Review

Mostafazadeh Mostafa et al. Correlation Between Resistin Level … Horm Metab Res 2018; 00: 00–00 Correlation Between Resistin Level and Metabolic Syndrome Component: A Review

Authors Mostafa Mostafazadeh1, 2, Sanya Haiaty3, Ali Rastqar4, 5, Mahtab Keshvari6

Affiliations Isfahan University of medical Sciences 1 Immunology Research Center, Faculty of Medicine, Tabriz Isfahan University of Medical Sciences, Tabriz, Iran Iran 2 Department of Biochemistry and Clinical Laboratories, Tel.: + 98/311/36115 115, Fax: + 98/311/36115 115 Tabriz University of Medical Sciences, Tabriz, Iran [email protected] 3 Infectious and Tropical Diseases Research Center, Department of Clinical Biochemistry, Tabriz University of Abstract Medical Sciences, Tabriz, Iran Metabolic syndrome (MetS) has a collection of some abnormal 4 Department de Psychiatry et Neuroscience, Université and pathological conditions that cause many critical diseases. Laval, Québec, QC, Canada Resistin is one of the possible candidates for these pathologies 5 Centre Hospitalier de l’Université Laval (CHUL), Québec, but there are not enough data to prove if resistin has positive, QC, Canada neutral, or negative effects on one or some components of 6 Isfahan Cardiovascular Research Center, Cardiovascular MetS. This review summarizes data about comparing the ef- Research Institute, Isfahan University of medical fects and contribution of resistin in initiation and progression Sciences, Isfahan, Iran of MetS components and also its different actions between human and other mammalians. This summarized data about Key words the relationship of resistin and MetS components have been correlation, resistin, metabolic syndrome obtained from clinical researches and in some cases even ani- received 01.02.2018 mal studies. To find the relevant studies, the search in PubMed, accepted 22.05.2018 Science Direct, and Scopus were performed. Human and ani- mal studies on relationships between resistin and MetS (initi- Bibliography ation and progression of components) were included in our DOI https://doi.org/10.1055/a-0637-1975 search. In experiments reported among different human ge- Horm Metab Res 2018; 50: 521–536 netic groups as well as the patients with various disease such © Georg Thieme Verlag KG Stuttgart · New York as diabetes, no significant correlation is shown between FBG ISSN 0018-5043 and resistin level. Furthermore, this review shows that the re- sults of correlation between resistin and TG, HDL, and central Correspondence or abdominal obesity were inconsistent. These inconsistencies Dr. Mahtab Keshvari can arise from different sample size or genetic groups, gender, Isfahan Cardiovascular Research Center and also from experimental studies. Therefore, to obtain pre- Cardiovascular Research Institute cise results systematic review and meta-analyses are required.

Introduction proinflammatory and prothrombotic (thrombosis) states, and vis- The term of metabolic syndrome (MetS) is applied for a major and ceral adipose tissue play a key role in the initiation and future patho- escalating group of risk factors that raises risk for public health and genesis of it and also its complications [3]. Adipose tissue is an ac- clinical challenge worldwide. The term “metabolic” refers to the tive endocrine organ capable of producing several regulatory me- biochemical processes involved in the body’s normal functioning. diators that is called adipokines. Adipokines have been shown to Risk factors are traits, conditions, or habits that increase the chance be involved in several biological processes. Several adipokines have of developing a disease [1, 2]. been illustrated to exert regulatory roles on cardiovascular risk fac- There is a cluster of metabolic risk factors for cardiovascular dis- tors, for example, inflammation, adipogenesis, lipid metabolism, eases and type-2 diabetes mellitus (T2DM). In the major compo- and oxidative stress [4, 5]. nents of metabolic syndrome, excess abdominal fat, atherogenic Resistin is an adipokine with 114 amino acids, belonging to the dyslipidemia, hypertension, hyperglycemia, insulin resistance, resistin-like family of proteins [6]. In humans, resistin is an adipo-

Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 521 Review cyte- and monocyte-derived cytokine, which modulates insulin ac- tions are significantly higher in females versus males. It has been tion, energy, glucose, and lipid homeostasis [7]. It has been pro- reported that in obese and diabetic patients, the serum level of re- posed that resistin might serve as a molecular link between inflam- sistin is significantly increased [6, 22]. Resistin expression in rodent mation, metabolic parameters, and vascular dysfunction, and can adipocytes is stimulated by high levels of glucose but suppressed thus contribute to the risk for MetS, T2DM, and cardiovascular dis- by tumor necrosis factor α (TNF-α) while human resistin is strong- ease (CVD) [8, 9]. However, studies show controversial role of re- ly induced by various inflammatory stimuli, including interleukin 6 sistin in regulating insulin sensitivity and obesity [10, 11]. There- (IL-6), IL-1β, lipopolysaccharide (LPS), TNF-α, and resistin itself in fore, the present study was aimed to compare the effects and con- PBMCs and macrophages [23]. tribution of resistin in initiation and progression of MetS components and also its different actions among human and other mammalians. Resistin Receptors According to the data obtained from animal and human studies, the receptor or receptors of resistin especially in human is not fully Methods for Review understood. But, Toll-like receptor 4 (TLR4) and adenylyl cyclase-as- An extensive search was performed in PubMed, Science Direct, sociated protein 1 (CAP1) are accepted as putative candidates for Scopus, and Google scholar to identify clinical and animal studies its receptors [24]. TRL family is expressed in various organisms in- on the correlation between resistin level and MetS components cluding mammalians. Among the reported 13 TLR (TLR1–13), TLR1 published from inception up to November 15, 2017. Search terms to 9 are both in human and mice, TRL10 is not functional in mice were (“Resistin” OR” Adipokines”) AND (“Metabolic Syndrome” OR but in human is active, and the other ones do not express in human “metabolic”). The search was performed in titles and abstracts that but only in mice [25–27]. TLR1, 2, 4, 5, 6, and 10 are present on the were restricted to articles published in English and sometimes cell surface, whereas the others are endosomal or lysosomal recep- French languages. All titles, abstracts, and full texts of potentially tors [25, 26]. relevant studies were assessed for eligibility. Papers were excluded TLRs participate essentially in immunologic pathways and are if: 1) data on exposure (Resistin) or outcome (Metabolic Syndrome) divided in some groups while each group has own signaling path- were not reported and 2) no data were reported on the relation- way (for more details, see ref. [26]). Among TLRs, TLR4 is proposed ship between exposure and outcome. to be the one of resistin membrane receptors that mediates its in- tracellular functions [28, 29]. In fact, TLR4 is considered as an im- munoreceptor that promotes the production of inflammatory sub- Resistin and its Secretion stances in macrophages but, for example, it can also mediate the Resistin (or ‘resistance to insulin’), also known as the adipose tis- effects of resistin in hypothalamus for activating proinflammatory sue-specific secretory factor, C/EBP-epsilon-regulated myeloid-spe- pathways [25, 29]. cific secreted cysteine-rich protein (XCP1), found in inflammatory TLRs are found in macrophages, neutrophils, dendritic cells, nat- zone 3, was discovered in 2001 by Lazar’s group from the Univer- ural killer cells, and mast cells of the innate-immune system; in T- sity of Pennsylvania, who named resistin for its ability to interfere and B-lymphocytes of the adaptive-immune system, as well as in with insulin action and is identified as a link between obesity and some non-immune cells, such as epithelial and endothelial cells diabetes [6, 12]. [30]. According to some evidences, among TLRs, TLR4 is unique Resistin, encoded by the RETN gene, is a secretory protein that because after binding to appropriate ligand, this receptor can un- belongs to the resistin like molecules family with a distinct expres- dergo endocytosis and follow its action as an internal receptor [31]. sion patterns and biological functions [13]. The resistin expression Up to now, it was found that many endogenous ligands can ac- is identified in several cell types including adipocytes [6, 14], intes- tivate TLR4. These include HSP22, EDA fibronectin, low molecular tinal epithelium, adrenal gland, stomach, skeletal muscle cells [15], weight fragments of hyaluronic acid, fibrinogen, and tenascin-C, testis [16], and possibly astrocytes [17]. The main source of ro- whereas lipoteichoic acid, LPS, CpG motifs of bacterial DNA, and dent’s resistin is the white adipose tissue. Resistin in mouse has an viral RNA are exogenous ligands [26, 32]. After binding the ligands, 11 kDa cysteine-rich polypeptide, and its gene (RETN) is located on TLR4 usually exerts its effects via two classic models of signaling chromosome 8A1. It is synthesized as a 114 amino acid (aa) pre- pathways. They are MyD88 (myeloid differentiation primary re- cursor, with a signal peptide of 20 aa and a 94 aa mature segment. sponse gene 88) and Toll-interleukin 1 receptor domain-contain- Amino acid identity in the mature segment within mice and rats is ing adaptor inducing interferon-beta (TRIFβ) pathways. Then, au- 72 % [6, 18]. The human resistin gene, located on chromosome tophosphorylation of interleukin-1 receptor-associated kinases 19p13.3, encodes a 12.5 kDa cysteine-rich polypeptide with a ma- (IRAK) and oligomerization of TNF receptor-associated factor 6 ture segment consisting of 108 aa and has 55 % aa identity between (TRAF6) occurs and cause the activation of IKK and mitogen-acti- mice and humans [6, 19]. In humans, resistin is predominantly pro- vated protein kinase (MAPK). Finally, subsequent signal propaga- duced by peripheral blood mononuclear cells (PBMCs), macrophag- tion results in the translocation of nuclear factor kappa B (NF-κB) es, and bone marrow cells [20, 21]. The mature protein has a ten- to the nucleus and the activation of the activator protein-1 (AP-1) dency to form dimers and oligomers, thus circulating resistin con- transcriptional program [25, 26, 30, 32]. sists of low molecular weight and high molecular weight isoforms On the other hand, downstream of TRIF, in addition to the de- [22]. Normally, the serum resistin levels ranges from 7 to 22 and layed activation of NF-κB via an interaction with TRAF6, the ubiq- 36–43 ng/ml in human and rats, respectively, and its concentra- uitination of TNF receptor-associated factor 3 (TRAF3) induces

522 Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 in rats is not significantly affected by intracerebroventricular and intravenous administration of resistin [37]. Furthermore, another study reported that there was no significant relationship between circulating resistin levels and blood pressure in obese women [38]. Some clinical studies have suggested a correlation between cir- culating resistin levels and hypertension in humans [39, 40]. A pos- itive correlation between circulating resistin levels and blood pres- sure has been reported in subjects both with and without type 2 diabetes mellitus [40, 41]. Plasma resistin levels are significantly higher in the young healthy offspring of individuals with essential hypertension compared to the young healthy offspring of normo- tensives [42]. Moreover, it has been reported that higher blood re- sistin levels are correlated with a raised risk for incident hyperten- sion among women without diabetes or hypertension, which rep- resents the effects of resistin on blood pressure [43]. Furthermore, a recent meta-analysis, which was conducted to evaluate the sig- nificance of serum resistin levels in hypertensive patients, show that serum resistin level in hypertensive patients is significantly higher than normotensive individuals [44]. Although, the precise mechanisms by which resistin affects blood pressure is unclear, but several mechanisms have been proposed for this effect. As a potential mechanism linking resistin to hypertension, re- sistin has vasoconstrictor property [45] and also promotes smooth muscle cell proliferation [46]. In other mechanism, resistin via af- fecting on renin-angiotensin system (RAS) causes hypertension. Angiotensinogen (a precursor of angiotensin II or ANG II) is released from the liver and converted to angiotensin I (ANG I) by renin. Then, ANG I is converted to ANG II (a major RAS effector) through the ac- tion of angiotensin converting enzyme (ACE) [47]. In an experimen- tal study, treatment of mice with resistin significantly upregulates the expression of angiotensinogen in the liver. An increase in ex- ▶Fig. 1 Tool-Like Receptor 4 (TLR4). A possible mechanism for pression of angiotensinogen could cause an increase in ANG II and resistin cytoplasmic and nuclear signal transduction by TLR4 in activation of RAS, leading to an elevation in blood pressure [36]. vertebrates. However, further studies are needed to determine the exact mech- anisms linking resistin to hypertension (see ▶Table 1). TANK-binding kinase 1 (TBK1) binding to IκB (inhibitor of NF-κB) kinase epsilon (IKKε). Then, the TBK1-IKKε complex phosphorylates the transcription factor interferon regulatory factor 3 (IRF3), ulti- Resistin and Triglycerides mately driving the expression of interferon beta (IFNβ) and inter- The relationship between resistin and hypertriglyceridemia has feron-inducible protein 10 (IP-10) [25, 27, 32]. ▶Fig. 1 shows the been demonstrated in several studies. Over-expression of resistin summary of this process. in rat, by intramuscular injection of a recombinant eukaryotic ex- The other receptor, which was proposed as a putative resistin pression vector pcDNA3.1-Retn, not altered significantly serum tri- receptor, is CAP1. Although TLR4 has been extensively studied and glyceride (TG) levels compared to control group [48]. In contrast, even there is a report that revealed that resistin in mice binds to ty- adenovirus-mediated over-expression of resistin causes a signifi- rosine kinase-like orphan receptor 1 (ROR1) [33, 34], it can direct- cantly higher levels of triglyceride in mice [49]. Furthermore, a re- ly bind to CAP1 in human monocytes [34]. During the evolution, cent experimental study indicated that the treatment of human CAP1 is conserved from yeast to human. It is an action-binding pro- hepatocytes with resistin strongly stimulated the secretion of VLDL tein that regulates actin cytoskeleton and cell adhesion [34, 35]. (apolipoprotein B) and increased hepatocyte lipid content and elim- ▶Fig. 2 shows the summary of this process. ination of plasma resistin by reducing immunoprecipitation hepat- ocyte apoB production [50]. In studies conducted on human populations, there are conflict- Resistin and Hypertension ing results regarding the relationship between circulating levels of Several recent experimental and clinical studies have highlighted resistin and triglycerides. In a study, which was conducted in Tai- a relationship between resistin and hypertension. In an experimen- wan on 124 hypertensive patients, no correlation was found be- tal study, daily intravenous injections of 400 ng of recombinant tween plasma levels of resistin and triglycerides [51]. Moreover, mouse resistin for 6 consecutive days induces hypertension in mice among Iranian population, also no significant correlation between [36]. In another study, Kosari et al. have shown that blood pressure resistin serum levels and TG was observed [11]. As well as it has

Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 523 Review

▶Fig. 2 Adenylyl cyclase-associated protein 1 (CAP1). Intracellular signaling of resistin via CAP1 in human monocytes.

been shown that resistin did not correlate significantly with TG cir- ▶Table 2). Although reports are contradictory in this regard, taken culating levels in Chinese type 2 diabetes mellitus (T2DM) patients together, these results indicate that circulating concentration of [52]. In another study on 551 obese Spanish women, it has been resistin is positively correlated with increased levels of triglycerides. shown that there is no significant relationship between serum lev- els of resistin and TG [38]. Unlike the above studies, in a large population-based study, it Resistin and HDL Cholesterol was found that circulating resistin levels have a strong positive cor- In the experimental studies, a significantly negative correlation be- relation with fasting levels of plasma TG [53]. In Indian men, serum tween the plasma levels of resistin and high density lipoprotein cho- resistin levels are positively correlated with TG and very low densi- lesterol (HDL-C) has been demonstrated. Upregulation of resistin ty lipoprotein (VLDL) [54]. Osawa et al. showed a positive correla- expression, by intramuscular injection of a recombinant eukaryotic tion between serum resistin and TG levels in levels in Japanese expression vector pcDNA3.1-Retn, significantly decreased serum T2DM patients [55]. Luis et al. showed a significant correlation HDL levels compared to control group [48]. Aligning with this result, among resistin levels and TG in patients with morbid obesity [56]. adenovirus-mediated over-expression of resistin causes a significant- Furthermore, a study on general population (6637 normal subjects) ly lower levels of HDL in mice [49]. Human population studies have in Spain, between 2000 and 2005, showed a strong positive corre- shown a conflicting relationship between circulating levels of resis- lation between serum levels of resistin and triglyceride [57] (see tin and HDL. In a study, which was conducted in China on first-de-

524 Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 ▶Table 1 Studies on correlation between resistin and hypertension.

Article title Correlation Subjects Ref.

Effects of antihypertensive treatment on plasma Mean daily plasma resistin concentrations were significantly lower after Human [96] apelin, resistin, and visfatin concentrations 6 weeks treatment with amlodipine, bisoprolol, or indapamide compared with the baseline values

Resistin induces hypertension and insulin Both systolic blood pressure (BP) and diastolic BP were markedly higher Mice [36] resistance in mice via a TLR4-dependent pathway in WT mice treated with resistin for 6 days Lack of association of serum resistin levels with There was no significant relationship between circulating resistin levels Human [38] metabolic syndrome criteria in obese female and blood pressure in obese women patient. Hyperresistinemia is associated with coexistence A positive correlation between circulating resistin levels and blood Human [41] of hypertension and type 2 diabetes pressure has been reported in subjects both with and without type 2 diabetes mellitus Plasma resistin levels associate with risk for hyper- Higher blood resistin levels are correlated with a raised risk for incident Human [43] tension among nondiabetic women hypertension among women without diabetes or hypertension, which represents the effects of resistin on blood pressure Centrally administered resistin enhances Blood pressure in rats is not significantly affected by intracerebroven- Human [37] sympathetic nerve activity to the hindlimb but tricular and intravenous administration of resistin attenuates the activity to brown adipose tissue Association of resistin and adiponectin with Increased resistin levels are associated without of clinic hypertension Human [40] different clinical blood pressure phenotypes Plasma resistin levels associate with risk for hyper- Higher plasma resistin levels independently associated with an increased Human [44] tension among nondiabetic women risk for incident hypertension among women without diabetes Masked hypertension and atherogenesis: the Patients with masked hypertension have higher resistin levels compared Human [39] impact on adiponectin and resistin plasma levels with normotensive individuals Serum resistin is positively correlated with the Serum resistin was positively correlated with hypertension Human [55] accumulation of metabolic syndrome factors in type 2 diabetes Adiponectin, insulin, and resistin plasma levels in Plasma resistin levels are significantly higher in the young healthy Human [42] young healthy offspring of patients with essential offspring of individuals with essential hypertension compared to the hypertension young healthy offspring of normotensives Adiponectin and resistin plasma levels in healthy Healthy individuals with prehypertension have significantly higher Human [97] individuals with prehypertension resistin plasma levels compared to healthy normotensives The relationship between human serum resistin Fasting serum resistin concentrations not correlated with systolic blood Human [98] level and body fat content, plasma glucose as well pressure (SBP) and diastolic blood pressure (DBP) as blood pressure Serum resistin levels in patients of hypertension Serum resistin levels were significantly raised in patients with hyperten- Human [99] and coronary artery disease sion and coronary artery disease as compared to normotensives Resistin, blood pressure, and cardiovascular Systolic and diastolic blood pressures showed an inverse correlation with Human [100] events resistin. Individuals above the 80 percentile of resistin had an inverse association with hypertension Evaluation of resistin in obese patients with 1. Plasma resistin levels in hypertensive patients with obesity signifi- Human [101] hypertension cantly exceeded those observed in the group without hypertension 2. Significantly higher resistin concentrations were found in non-dipper hypertensives as compared to dipper hypertensives 3. Positive correlation between resistin levels and systolic blood pressure was found Association between serum resistin concentration Serum resistin level in hypertensive patients is higher than normoten- Meta-analysis [44] and hypertension: A systematic review and sive controls, indicating resistin might be a risk factor for hypertension meta-analysis Relation of resistin with obesity and some In obese hypertensive female patients resistin levels were higher than Human [102] cardiovascular risk factors in hypertensive women the nonobese patients

gree relatives of type-2 diabetes patients, serum levels of resistin did Moreover, among Iranian population, serum levels of resistin were not correlate significantly with HDL-C [52]. Luis et al. have also shown not found to be correlated with levels of HDL-C [11]. It was also that there is no significant relationship between serum levels of re- shown that the increased serum levels of resistin did not correlate sistin and cholesterol in obese female patients [38]. significantly with HDL-C circulating levels in nonalcoholic fatty liver

Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 525 Review

▶Table 2 Studies on correlation between resistin and triglycerides.

Article title Correlation Subjects Ref.

Effects of over-expressing resistin on glucose and lipid Over-expression of resistin in rat, by intramuscular injection Rat [48] metabolism in mice of a recombinant eukaryotic expression vector pcD- NA3.1-Retn, not altered significantly serum triglyceride (TG) levels compared to control group

Adenovirus-mediated high expression of resistin causes Adenovirus-mediated over-expression of resistin causes a Mouse [49] dyslipidemia in mice significantly higher levels of triglyceride in mice Lack of association of serum resistin levels with metabolic There is no significant relationship between serum levels of Human [38] syndrome criteria in obese female patients resistin and TG Resistin levels and inflammatory markers in patients with There is a significant correlation among resistin levels and Human [56] morbid obesity TG in patients with morbid obesity Human resistin stimulates hepatic overproduction of Treatment of human hepatocytes with resistin strongly Cell [50] atherogenic ApoB-containing lipoprotein particles by stimulated the secretion of VLDL (apolipoprotein B) and culture enhancing ApoB stability and impairing intracellular insulin increased hepatocyte lipid content and elimination of signaling plasma resistin via immunoprecipitation reduces hepatocyte apoB production High serum resistin levels are associated with peripheral artery Plasma levels of resistin was not correlated with triglyceride Human [51] disease in the hypertensive patients Relationship between serum resistin concentrations with Serum levels of resistin were not significantly correlated Human [11] metabolic syndrome and its components in an Iranian population with triglycerides concentration Serum resistin positively correlates with serum lipids, but not Serum resistin did not correlate significantly with TG Human [52] with insulin resistance, in first-degree relatives of type-2 circulating levels diabetes patients: an observational study in China Plasma resistin levels correlate with determinants of the Circulating resistin levels have a strong positive correlation Human [53] metabolic syndrome with fasting levels of plasm TG Association of resistin with insulin resistance and factors of Plasma resistin levels were well correlated with triglycerides Human [54] metabolic syndrome in north Indians Serum resistin is positively correlated with the accumulation of Positive correlation between serum resistin and TG levels Human [55] metabolic syndrome factors in type 2 diabetes observed in Japanese T2DM patients The relationship between hepatic resistin overexpression and Serum levels of resistin have a strong positive correlation Human [57] inflammation in patients with nonalcoholic steatohepatitis with triglycerides Association of resistin with metabolic syndrome in Indian Resistin was positively and significantly associated with Human [60] subjects serum triglycerides Resistin - 420C/G polymorphism and serum resistin level in Serum resistin level was correlated with serum triglycerides Human [103] Iranian patients with gestational diabetes mellitus Resistin - 420C/G gene polymorphism on circulating resistin, 420C/G polymorphism of resistin gene directly correlated Human [104] metabolic risk factors and insulin resistance in adult women with high circulating level triglycerides Increased serum leptin and resistin levels and increased carotid Positive correlations were found between serum resistin Human [105] intima-media wall thickness in patients with psoriasis: Is levels and serum TG concentration in both study groups psoriasis associated with atherosclerosis? Effect of six-month lifestyle intervention on adiponectin, Changes in resistin positively correlated with changes in Human [106] resistin and soluble tumor necrosis factor-α receptors in obese triglycerides adolescent The relationship between hepatic resistin overexpression and Serum resistin level in NAFLD patients had a positive Human [107] inflammation in patients with nonalcoholic steatohepatitis correlation with triglycerides Assessment of serum leptin and resistin levels in association Resistin has no significant relationship with triglycerides in Human [108] with the metabolic risk factors of pre- and post-menopausal pre- and post-menopausal women rural women in south India Relationship of adipokines (adiponectin, resistin and RBP4) with Resistin concentrations were significantly inversely Human [109] metabolic syndrome components in pubertal obese children correlated with triglyceride Correlates of resistin in children with chronic kidney disease: Resistin level was positively correlated with serum Human [110] the chronic kidney disease in children cohort triglycerides Association of circulating resistin with metabolic risk factors in Triglyceride levels were positively correlated with resistin Human [61] Indianfemales having metabolic syndrome serum levels

526 Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 ▶Table 3 Studies on correlation between resistin and HDL-cholesterol.

Article title Correlation Subjects Ref.

Association of adiponectin, leptin and resistin with inflamma- A negative correlation between the levels of resistin with Human [62] tory markers and obesity in dementia HDL-cholesterol was stated in patients with all-cause dementia

Relationships between serum resistin and fat intake, serum An elevated resistin concentration (fifth quintile) was Human [57] lipid concentrations and adiposity in the general population associated with a low HDL cholesterol level Inverse association of resistin with physical activity in the Mean resistin level was correlated inversely with HDL Human [63] general population cholesterol Resistin as an inflammatory marker in patients with schizo- Levels of resistin among male patients was associated with low Human [111] phrenia treated with clozapine levels of HDL-cholesterol Circulating resistin protein and mRNA concentrations and Both plasma resistin and peripheral blood mononuclear cells Human [112] clinical severity of coronary artery disease resistin mRNA were negatively associated with plasma HDL-C Serum resistin is related to plasma HDL cholesterol and inversely In diabetic and nondiabetic subjects the protective anti-athero- Human [59] correlated with LDL cholesterol in diabetic and obese humans sclerotic HDL cholesterol is positively correlated with resistin Patients with nonalcoholic fatty liver disease display increased No correlation was found between resistin levels and serum Human [58] serum resistin levels and decreased adiponectin levels HDL levels Associations of resistin with inflammatory and fibrinolytic Resistin was negatively correlated weakly with high-density Human [113] markers, insulin resistance, and metabolic syndrome in lipoprotein (HDL) cholesterol middle-aged and older Chinese Relationship of serum resistin level to traits of metabolic No association was detected between the serum concentra- Human [85] syndrome and serum paraoxonase 1 activity in a population tions of resistin and HDL-C with a broad range of body mass index Lack of association of serum resistin levels with metabolic There is no significant relationship between serum levels of Human [38] syndrome criteria in obese female patients resistin and cholesterol in obese female patients Resistin increases with obesity and atherosclerotic risk factors Negative relation was observed between resistin and Human [74] in patients with myocardial infarction high-density lipoprotein cholesterol Effects of over-expressing resistin on glucose and lipid Over-expression of resistin in rat, by intramuscular injection of a Rat [48] metabolism in mice recombinant eukaryotic expression vector pcDNA3.1-Retn decreased significantly serum HDL levels compared to control group Plasma resistin, associated with single nucleotide polymor- Simple regression analysis revealed that low HDL cholesterol Human [114] phism-420, is correlated with insulin resistance, lower HDL were positively correlated with plasma resistin cholesterol, and high-sensitivity C-reactive protein in the Japanese general population Serum resistin level among healthy subjects: relationship to Serum resistin level only negatively correlated with high-densi- Human [83] anthropometric and metabolic parameters ty lipoprotein cholesterol (HDL-C) level in men; there was no correlation between serum resistin level and lipid profiles in women Variation in the resistin gene is associated with obesity and The + 1084 G allele was associated with lower HDL cholesterol Human [115] insulin-related phenotypes in Finnish subjects in both type-2 diabetes patients and controls Circulating adiponectin and resistin levels in relation to A negative correlation was found between serum levels of Human [116] metabolic factors, inflammatory markers, and vascular reactiv- resistin and HDL ity in diabetic patients and subjects at risk for diabetes Adenovirus-mediated high expression of resistin causes Adenovirus-mediated over-expression of resistin caused a Mouse [49] dyslipidemia in mice significantly lower levels of HDL in mice Relationship between serum resistin concentrations with Serum levels of resistin were not found to be correlated with Human [11] metabolic syndrome and its components in an Iranian levels of HDL-C population Serum resistin positively correlates with serum lipids, but not Serum resistin did not correlate significantly with high-density Human [52] with insulin resistance, in first-degree relatives of type-2 lipoprotein cholesterol (HDL) diabetes patients: an observational study in China Plasma resistin levels correlate with determinants of the Plasma resistin levels were inversely correlated with high Human [53] metabolic syndrome density lipoprotein (HDL) levels Association of resistin with insulin resistance and factors of Plasma resistin levels were well correlated with high density Human [54] metabolic syndrome in north Indians lipoprotein (HDL) levels Serum resistin is positively correlated with the accumulation Serum resistin was correlated with lower HDL Human [55] of metabolic syndrome factors in type-2 diabetes

Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 527 Review

▶Table 3 StudiesContinued. on correlation between resistin and HDL-cholesterol.

Article title Correlation Subjects Ref.

Association of resistin with metabolic syndrome in Indian Resistin was negatively and significantly associated with serum Human [60] subjects high-density lipoprotein (HDL) levels Correlates of resistin in children with chronic kidney disease: Resistin level was negatively correlated with high-density Human [110] the chronic kidney disease in children cohort lipoprotein cholesterol Association of circulating resistin with metabolic risk factors in Resistin levels was negatively associated with high-density Human [61] Indian females having metabolic syndrome lipoprotein Plasma resistin concentration determined by common variants Multiple linear regression analysis showed that the plasma Human [90] in the resistin gene and associated with metabolic traits in an resistin level was significantly associated with serum aged Japanese population concentrations of HDL-cholesterol

disease (NAFLD) patients [58]. In a study, which was conducted on key showed serum resistin levels was positively correlated with FBG, diabetic and obese humans, a positive correlation between circulat- fasting insulin, and HbA1c insulin resistance index, but had a neg- ing levels of resistin and HDL-C has been reported [59]. ative correlation with islet β-cell function [67]. Unlike the mentioned studies, the negative correlations be- The relationship between resistin and FBG levels in human has tween circulating levels of resistin and HDL-C have been demon- been investigated in several studies. A study on north Indians indi- strated in several other studies. In a large population-based study, cated that plasma resistin levels were well correlated with FBG, in- it was found that plasma levels of resistin have a strong negative sulin, and IR [54]. Increased serum resistin levels in patients with correlation with circulating HDL-C [53]. A study on Indian MetS pa- coronary slow-flow phenomenon was correlated positively with the tients showed that resistin was negatively and significantly associ- plasma levels of glucose [68]. Another study, which aimed to inves- ated with serum HDL-C levels [60]. Moreover, in Indian females with tigate the relationship between plasma levels of resistin with MetS MetS, serum resistin levels was negatively correlated with HDL-C factors among Indian females with MetS, showed circulating levels [61]. In Japanese T2DM patients, serum resistin was correlated with of resistin were positively associated with plasma glucose [61]. An- lower HDL [55]. other study demonstrated that the fasting plasma resistin level was Furthermore, a study on general population showed a negative positively correlated with FBG in obstructive sleep apnea hypopnea correlation between serum levels of HDL-C and resistin [57]. A neg- syndrome [69]. A significant correlation of plasma resistin with fast- ative correlation between the levels of resistin with HDL-cholester- ing blood glucose, and HOMA-IR score in nondiabetic and diabet- ol was stated in patients with all-cause dementia [62]. Also, in an- ic, overweight/obese Thai had been observed [70]. Furthermore, other general population based study, it has been shown that re- the serum resistin concentration was positively correlated with FBG sistin level was correlated inversely with HDL cholesterol [63] (see in obese children [71]. Also, another study showed that in type 2 ▶Table 3). diabetic patients, plasma levels of resistin had a significant positive Although reports are contradictory in this regard, taken togeth- correlation with FBG [72]. In the studies on Saudi women with type er, these results indicate that circulating resistin levels circulating 2 diabetes mellitus, it was shown that resistin correlated signifi- concentration of resistin is negatively correlated with of HDL-C. cantly and positively with FBG in diabetic women but in nondiabet- ic subjects, no correlation was observed between resistin and blood glucose levels [73]. A significant positive correlation has been Resistin and Fasting Blood Glucose shown between blood resistin concentration and fasting glucose It has been postulated that resistin is involved in the regulation of levels in patients with myocardial infarction [74]. glucose metabolism since its administration to rodents increased Unlike the above mentioned reports, many studies have shown blood glucose levels, while injection of anti-resistin antibodies into that there is no significant relationship between plasma levels of rodent ameliorated insulin action [6]. Experimental studies have resistin and fasting blood glucose. The Pearson analysis indicated shown that resistin impairs glucose-induced insulin release from that serum levels of resistin did not correlate significantly with pancreatic islets of rats [64], and decreases insulin signaling and blood glucose, insulin level, and HbA1c in first-degree relatives of glucose uptake in rat skeletal muscle cells [65]. Consistent with type-2 diabetes Chinese patients [52]. Another assessment on these evidence, transiently resistin-expressing mice exhibit an im- obese Chinese children revealed resistin levels were not related to paired insulin secretory response to glucose resulting in insulin re- fasting blood glucose [75]. In another study, also, circulating levels sistance (IR) [64]. Transgenic mice that have high plasma levels of of resistin were not significantly correlated with FBG in obese sub- resistin showed higher fasting blood glucose (FBG) levels [66]. jects [22]. Among diabetic patients with acute ST segment eleva- Against this, adenovirus-mediated high expression of resistin tion myocardial infarction, serum resistin was not correlated with caused an elevation in basal insulin concentration, but did not fasting blood glucose [76]. Another study, which aimed to investi- change FBG levels [49]. Another study on obese T2DM Rhesus mon- gate the relationship between serum resistin concentration and

528 Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 ▶Table 4 Studies on correlation between resistin and fasting blood glucose.

Article title Correlation Subjects Ref.

Adenovirus-mediated high expression of resistin causes Fasting plasma glucose levels did not differ between AdmRes-treat- Mouse [49] dyslipidemia in mice ed mice and controls, but the basal insulin concentration was significantly elevated in AdmRes-treated mice

Relevance and clinical significance of serum resistin level Serum resistin levels was positively correlated with fasting plasma Monkey [67] in obese T2DM rhesus monkey models glucose, fasting insulin and HbA1c, insulin resistance index, but had a negative correlation with islet β-cell function Association of resistin with insulin resistance and factors Plasma resistin levels were well correlated with fasting glucose, Human [54] of metabolic syndrome in north Indians insulin and insulin resistance Increased serum resistin levels in patients with coronary The resistin levels correlated positively with the plasma levels of Human [68] slow-flow phenomenon glucose Association of circulating resistin with metabolic risk Resistin levels were positively associated with plasma glucose Human [61] factors in Indian females having metabolic syndrome Plasma resistin level in obstructive sleep apnea hypopnea Correlation analysis demonstrated that the fasting plasma resistin Human [69] syndrome level was positively correlated with fasting blood glucose Plasma resistin and insulin concentration in nondiabetic A significant correlation of plasma resistin with fasting blood sugar, Human [70] and diabetic overweight/obese Thai and HOMA score had been observed Serum resistin concentration and insulin resistance in The serum resistin concentration was positively correlated with Human [71] obese children fasting glucose Roles of adipocyte derived hormone adiponectin and Plasma resistin concentration correlated positively with fasting Human [72] resistin in insulin resistance of type 2 diabetes blood glucose levels Serum resistin, adiposity and insulin resistance in Saudi Resistin correlated significantly and positively with fasting blood Human [73] women with type-2 diabetes mellitus glucose in diabetic women but in non-diabetic subjects, no correlation was observed between resistin and blood glucose levels Resistin increases with obesity and atherosclerotic risk Significant positive correlation was revealed between blood resistin Human [74] factors in patients with myocardial infarction concentration and fasting glucose levels Serum resistin positively correlates with serum lipids, but The Pearson analysis showed that serum levels of resistin did not Human [52] not with insulin resistance, in first-degree relatives of correlate significantly with HOMA indexes, blood glucose, insulin, type-2 diabetes patients: an observational study in China and HbA1c in Chinese T2DM patients Association of serum resistin levels with metabolic The resistin levels positively correlated with fasting insulin, Human [75] syndrome and early atherosclerosis in obese Chinese HOMA-IR, but not related to fasting blood glucose children Serum resistin levels of obese and lean children and No significant correlation was found between resistin levels and Human [22] adolescents: biochemical analysis and clinical relevance glucose concentrations in obese subjects Serum resistin in acute myocardial infarction patients with Among diabetic patients with acute ST segment elevation Human [76] and without diabetes mellitus myocardial infarction, serum resistin was not correlated with fasting blood glucose Relationship between serum resistin concentration and The results showed that serum resistin concentrations did not Human [77] proinflammatory cytokines in obese women with impaired correlate with fasting plasma glucose level, or fasting plasma insulin and normal glucose tolerance level Resistin serum levels are increased but not correlated with No significant correlation was observed between serum resistin Human [78] insulin resistance in chronic hemodialysis patients levels with insulin and glucose levels Circulating resistin levels are not associated with fat Resistin levels were not correlated with fasting glucose, insulin, and Human [79] redistribution, insulin resistance, or metabolic profile in homeostasis model assessment of insulin resistance index patients with the highly active antiretroviral therapy-in- duced metabolic syndrome High serum resistin is associated with an increase in Serum resistin levels were not associated with fasting blood glucose Human [80] adiposity but not a worsening of insulin resistance in Pima and insulin levels Indians Serum resistin levels in women with polycystic ovary Multiple regression analysis showed that resistin levels do not corre- Human [81] syndrome late with fasting blood glucose concentrations Increased resistin blood levels are not associated with Plasma resistin levels were not significantly correlated with insulin Human [82] insulin resistance in patients with renal disease and fasting blood glucose levels

Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 529 Review

▶Table 4 StudiesContinued. on correlation between resistin and fasting blood glucose.

Article title Correlation Subjects Ref.

Relationship between serum resistin concentrations with Serum levels of resistin were not correlated with levels of FBS Human [11] metabolic syndrome and its components in an Iranian population Serum resistin level among healthy subjects: relationship The results revealed that serum resistin level did not correlate with Human [83] to anthropometric and metabolic parameters fasting plasma levels in women Increased serum resistin in nonalcoholic fatty liver disease No correlation was found between resistin and insulin and glucose Human [84] is related to liver disease severity and not to insulin values resistance Relationship of serum resistin level to traits of metabolic No association was detected between the serum concentrations of Human [85] syndrome and serum paraoxonase 1 activity in a resistin and glucose, insulin, or insulin resistance (HOMA-IR) population with a broad range of body mass index High plasma resistin level is associated with enhanced Plasma resistin concentration was not associated with plasma Human [86] highly sensitive C-reactive protein and leukocytes insulin or glucose levels Association of plasma levels of resistin with subcutaneous The plasma resistin levels were not correlated with the HOMA-IR, Human [87] fat mass and markers of inflammation but not with fasting plasma glucose or insulin levels metabolic determinants or insulin resistance Elevated resistin levels in cirrhosis are associated with the Plasma resistin in cirrhosis was negatively associated with hepatic Human [93] proinflammatory state and altered hepatic glucose metab- glucose production olism but not with insulin resistance

proinflammatory cytokines in obese women with impaired and nor- to investigate the relationship between plasma levels of resistin mal glucose tolerance, showed that serum resistin concentrations with MetS factors among Indian females with MetS, showed circu- did not correlate with fasting plasma glucose level, or fasting plas- lating levels of resistin were positively associated with waist circum- ma insulin level [77]. Furthermore, no significant correlation was ference [61]. Also it has been demonstrated that the fasting plas- observed between serum resistin levels with insulin and glucose ma resistin level was positively correlated with waist circumference levels in chronic hemodialysis patients [78]. However, in patients and WHR in obstructive sleep apnea hypopnea syndrome [69]. A with the highly active antiretroviral therapy-induced metabolic syn- significant correlation of plasma resistin with body mass index drome, resistin levels were not correlated with FBG and insulin lev- (BMI), waist circumference, and WHR in nondiabetic and diabetic els [79]. Serum resistin levels were not associated with FBG and in- overweight/obese Thai had been observed [70]. Furthermore, the sulin levels in Pima Indians [80]. In addition, serum resistin levels in serum resistin concentration was positively correlated with BMI, women with polycystic ovary syndrome was not correlated with percent of body fat (BF %), and WHR in obese children [71]. Also, FBG concentrations [81]. Increased resistin blood levels are not as- another study showed that in type 2 diabetic patients, plasma lev- sociated with insulin resistance, and insulin and FBG levels in pa- els of resistin had a significant positive correlation with BMI [72]. A tients with renal disease [82]. Another study conducted to investi- study on Saudi women with type 2 diabetes mellitus showed that gate the relationship between plasma levels of resistin and MetS resistin correlated significantly and positively with hip circumfer- and its components among Iranian population revealed that serum ences in diabetic women, but no correlation was observed with hip, levels of resistin were not correlated with FBG levels [11]. Further- waist, and WHR in overweight and obese nondiabetic subjects [73]. more, a study on healthy subjects revealed that serum resistin level A significant positive correlation has been reported between blood did not correlate with fasting plasma levels [83]. In nonalcoholic resistin concentration against waist and hip circumferences in pa- fatty liver disease (NAFLD), increased serum resistin was not relat- tients with myocardial infarction [74]. ed to insulin resistance and glucose values [84]. In addition, the Correlation of serum resistin with waist circumference, fat-mass lack of correlation between plasma levels of resistin and fasting glu- percentage, WHR, and BMI was positive in both genders among cose has also been shown in several other studies [85–87] (see Chinese children and adolescents [88]. In addition, the concentra- ▶Table 4). tion of serum resistin was positively correlated with waist circum- ference in patients with nonalcoholic fatty liver disease [58]. In an- other cross-sectional study, visceral adipose tissue, subcutaneous Resistin and Central or Abdominal Obesity adipose tissue, pericardial fat, and intrathoracic fat were positively The relationship between circulating levels of resistin and abdom- correlated with plasma levels of resistin [89]. inal obesity (measured by waist circumference) in human has been A study conducted on Spanish female obese patients showed investigated in several studies. A study on north Indians indicated that serum resistin was correlated with weight, fat mass, waist cir- that plasma resistin levels were well correlated with waist circum- cumference of obese subjects, although, serum resistin was not ference and waist/hip ratio (WHR) [54]. Another study, which aimed associated with the presence of metabolic syndrome [38]. In addi-

530 Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 ▶Table 5 Studies on correlation between resistin and central or abdominal obesity.

Article title Correlation Subjects Ref.

Association of resistin with insulin resistance and factors of Plasma resistin levels were well correlated with waistt Human [54] metabolic syndrome in north Indians circumference and waist/hip ratio

Association of circulating resistin with metabolic risk factors in Resistin levels were positively associated with waist Human [61] Indian females having metabolic syndrome circumference and waist/hip ratio Lack of association of serum resistin levels with metabolic There was a significant relationship between serum levels of Human [38] syndrome criteria in obese female patients resistin and waist circumference and waist/hip ratio in obese female patients Resistin levels and inflammatory markers in patients with There was a significant correlation among resistin levels and Human [56] morbid obesity weight, BMI, and fat mass Plasma resistin level in obstructive sleep apnea hypopnea Correlation analysis demonstrated that the fasting plasma Human [69] syndrome resistin level was positively correlated with waist circumfer- ence and waist/hip ratio Plasma resistin and insulin concentration in non-diabetic and A significant correlation of plasma resistin with BMI, waist Human [70] diabetic overweight/obese Thai circumference, and waist-to-hip ratio Serum resistin concentration and insulin resistance in obese The serum resistin concentration was positively correlated Human [71] children with BMI, percent of body fat (BF %), and waist-hip ratio Roles of adipocyte derived hormone adiponectin and resistin in Plasma resistin concentration was positively correlated with Human [72] insulin resistance of type 2 diabetes body mass index. Serum resistin, adiposity and insulin resistance in Saudi women Resistin correlated significantly and positively with hip Human [73] with type 2 diabetes mellitus circumferences in diabetic women, but no correlation was observed with hip, waist, and waist/hip ratio (WHR) in overweight and obese nondiabetic subjects Resistin increases with obesity and atherosclerotic risk factors in Significant positive correlation was revealed between blood Human [74] patients with myocardial infarction resistin concentration and waist and hip circumferences Serum resistin positively correlates with serum lipids, but not The Pearson analysis showed that serum levels of resistin did Human [52] with insulin resistance, in first-degree relatives of type-2 not significantly correlate with BMI and waist or hip diabetes patients: an observational study in China circumference in Chinese T2DM patients Resistin serum levels are increased but not correlated with No significant correlation was observed between serum Human [78] insulin resistance in chronic hemodialysis patients resistin levels with BMI and body fat content Circulating resistin levels are not associated with fat redistribu- Resistin levels were weak positively correlated with percent of Human [79] tion, insulin resistance, or metabolic profile in patients with the total body fat, total extremity fat, and abdominal sub highly active antiretroviral therapy-induced metabolic syndrome cutaneous fat, but not abdominal visceral fat or waist/hip ratio Increased resistin blood levels are not associated with insulin Plasma resistin levels not correlated significantly with body Human [82] resistance in patients with renal disease mass index, and waist/hip ratio Relationship between serum resistin concentrations with Serum levels of resistin were not correlated with waist Human [11] metabolic syndrome and its components in an Iranian circumference and body mass index population Serum resistin level among healthy subjects: relationship to The results revealed that serum resistin level did not correlate Human [83] anthropometric and metabolic parameters with body mass index, waist and hip circumferences, and waist/hip ratio in women Association of plasma levels of resistin with subcutaneous fat The plasma resistin levels were positively correlated with the Human [87] mass and markers of inflammation but not with metabolic abdominal subcutaneous fat determinants or insulin resistance Elevated resistin levels in cirrhosis are associated with the No correlation was observed between resistin and body fat Human [93] proinflammatory state and altered hepatic glucose metabolism mass but not with insulin resistance Serum resistin correlates with central obesity but weakly with Waist circumference, fat-mass percentage, waist/height ratio Human [88] insulin resistance in Chinese children and adolescents and body mass index are (BMI) positively correlated with resistin in both genders Patients with nonalcoholic fatty liver disease display increased Serum resistin concentration was positively correlated with Human [58] serum resistin levels and decreased adiponectin levels waist circumference Cross-sectional associations between abdominal and thoracic Cross-sectional visceral adipose tissue, subcutaneous adipose Human [89] adipose tissue compartments and adiponectin and resistin in tissue, pericardial fat, and intrathoracic fat were positively the Framingham heart study correlated with resistin

Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 531 Review

▶Table 5 Continued.Studies on correlation between resistin and central or abdominal obesity.

Article title Correlation Subjects Ref.

Plasma resistin levels correlate with determinants of the Plasma resistin levels were high positive correlated with waist Human [53] metabolic syndrome circumference and waist/hip ratio The association of resistin with coronary disease in the general The serum resistin concentration was higher in women than Human [57] population in men. Individuals in the 5th quintile or higher of resistin (RQ5) had a lower prevalence of abdominal obesity Resistin levels in morbid obese patients following the A massive weight reduction after 1 year of BPD is not Human [117] biliopancreatic diversion surgery associated with a significant change in serum levels of resistin Association between resistin + 299 A/A genotype and The AA genotype was found to be associated with a 2.37-fold Human [118] nonalcoholic fatty liver disease in Chinese patients with type-2 increased risk for obesity of abdominal type compared to the diabetes mellitus GG genotype 3′UTR + 62 G > A polymorphism of the RETN gene coding resistin Significant associations between the G/A genotype and high Human [119] and its association with metabolic syndrome components values of abdominal circumference were found Visfatin, resistin, hsCRP and insulin resistance in relation to Resistin did not correlate with anthropometric parameters Human [95] abdominal obesity in women with rheumatoid arthritis Plasma resistin concentration determined by common variants Multiple linear regression analysis showed that the plasma Human [90] in the resistin gene and associated with metabolic traits in an resistin level was significantly associated with BMI aged Japanese population Inverse association between serum resistin and insulin The correlations between resistin and abdominal obesity (waist/ Human [92] resistance in humans hip ratio > or = 1 in men or > or = 0.9 in women) were inverse Expression of resistin protein in normal human subcutaneous Resistin was closely related with central obesity Human [91] adipose tissue and pregnant women subcutaneous adipose tissue and placenta Association of adiponectin and resistin with adipose tissue There were no significant correlations between resistin levels Human [94] compartments, insulin resistance and dyslipidaemia and adipose tissue masses

tion, another study showed a significant correlation among resis- and hip circumferences, and WHR [83]. In addition, the lack of cor- tin levels and weight, BMI, and fat mass in patients with morbid relation between plasma levels of resistin and abdominal obesity obesity [56]. has been shown in several other studies [93–95]. Also, in patients with the highly active antiretroviral therapy-in- In a prospective observational study on morbid obese patients duced metabolic syndrome, resistin levels were weakly positively without diabetes mellitus undergoing open biliopancreatic diver- correlated with percent of total body fat, total extremity fat, and sion (BPD) showed that a massive weight reduction after 1 year of abdominal subcutaneous fat, but not with abdominal visceral fat BPD is not associated with a significant change in serum levels of or waist/hip ratio [79]. Furthermore, a positive correlation between resistin. [38]. (See ▶Table 5). plasma levels of resistin and abdominal obesity has also been ob- served in several other studies [53, 87, 90, 91]. The inverse corre- lations between resistin and abdominal obesity, also have been re- Conclusion ported [92]. The resistin gene expression is identified in several cell types includ- Unlike the above mentioned reports, many studies have shown ing adipocytes [6, 14]. In humans, resistin is predominantly pro- that there is no significant relationship between plasma levels of duced by peripheral blood mononuclear cells (PBMCs), macrophag- resistin and fasting blood glucose. The Pearson analysis showed es, and bone marrow cells [20, 21]. The main source of rodent’s re- that serum levels of resistin did not correlate significantly with BMI sistin is white adipose tissue [6, 18]. It has been reported that in and waist or hip circumference in first-degree relatives of type-2 obese and diabetic patients, the serum level of resistin is signifi- diabetes patients in China [52]. No significant correlation was ob- cantly increased [6, 22]. served between serum resistin levels with BMI and body fat con- Resistin gene expression in rodent adipocytes is stimulated by tent in chronic hemodialysis patients [78]. Increased resistin blood high levels of glucose but is suppressed by tumor necrosis factor α levels are not associated significantly with body mass index and (TNF-α) while human resistin is strongly induced by various inflam- WHR in patients with renal disease [82]. Another study conducted matory stimuli, including interleukin 6 (IL-6), IL-1β, lipopolysaccha- to investigate the relationship between plasma levels of resistin and ride (LPS), TNF-α, and resistin itself, in PBMCs and macrophages [23]. MetS and its components among Iranian population showed that Among TLRs, TLR4 is proposed as the one resistin membrane serum levels of resistin were not correlated with waist circumfer- receptors that mediates its intracellular functions [28, 29]. In fact, ence and BMI [11]. Furthermore, a study on healthy subjects re- TLR4 is considered as an immune-receptor that promotes the pro- vealed that serum resistin level did not correlate with BMI, waist duction of inflammatory substances in macrophages but, for ex-

532 Mostafazadeh M et al. Resistin and Metabolic Syndrome... Horm Metab Res 2018; 50: 521–536 ample, it can also mediate the effects of resistin in hypothalamus [12] Lazar M. Resistin-and obesity-associated metabolic diseases. Horm for activating pro-inflammatory pathways [25, 29]. In contrast with Metab Res 2007; 39: 710–716 TLR4, there is not enough data about CAP1 receptor for modulat- [13] Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, Enders GH, Silberg DG, Wen X, Wu GD. A family of tissue-specific ing effects of resistin in human. resistin-like molecules. Proc Natl Acad Sci U S A 2001; 98: 502–506 Furthermore, a recent meta-analysis, which was conducted to [14] Rajala MW, Lin Y, Ranalletta M, Yang XM, Qian H, Gingerich R, Barzilai evaluate the significance of serum resistin levels in hypertensive N, Scherer PE. Cell type-specific expression and coregulation of patients, shows that serum resistin level in hypertensive patients murine resistin and resistin-like molecule-a in adipose tissue. Mol is significantly higher than normotensive individuals [44]. Endocrinol 2002; 16: 1920–1930 In experiments among different human genetic groups as well [15] Nogueiras R, Gallego R, Gualillo O, Caminos JE, García-Caballero T, as the patients with various diseases such as diabetes, polycistic Casanueva FF, Diéguez C. Resistin is expressed in different rat tissues ovary and NAFLD that is used by authors, no significant correlation and is regulated in a tissue-and gender-specific manner. FEBS Lett 2003; 548: 21–27 between FBG and resistin level was shown. Furthermore, this re- [16] Nogueiras R, Barreiro ML, Caminos JE, Gaytán F, Suominen JS, Navarro view reveals that the results of correlation between resistin and TG, VM, Casanueva FF, Aguilar E, Toppari J, Diéguez C. 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