Alternative titles; symbols
HGNC Approved Gene Symbol: RETN
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:7,669,049-7,670,455 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | {Diabetes mellitus, noninsulin-dependent, susceptibility to} | 125853 | Autosomal dominant | 3 |
| {Hypertension, insulin resistance-related, susceptibility to} | 125853 | Autosomal dominant | 3 |
By searching sequence databases for genes similar to mouse Fizz1, Holcomb et al. (2000) identified cDNAs encoding human FIZZ2 (RETNLB; 605645), which the authors incorrectly called FIZZ1, and human and mouse FIZZ3 (RETN). The deduced 108-amino acid FIZZ3 protein, 53% identical to mouse Fizz3 and 47% identical to human FIZZ2, shares an N-terminal signal peptide and a C-terminal stretch of 10 cysteine residues with identical spacing with the other FIZZ family members. In situ hybridization analysis detected diffuse expression of mouse Fizz3 in white but not brown adipose tissue in a variety of organs.
Type II diabetes mellitus (T2D; 125853), characterized by target-tissue resistance to insulin (176730), is epidemic in industrialized societies and is strongly associated with obesity. Steppan et al. (2001) studied the mechanism by which increased adiposity causes insulin resistance. They demonstrated that adipocytes secrete a unique signaling molecule, which they called resistin (for resistance to insulin), that may be the hormone potentially linking obesity to diabetes. Steppan et al. (2001) identified resistin, which is identical to FIZZ3, by screening for genes that are induced during adipocyte differentiation but downregulated in mature adipocytes exposed to thiazolidinediones (TZD), insulin-secreting, antidiabetic drugs that interact with the peroxisome proliferator-activated receptor-gamma (PPARG; 601487). Resistin gene expression is induced during adipocyte differentiation, and the resistin polypeptide is specifically expressed and secreted by adipocytes. Resistin circulates in mouse serum, and its level is increased markedly in both genetic and diet-induced obesity. Immunoneutralization improves blood glucose and insulin action in this model of type II diabetes. By contrast, administration of resistin impairs glucose tolerance and insulin action in normal mice. In mouse, a single mRNA of roughly 750 residues is robustly expressed in white adipose tissue but not in several other mouse tissues. Resistin expression is greater in white adipose tissue than in brown adipose tissue, where resistin mRNA is barely detectable. Resistin mRNA levels varied as a function of white adipose depot and gender, with the highest level of expression in female gonadal fat. Immunohistochemistry of epididymal white adipose tissue showed that the resistin protein is abundant in adipocyte cytoplasm. Steppan et al. (2001) found that a unique pattern of C-terminal cysteines (X11-C-X8-C-X-C-X3-C-X10-C-X-C-X-C-X9-CC-X3-6-END) is conserved in a family of resistin-like molecules, including at least 3 distinct mouse subtypes.
McTernan et al. (2002) found that resistin mRNA expression was similar in both subcutaneous abdominal and omental fat depots. However, the abdominal depots showed a 418% increase in resistin mRNA expression compared with the thigh. The authors suggested that increased resistin expression in abdominal fat could explain the increased risk of type II diabetes associated with central obesity.
Degawa-Yamauchi et al. (2003) investigated the role of resistin in obesity and insulin resistance by quantitating resistin protein by ELISA in serum of 27 lean and 50 obese subjects. There was more serum resistin protein in obese than lean subjects. The elevation of serum resistin in obese humans was confirmed by Western blot as was expression of resistin protein in human adipose tissue and isolated adipocytes. There was a significant positive correlation between resistin and body mass index (BMI). Multiple regression analysis with predictors BMI and resistin explained 25% of the variance in the homeostasis model assessment of insulin resistance score. BMI was a significant predictor of insulin resistance (P = 0.0002), but resistin adjusted for BMI was not (P = 0.11). The authors concluded that their data demonstrate that resistin protein is present in human adipose tissue and blood, and that there is significantly more serum resistin in obese subjects, but it is not a significant predictor of insulin resistance when adjusted for adiposity.
Verma et al. (2003) incubated endothelial cells with human recombinant resistin and observed an increase in ET1 (EDN1; 131240) release and ET1 mRNA expression, with no change in nitric oxide production. Treatment with resistin increased ET1 promoter activity via the activator protein-1 (AP1; see 165160) site. Resistin upregulated adhesion molecules and chemokines and downregulated tumor necrosis factor receptor-associated factor-3 (TRAF3; 601896), an inhibitor of CD40 ligand (CD40LG; 300386) signaling. Verma et al. (2003) concluded that these effects may represent the mechanistic link between resistin and cardiovascular disease in the metabolic syndrome (see 605552).
Using coimmunoprecipitation analysis with overexpression and knockdown studies, Lee et al. (2014) found that CAP1 (617801) directly bound resistin multimers in THP-1 monocytes via its polyproline SH3-binding region. CAP1 overexpression upregulated resistin-dependent cAMP concentration, protein kinase A (see 601639) activity, and NF-kappa-B (see 164011)-related transcription of inflammatory cytokines. CAP1 overexpression significantly enhanced invasion of THP-1 cells toward resistin. Moreover, expression of human CAP1 in monocytes in transgenic mice aggravated adipose tissue infiltration and inflammation. Suppression of CAP1 expression abrogated resistin-mediated inflammatory activity in vitro and in vivo.
Using RT-PCR analysis, Kumowski et al. (2025) showed that resistin-like molecule-gamma (Retnlg), a mouse homolog of human RETN, was highly expressed in neutrophils after myocardial infarction (MI). Transplantation of Retnlg -/- bone marrow demonstrated that neutrophil-derived Retnlg facilitated ventricular arrhythmia in recipient mice. Retnlg/RETN caused membrane defects in liposomes and cardiomyocytes and promoted mammalian cell death, not by affecting programmed cell death but by enhancing externally caused necrosis. Analysis of a mouse model of ischemic stroke suggested that larger brain infarcts and neuronal cell membrane defects in the presence of Retnlg were caused by pore formation.
Wang et al. (2002) determined that the resistin gene comprises 4 exons, the first of which is untranslated, and spans approximately 1,750 bp.
Crystal Structure
Patel et al. (2004) determined the crystal structure of resistin and RELM-beta (605645), which revealed an unusual multimeric structure. Each protomer comprises a carboxy-terminal disulfide-rich beta-sandwich 'head' domain and an amino-terminal alpha-helical 'tail' segment. The alpha-helical segments associate to form 3-stranded coiled-coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. Analysis of serum samples showed that resistin circulates in 2 distinct assembly states, likely corresponding to hexamers and trimers. Infusion of a resistin mutant, lacking the intertrimer disulfide bonds, in pancreatic insulin clamp studies revealed substantially more potent effects on hepatic insulin sensitivity than those observed with wildtype resistin.
Cao and Hegele (2001) identified 2 noncoding single-nucleotide polymorphisms (SNPs) in the RSTN gene useful for the study of diabetes, obesity, or disorders of adipocyte biology such as lipodystrophy.
Pizzuti et al. (2002) searched for polymorphisms in the resistin gene by SSCP and direct sequencing. They identified an ATG triplet repeat in the 3-prime-untranslated region and considered it for association with insulin resistance. They identified 3 alleles: allele 1, with 8 repeats and an allele frequency of 0.3%; allele 2, with 7 repeats and an allele frequency of 94.5%; and allele 3, with 6 repeats and an allele frequency of 5.2%. Allele 1 was not tested for association with insulin resistance because of its very low allele frequency. Among Sicilians, subjects carrying allele 3 had lower fasting insulin and insulin resistance index, and lower glucose and insulin levels during the oral glucose tolerance test. In subjects from Gargano (a region geographically close to Sicily but with a different ethnicity), those carrying allele 3 had lower fasting plasma glucose levels and serum triglycerides. When the 2 populations were analyzed together, subjects carrying allele 3 had lower fasting insulin levels (P less than 0.005), homeostasis model assessment of insulin resistance (P less than 0.005), and serum triglycerides (P = 0.01). The authors concluded that subjects carrying the 6-repeat allele of the resistin gene are characterized by relatively high insulin sensitivity.
Wang et al. (2002) hypothesized that genetic variation in the RSTN gene might explain the heritability of insulin action in familial type II diabetes kindreds. They screened 44 subjects with type II diabetes and 20 nondiabetic family members who were at the extremes of insulin sensitivity. They identified 8 noncoding SNPs and 1 GAT microsatellite repeat. Three SNPs, which were in incomplete linkage disequilibrium with each other and had allelic frequencies exceeding 5%, were selected for further study. No SNP was associated with type II diabetes, but the SNP in the promoter region was a significant determinant of insulin sensitivity index (P = 0.04) among nondiabetic family members who had undergone intravenous glucose tolerance tests. The authors concluded that the 3 common SNPs showed statistical significance as determinants of insulin sensitivity index (P less than 0.01) in interaction with body mass index.
Ma et al. (2002) sequenced the resistin gene in 32 subjects with type II diabetes and identified 8 SNPs in the 5-prime flanking region and introns of the gene. Allele and genotype distributions were determined for all 8 SNPs in 312 cases with type II diabetes and in 303 nondiabetic controls, all of Caucasian origin. No significant association with type II diabetes was found at any of the polymorphic loci; however, an interactive effect of one SNP, IVS2+181G-A, with obesity was a significant determinant of type II diabetes risk in this population.
Insulin resistance is a major cause of type II diabetes mellitus. Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress Retn in adipose tissue are insulin resistant (Pravenec et al., 2003), whereas Retn-null mice show lower fasting blood glucose (Banerjee et al., 2004), suggesting that the altered Retn promoter function could cause diabetes. To determine the possible role of RETN in human type II diabetes, Osawa et al. (2004) analyzed polymorphisms in its 5-prime flanking region. They found that the GG genotype at the -420C-G SNP was associated with type II diabetes with an adjusted odds ratio of 1.97 and could accelerate the onset of diabetes by 4.9 years. Linkage disequilibrium analysis revealed that the GG genotype itself was a primary variant in determining type II diabetes susceptibility. Functionally, transcription factors Sp1 (189906) and Sp3 (601804) bound specifically to the susceptible DNA element that included -420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity. Consistent with these findings, fasting serum resistin levels were higher in type II diabetes patients with the GG genotype. Osawa et al. (2004) concluded that the specific recognition of -420G by Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human type II diabetes.
Mattevi et al. (2004) studied the association of the -420C-G SNP of the RETN gene with obesity-related phenotypes in 585 nondiabetic Brazilians of European descent. In the 356 women in the study, the G allele was somewhat less frequent in the overweight/obese group than in normal weight individuals (p = 0.040). Female carriers of the G allele had a lower mean BMI and waist circumference than C/C homozygotes (p = 0.010). When women were stratified by menopausal status, the association was restricted to premenopausal women. Mattevi et al. (2004) suggested that RETN gene variation has gender-specific effects on BMI.
Steppan et al. (2001) localized the human resistin gene to a cloned fragment of human chromosome 19 (GenBank AC008763).
Rajala et al. (2003) found that an infusion of either resistin or RETNLB in rats rapidly induced severe hepatic but not peripheral insulin resistance. Increases in circulating resistin or RETNLB levels markedly stimulated hepatic glucose production despite the presence of fixed physiologic insulin levels. This enhanced rate of glucose output was due to increased flux through glucose-6-phosphatase. The results supported the notion that a novel family of fat- and gut-derived circulating proteins modulates hepatic insulin action.
Banerjee et al. (2004) generated mice deficient in resistin by targeted disruption. Resistin-null mice exhibited low blood glucose levels after fasting due to reduced hepatic glucose production. This was partly mediated by activation of AMP-activated protein kinase (see 602739) and decreased expression of gluconeogenic enzymes in the liver. Banerjee et al. (2004) suggested that their data supported a physiologic function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminished the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.
To determine whether resistin plays a causative role in the development of diet-induced insulin resistance, Muse et al. (2004) lowered circulating resistin levels in mice by use of a specific antisense oligodeoxynucleotide (ASO) directed against resistin mRNA and assessed in vivo insulin action by the insulin clamp technique. After 3 weeks on a high-fat diet, mice displayed severe insulin resistance associated with an approximately 80% increase in plasma resistin levels. In particular, the rate of endogenous glucose production increased more than 2-fold compared with that in mice fed a standard chow. Treatment with the resistin ASO for 1 week normalized the plasma resistin levels and completely reversed the hepatic insulin resistance. Acute infusion of purified recombinant mouse resistin in these mice, designed to elevate acutely the levels of circulating resistin up to those observed in the mice fed a high-fat diet, was sufficient to reconstitute hepatic insulin resistance. These results provided strong support for the physiologic role of resistin in the development of hepatic insulin resistance.
Cao and Hegele (2001) identified a single-nucleotide polymorphism (SNP) of the RETN gene, +62G-A, located 62 bp downstream of the last base of the codon for termination in the 3-prime untranslated region of exon 4.
Tan et al. (2003) studied the association of the resistin gene +62G-A polymorphism with type 2 diabetes (T2D; 125853) in 1,102 Chinese type II diabetes patients and 743 subjects without diabetes. Type II diabetes subjects had a lower frequency of the A allele (GG:GA/AA, 83.5%:16.5%) than did the controls (GG:GA/AA, 75.1%:24.9%; odds ratio, 1.524; 95% CI, 1.268-1.831; P less than 0.001). Unexpectedly, diabetic patients with the GG genotype had a higher prevalence of hypertension (GG:GA/AA, 49.8%:36.2%; odds ratio, 1.375; 95% CI, 1.116-1.693; P = 0.001). Logistic regression analysis confirmed that the +62G-A polymorphism acts as an independent contributing factor to type II diabetes and hypertension. The mean systolic and diastolic blood pressure levels in diabetic subjects with the GG genotype (144 +/- 21/87 +/- 13 mm Hg) were significantly higher than those in subjects with GA/AA variants (139 +/- 21/84 +/- 14 mm Hg; P = 0.004 and P = 0.002, respectively). The authors concluded that resistin may play a role in the pathogenesis of type II diabetes and insulin resistance-related hypertension.
Banerjee, R. R., Rangwala, S. M., Shapiro, J. S., Rich, A. S., Rhoades, B., Qi, Y., Wang, J., Rajala, M. W., Pocai, A., Scherer, P. E., Steppan, C. M., Ahima, R. S., Obici, S., Rossetti, L., Lazar, M. A. Regulation of fasted blood glucose by resistin. Science 303: 1195-1198, 2004. [PubMed: 14976316] [Full Text: https://doi.org/10.1126/science.1092341]
Cao, H., Hegele, R. A. Single nucleotide polymorphisms of the resistin (RSTN) gene. J. Hum. Genet. 46: 553-555, 2001. [PubMed: 11558907] [Full Text: https://doi.org/10.1007/s100380170040]
Degawa-Yamauchi, M., Bovenkerk, J. E., Juliar, B. E., Watson, W., Kerr, K., Jones, R., Zhu, Q., Considine, R. V. Serum resistin (FIZZ3) protein is increased in obese humans. J. Clin. Endocr. Metab. 88: 5452-5455, 2003. [PubMed: 14602788] [Full Text: https://doi.org/10.1210/jc.2002-021808]
Holcomb, I. N., Kabakoff, R. C., Chan, B., Baker, T. W., Gurney, A., Henzel, W., Nelson, C., Lowman, H. B., Wright, B. D., Skelton, N. J., Frantz, G. D., Tumas, D. B., Peale, F. V., Jr., Shelton, D. L., Hebert, C. C. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19: 4046-4055, 2000. [PubMed: 10921885] [Full Text: https://doi.org/10.1093/emboj/19.15.4046]
Kumowski, N., Pabel, S., Grune, J., Momin, N., Ninh, V. K., Stengel, L., Mentkowski, K. I., Iwamoto, Y., Zheng, Y., Lee, I.-H., Matthias, J., Wirth, J. O., and 21 others. Resistin-like molecule gamma attacks cardiomyocyte membranes and promotes ventricular tachycardia. Science 389: 1043-1048, 2025. [PubMed: 40906843] [Full Text: https://doi.org/10.1126/science.adp7361]
Lee, S., Lee, H.-C., Kwon, Y.-W., Lee, S. E., Cho, Y., Kim, J., Lee, S., Kim, J.-Y., Lee, J., Yang, H.-M., Mook-Jung, I., Nam, K.-Y., Chung, J., Lazar, M. A., Kim, H.-S. Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes. Cell Metab. 19: 484-497, 2014. [PubMed: 24606903] [Full Text: https://doi.org/10.1016/j.cmet.2014.01.013]
Ma, X., Warram, J. H., Trischitta, V., Doria, A. Genetic variants at the resistin locus and risk of type 2 diabetes in Caucasians. J. Clin. Endocr. Metab. 87: 4407-4410, 2002. [PubMed: 12213908] [Full Text: https://doi.org/10.1210/jc.2002-020109]
Mattevi, V. S., Zembrzuski, V. M., Hutz, M. H. A resistin gene polymorphism is associated with body mass index in women. Hum. Genet. 115: 208-212, 2004. [PubMed: 15221446] [Full Text: https://doi.org/10.1007/s00439-004-1128-4]
McTernan, C. L., McTernan, P. G., Harte, A. L., Levick, P. L., Barnett, A. H., Kumar, S. Resistin, central obesity, and type 2 diabetes. Lancet 359: 46-47, 2002. [PubMed: 11809189] [Full Text: https://doi.org/10.1016/s0140-6736(02)07281-1]
Muse, E. D., Obici, S., Bhanot, S., Monia, B. P., McKay, R. A., Rajala, M. W., Scherer, P. E., Rossetti, L. Role of resistin in diet-induced hepatic insulin resistance. J. Clin. Invest. 114: 232-239, 2004. [PubMed: 15254590] [Full Text: https://doi.org/10.1172/JCI21270]
Osawa, H., Yamada, K., Onuma, H., Murakami, A., Ochi, M., Kawata, H., Nishimiya, T., Niiya, T., Shimizu, I., Nishida, W., Hashiramoto, M., Kanatsuka, A., Fujii, Y., Ohashi, J., Makino, H. The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. Am. J. Hum. Genet. 75: 678-686, 2004. [PubMed: 15338456] [Full Text: https://doi.org/10.1086/424761]
Patel, S. D., Rajala, M. W., Rossetti, L., Scherer, P. E., Shapiro, L. Disulfide-dependent multimeric assembly of resistin family hormones. Science 304: 1154-1158, 2004. [PubMed: 15155948] [Full Text: https://doi.org/10.1126/science.1093466]
Pizzuti, A., Argiolas, A., Di Paola, R., Baratta, R., Rauseo, A., Bozzali, M., Vigneri, R., Dallapiccola, B., Trischitta, V., Frittitta, L. An ATG repeat in the 3-prime-untranslated region of the human resistin gene is associated with a decreased risk of insulin resistance. J. Clin. Endocr. Metab. 87: 4403-4406, 2002. [PubMed: 12213907] [Full Text: https://doi.org/10.1210/jc.2002-020096]
Pravenec, M., Kazdova, L., Landa, V., Zidek, V., Mlejnek, P., Jansa, P., Wang, J., Qi, N., Kurtz, T. W. Transgenic and recombinant resistin impair skeletal muscle glucose metabolism in the spontaneously hypertensive rat. J. Biol. Chem. 278: 45209-45215, 2003. [PubMed: 12944409] [Full Text: https://doi.org/10.1074/jbc.M304869200]
Rajala, M. W., Obici, S., Scherer, P. E., Rossetti, L. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J. Clin. Invest. 111: 225-230, 2003. [PubMed: 12531878] [Full Text: https://doi.org/10.1172/JCI16521]
Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S., Lazar, M. A. The hormone resistin links obesity to diabetes. Nature 409: 307-312, 2001. [PubMed: 11201732] [Full Text: https://doi.org/10.1038/35053000]
Tan, M.-S., Chang, S.-Y., Chang, D.-M., Tsai, J. C.-R., Lee, Y.-J. Association of resistin gene 3-prime-untranslated region +62G-A polymorphism with type 2 diabetes and hypertension in a Chinese population. J. Clin. Endocr. Metab. 88: 1258-1263, 2003. [PubMed: 12629116] [Full Text: https://doi.org/10.1210/jc.2002-021453]
Verma, S., Li, S.-H., Wang, C.-H., Fedak, P. W. M., Li, R.-K., Weisel, R. D., Mickle, D. A. G. Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation 108: 736-740, 2003. Note: Erratum: Circulation 109: 2254 only, 2004. [PubMed: 12874180] [Full Text: https://doi.org/10.1161/01.CIR.0000084503.91330.49]
Wang, H., Chu, W. S., Hemphill, C., Elbein, S. C. Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians. J. Clin. Endocr. Metab. 87: 2520-2524, 2002. [PubMed: 12050208] [Full Text: https://doi.org/10.1210/jcem.87.6.8528]