhibitors or their small interfering RNAs (siRNAs) inhibit resistin-induced VEGF-A expression as well as endothelial progenitor cell (EPC) migration and tube formation. We also found that resistin upregulates VEGF-A expression by enhancing activation of the transcription factor nuclear factor-kappa B (NF-κB). Finally, resistin promotes angiogenesis in the chick chorioallantoic membrane (CAM) model. Resistin appears to be a promising target for human osteosarcoma.

Vasodilator-Stimulated Phosphoprotein: Regulators of Adipokines Resistin and Phenotype Conversion of Epicardial Adipocytes.

BACKGROUND Endothelial dysfunction plays a central part in the pathogenesis of coronary atherosclerosis. The adipokine resistin is one of the key players in endothelial cell dysfunction. In addition, the role of epicardial fat in coronary artery endothelial dysfunction is also emphasized. We investigated whether vasodilator-stimulated phosphoprotein (VASP) is involved in resistin-related endothelial dysfunction and the phenotype conversion of epicardial adipocytes. MATERIAL AND METHODS Cell proliferation and migration were evaluated by MTT and Transwell chamber assay, respectively. Next, we took epicardial fat samples from patients with valvular heart disease and non- coronary artery disease. Gene expression was determined by reverse transcription- quantitative polymerase chain reaction and relative abundance of the protein by Western blotting. RESULTS Resistin induced endothelial proliferation and migration in a dose-dependent manner. Both resistin-induced cell proliferation and migration were effectively blocked by ablation of VASP. The brown adipose tissue-specific genes for uncoupling protein 1 (UCP-1) and PR-domain-missing16 (PRDM16) decreased, but the white adipose tissue-specific genes for resistin and RIP140 increased in VASP-deficient adipocytes compared with the LV-sicntr group. However, disruption of the Ras homolog gene family member A (RhoA) /Rho-associated kinase (ROCK) in VASP-deficient adipocytes with specific inhibitors inverted the adipocyte phenotype existing in VASP-deficient adipocytes. Furthermore, the expressions of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractantprotein-1 (MCP-1) in VASP-deficient adipocytes were markedly upregulated compared with the LV-sicntr group. CONCLUSIONS These results suggest a physiological role for VASP in coronary atherosclerosis through regulating adipokine resistin and phenotype conversion of epicardial adipose tissue.

Resistin regulates reproductive hormone secretion from the ovine adenohypophysis depending on season.

Work in cattle and rodents has shown that resistin, in addition to its roles in insulin resistance and inflammation, is involved in the regulation of gonadal steroidogenesis. However, the role of resistin in the regulation of reproductive processes in other species, such as seasonally breeding sheep, is completely unknown. Herein, we tested the hypothesis that resistin can influence the secretion of anterior pituitary hormones and that its effect in ewes is dependent on the day length. Thirty Polish Longwool ewes, a breed that exhibits a strong seasonal reproductive pattern, were ovariectomized with estrogen replacement using subcutaneously inserted estradiol implants. Ewes were fed ad libitum and housed under a natural photoperiod (longitude: 19°57' E, latitude: 50° 04' N). Intravenous treatments consisted of control or recombinant bovine resistin (rbresistin) in saline: (1) control (saline; n = 10), (2) low resistin dose (1.0 µg/kg BW; n = 10), and (3) high resistin dose (10.0 µg/kg BW; n = 10). Experiments were conducted during both short-day (SD) and long-day (LD) seasons using 5 sheep per group within each season. Blood samples were collected every 10 min over 4 h. Blood plasma concentrations of FSH, LH, and prolactin (PRL) were assayed using RIA. A season × dose interaction was observed for all hormonal variables measured. Greater concentrations (P < 0.001) of LH and FSH were observed during SDs than during LDs in all groups. During SDs, the high dose (10 µg/kg BW) decreased (P < 0.001) basal LH levels and amplitude (P < 0.05) of LH pulses and increased (P < 0.001) circulating concentrations of FSH. However, the low dose of resistin decreased (P < 0.001) FSH concentrations compared to those of controls. During LDs, both the low and high resistin doses increased mean concentrations of LH (P < 0.001 and P < 0.05, respectively) and FSH (P < 0.001). A high dose of rbresistin increased (P < 0.001) the mean circulating concentrations of PRL during both seasons. However, in all groups, concentrations of PRL were greater during LDs than SDs. These results demonstrate for the first time that resistin is involved in the regulation of pituitary hormone secretion and that this effect is differentially mediated during LDs and SDs.

Resistin inhibits neuronal autophagy through Toll-like receptor 4.

Autophagy is a non-selective degradation pathway induced in energy-deprived cells and in non-starved cells by participating in cellular inflammatory responses mainly through the elimination of injured and aged mitochondria that constitute an important source of reactive oxygen species. We have previously reported that resistin/TLR4 signaling pathway induces inflammation and insulin resistance in neuronal cell. However, the impact of resistin-induced inflammation on neuronal autophagy is unknown. In the present study, we hypothesized that resistin-induced neuroinflammation could be attributed, at least partially, to the impairment of autophagy pathways in neuronal cells. Our data show that resistin decreases neuronal autophagy as evidenced by the repression of the main autophagy markers in SH-SY5Y human neuroblastoma cell line. Furthermore, the silencing of TLR4 completely abolished these effects. Resistin also inhibits AMPK phosphorylation and increases that of Akt/mTOR contrasting with activated autophagy where AMPK phosphorylation is augmented and mTOR inhibited. In vivo, resistin treatment inhibits the mRNA expression of autophagy markers in the hypothalamus of WT mice but not in Tlr4-/- mice. In addition, resistin strongly diminished LC3 (a marker of autophagy) labeling in the arcuate nucleus of WT mice, and this effect is abolished in Tlr4-/- mice. Taken together, our findings clearly reveal resistin/TLR4 as a new regulatory pathway of neuronal autophagy.

Adipocytokines and breast cancer.

A substantial number of studies have revealed that a growing list of cancers might be influenced by obesity. In this regard, one of the most prominent and well-characterized cancers is breast cancer, the leading cause of cancer death among women. Obesity is associated with an increased risk for the occurrence and development of breast cancer particular in postmenopausal women. Moreover, the relationship between adiposity and breast cancer risk is complex, with associations that differ depending on when body size is assessed (eg, premenopausal vs postmenopausal obesity) and when breast cancer is diagnosed (ie, premenopausal vs postmenopausal disease). Obesity is mainly due to excessive fat accumulation in the regional tissue. Adipocytes in obese individuals produce endocrine, inflammatory, and angiogenic factors to affect adjacent breast cancer cells. Adipocytokines, are biologically active polypeptides that are produced either exclusively or substantially by adipocytes, play a critical and complex role, and act by endocrine, paracrine, and autocrine pathways in the malignant progression of breast cancer. Furthermore, the increased levels of leptin, resistin, and decreased adiponectin secretion are directly associated with breast cancer development. And there are also many studies indicating that adipocytokines could mediate the survival, growth, invasion, and metastasis of breast cancer cells by different cellular and molecular mechanisms to reduce the survival time and prompt the malignancy. In present review, we discuss the correlations between several adipocytokines and breast cancer cells in obesity as well as the underlying signaling pathways to provide the novel ideas for the prevention and treatment of breast cancer.

Resistin-like molecule ß is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium.

The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule ß (RELMß) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMß selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMß, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMß promotes host-bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.

Effects of central administration of resistin on renal sympathetic nerve activity in rats fed a high-fat diet: a comparison with leptin.

Similar to leptin, resistin acts centrally to increase renal sympathetic nerve activity (RSNA). In high-fat fed animals, the sympatho-excitatory effects of leptin are retained, in contrast to the reduced actions of leptin on dietary intake. In the present study, we investigated whether the sympatho-excitatory actions of resistin were influenced by a high-fat diet. Further, because resistin and leptin combined can induce a greater sympatho-excitatory response than each alone in rats fed a normal chow diet, we investigated whether a high-fat diet (22%) could influence this centrally-mediated interaction. Mean arterial pressure (MAP), heart rate (HR) and RSNA were recorded before and for 3 hours after i.c.v. saline (control; n=5), leptin (7 µg; n=4), resistin (7 µg; n=5) and leptin and resistin combined (n=6). Leptin alone and resistin alone significantly increased RSNA (71±16%, 62±4%, respectively). When leptin and resistin were combined, there was a significantly greater increase in RSNA (195±41%) compared to either hormone alone. MAP and HR responses were not significantly different between hormones. When the responses in high-fat fed rats were compared to normal chow fed rats, there were no significant differences in the maximum RSNA responses. The findings indicate that sympatho-excitatory effects of resistin on RSNA are not altered by high-fat feeding, including the greater increase in RSNA observed when resistin and leptin are combined. Our results suggest that diets rich in fat do not induce resistance to the increase in RSNA induced by resistin alone or in combination with leptin.

Linking resistin, inflammation, and cardiometabolic diseases.

Adipose tissue secretes a variety of bioactive substances that are associated with chronic inflammation, insulin resistance, and an increased risk of type 2 diabetes mellitus. While resistin was first known as an adipocyte-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents, it is predominantly expressed and secreted by macrophages in humans. Epidemiological and genetic studies indicate that increased resistin levels are associated with the development of insulin resistance, diabetes, and cardiovascular disease. Resistin also appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and the formation of foam cells. Thus, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with cardiovascular disease and heart failure. Furthermore, recent evidence suggests that resistin is associated with atherogenic dyslipidemia and hypertension. The present review will focus on the role of human resistin in the pathogeneses of inflammation and obesity-related diseases.

Reversal of Acute Kidney Injury-Induced Neutrophil Dysfunction: A Critical Role for Resistin.

OBJECTIVES: To assess the reversibility of acute kidney injury-induced neutrophil dysfunction and to identify involved mechanisms. DESIGN: Controlled laboratory experiment and prospective observational clinical study. SETTING: University laboratory and hospital. SUBJECTS: C57BL/6 wild-type mice. PATIENTS: Patients with septic shock with or without acute kidney injury. INTERVENTIONS: Murine acute kidney injury was induced by intraperitoneal injections of folic acid (nephrotoxic acute kidney injury) or by IM injections of glycerol (rhabdomyolysis-induced acute kidney injury). After 24 hours, we incubated isolated neutrophils for 3 hours in normal mouse serum or minimum essential medium buffer. We further studied the effects of plasma samples from 13 patients with septic shock (with or without severe acute kidney injury) on neutrophilic-differentiated NB4 cells. MEASUREMENTS AND MAIN RESULTS: Experimental acute kidney injury significantly inhibited neutrophil migration and intracellular actin polymerization. Plasma levels of resistin, a proinflammatory cytokine and uremic toxin, were significantly elevated during both forms of acute kidney injury. Incubation in serum or minimum essential medium buffer restored normal neutrophil function. Resistin by itself was able to induce acute kidney injury-like neutrophil dysfunction in vitro. Plasma resistin was significantly higher in patients with septic shock with acute kidney injury compared with patients with septic shock alone. Compared with plasma from patients with septic shock, plasma from patients with septic shock and acute kidney injury inhibited neutrophilic-differentiated NB4 cell migration. Even after 4 days of renal replacement therapy, plasma from patients with septic shock plus acute kidney injury still showed elevated resistin levels and inhibited neutrophilic-differentiated NB4 cell migration. Resistin inhibited neutrophilic-differentiated NB4 cell migration and intracellular actin polymerization at concentrations seen during acute kidney injury, but not at normal physiologic concentrations. CONCLUSIONS: Acute kidney injury-induced neutrophil dysfunction is reversible in vitro. However, standard renal replacement therapy does not correct this defect in patients with septic shock and acute kidney injury. Resistin is greatly elevated during acute kidney injury, even with ongoing renal replacement therapy, and is sufficient to cause acute kidney injury-like neutrophil dysfunction by itself.

Fulvic Acid Attenuates Resistin-Induced Adhesion of HCT-116 Colorectal Cancer Cells to Endothelial Cells.

A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC). Hence, resistin may play a role in CRC development. Fulvic acid (FA), a class of humic substances, possesses pharmacological properties. However, the effect of FA on cancer pathophysiology remains unclear. The aim of this study was to investigate the effect of resistin on the endothelial adhesion of CRC and to determine whether FA elicits an antagonistic mechanism to neutralize this resistin effect. Human HCT-116 (p53-negative) and SW-48 (p53-positive) CRC cells and human umbilical vein endothelial cells (HUVECs) were used in the experiments. Treatment of both HCT-116 and SW-48 cells with resistin increases the adhesion of both cells to HUVECs. This result indicated that p53 may not regulate this resistin effect. A mechanistic study in HCT-116 cells further showed that this resistin effect occurs via the activation of NF-κB and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Co-treating cells with both FA and resistin revealed that FA significantly attenuated the resistin-increased NF-κB activation and ICAM-1/VCAM-1 expression and the consequent adhesion of HCT-116 cells to HUVECs. These results demonstrate the role of resistin in promoting HCT-116 cell adhesion to HUVECs and indicate that FA might be a potential candidate for the inhibition of the endothelial adhesion of CRC in response to resistin.

Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity.

The increase in obesity rate is a major public health issue associated with increased pathological conditions such as type 2 diabetes or cardiovascular diseases. Obesity also contributes to decreased testosterone levels in men. Indeed, the adipose tissue is an endocrine organ which produces hormones such as leptin, adiponectin and resistin. Obesity results in pathological accumulations of leptin and resistin, whereas adiponectin plasma levels are markedly reduced, all having a negative impact on testosterone synthesis. This review focuses on current knowledge related to transcriptional regulation of Leydig cells' steroidogenesis by leptin, adiponectin and resistin. We show that there are crosstalks between the regulatory mechanisms of these hormones and androgen production which may result in a dramatic negative influence on testosterone plasma levels. Indeed leptin, adiponectin and resistin can impact expression of different steroidogenic genes such as Star, Cyp11a1 or Sf1. Further investigations will be required to better define the implications of adipose derived hormones on regulation of steroidogenic genes expression within Leydig cells under physiological as well as pathological conditions.

S-resistin, a non secretable resistin isoform, impairs the insulin signalling pathway in 3T3-L1 adipocytes

S-resistin is a non-secretable resistin spliced variant, which is expressed mainly in the white adipose tissue from Wistar rats. Previous results confirmed that 3T3-L1 cells expressing s-resistin (3T3-L1-s-res) showed an inflammatory response and exhibited a decrease in glucose transport, both basal and insulin-stimulated. Here we present evidences demonstrating for the first time that s-resistin, like resistin, blocks insulin signalling pathway by inhibiting insulin receptor, insulin receptor substrate 1, protein kinase B/Akt and the mammalian target of rapamycin phosphorylation, and increasing the suppressor of cytokine signalling 3 levels being the later probably due to augmented of leptin expression. Thus, our data suggest that s-resistin could act by a still unknown intracrine pathway as an intracellular sensor, regulating the adipocyte insulin sensitivity

S-resistin, a non secretable resistin isoform, impairs the insulin signalling pathway in 3T3-L1 adipocytes.

S-resistin is a non-secretable resistin spliced variant, which is expressed mainly in the white adipose tissue from Wistar rats. Previous results confirmed that 3T3-L1 cells expressing s-resistin (3T3-L1-s-res) showed an inflammatory response and exhibited a decrease in glucose transport, both basal and insulin-stimulated. Here we present evidences demonstrating for the first time that s-resistin, like resistin, blocks insulin signalling pathway by inhibiting insulin receptor, insulin receptor substrate 1, protein kinase B/Akt and the mammalian target of rapamycin phosphorylation, and increasing the suppressor of cytokine signalling 3 levels being the later probably due to augmented of leptin expression. Thus, our data suggest that s-resistin could act by a still unknown intracrine pathway as an intracellular sensor, regulating the adipocyte insulin sensitivity.

Resistin: insulin resistance to malignancy.

Adipose tissue is recognized as an endocrine organ that secretes bioactive substances known as adipokines. Excess adipose tissue and adipose tissue dysfunction lead to dysregulated adipokine production that can contribute to the development of obesity-related co-morbidities. Among the various adipokines, resistin, which was initially considered as a determinant of the emergence of insulin resistance in obesity, has appeared as an important link between obesity and inflammatory processes. Several experimental and clinical studies have suggested an association between increased resistin levels and severe conditions associated with obesity such as cardiovascular disease and malignancies. In this review, we present the growing body of evidence that human resistin is an inflammatory biomarker and potential mediator of obesity-associated diseases. A common pathway seems to involve the combined alteration of immune and inflammatory processes that favor metabolic disturbances, atherosclerosis and carcinogenesis. The mode of action and the signaling pathways utilized by resistin in its interactions with target cells could involve oxidative and nitrosative stress. Therefore, resistin could function as a key molecule in the complications of obesity development and could potentially be used as a diagnostic and prognostic marker.

The common pathophysiology underlying the metabolic syndrome, schizophrenia and depression. A review.

BACKGROUND: There is a growing interest in metabolic alterations in patients with psychiatric disorders due to their increased risk for metabolic syndrome (MetS) development. Inflammation is known to underlie the pathophysiology of schizophrenia and depression as well as MetS. Vulnerability factors for schizophrenia/depression and MetS hence appear to be shared. METHODS AND RESULTS: Based on a Web of Science search, this review examines current evidence for MetS pathophysiology involving dysregulation of adipose tissue signaling - adipokines and pro-inflammatory cytokine, both also known to be aberrant in schizophrenia/depression. Further, gender differences in the incidence and course of schizophrenia/depression were reported. The disturbances linked to the MetS are also described. Therefore, this review further maps the gender differences in the psychiatric-metabolic comorbidities. CONCLUSION: There is evidence supporting a pathological predisposition to MetS in both schizophrenia and depression in both humans and animal models. This predisposition is dramatically enhanced by antipsychotic medication. Further, there are gender differences from clinical findings suggesting women with schizophrenia/depression are more vulnerable to MetS development. This has not yet been assessed in animal studies. We suggest further validation of existing schizophrenia and depression animal models for the assessment of metabolic disturbances to provide tools for developing new antipsychotics and antidepressants with "metabolically inert" profile or improving the metabolic status in schizophrenic/depressed patients.