Full text data of RETN
RETN
(FIZZ3, HXCP1, RSTN)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Resistin (Adipose tissue-specific secretory factor; ADSF; C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein; Cysteine-rich secreted protein A12-alpha-like 2; Cysteine-rich secreted protein FIZZ3; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Resistin (Adipose tissue-specific secretory factor; ADSF; C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein; Cysteine-rich secreted protein A12-alpha-like 2; Cysteine-rich secreted protein FIZZ3; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9HD89
ID RETN_HUMAN Reviewed; 108 AA.
AC Q9HD89; D6W649; Q540D9;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 100.
DE RecName: Full=Resistin;
DE AltName: Full=Adipose tissue-specific secretory factor;
DE Short=ADSF;
DE AltName: Full=C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein;
DE AltName: Full=Cysteine-rich secreted protein A12-alpha-like 2;
DE AltName: Full=Cysteine-rich secreted protein FIZZ3;
DE Flags: Precursor;
GN Name=RETN; Synonyms=FIZZ3, HXCP1, RSTN; ORFNames=UNQ407/PRO1199;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10921885; DOI=10.1093/emboj/19.15.4046;
RA Holcomb I.N., Kabakoff R.C., Chan B., Baker T.W., Gurney A.,
RA Henzel W., Nelson C., Lowman H.B., Wright B.D., Skelton N.J.,
RA Frantz G.D., Tumas D.B., Peale F.V. Jr., Shelton D.L., Hebert C.C.;
RT "FIZZ1, a novel cysteine-rich secreted protein associated with
RT pulmonary inflammation, defines a new gene family.";
RL EMBO J. 19:4046-4055(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11201732; DOI=10.1038/35053000;
RA Steppan C.M., Bailey S.T., Bhat S., Brown E.J., Banerjee R.R.,
RA Wright C.M., Patel H.R., Ahima R.S., Lazar M.A.;
RT "The hormone resistin links obesity to diabetes.";
RL Nature 409:307-312(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11090083;
RA Kubota T., Kawano S., Chih D.Y., Hisatake Y., Chumakov A.M.,
RA Taguchi H., Koeffler H.P.;
RT "Representational difference analysis using myeloid cells from C/EBP
RT epsilon deletional mice.";
RL Blood 96:3953-3957(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Rajala M.W., Scherer P.E.;
RT "Identification of a novel cysteine-rich secreted A12-alpha related
RT protein.";
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Li M., Wu Y.C., Deng Y.J., Yang J.;
RT "Homo sapiens resistin mRNA found in lymphocytes.";
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
CC -!- FUNCTION: Hormone that seems to suppress insulin ability to
CC stimulate glucose uptake into adipose cells. Potentially links
CC obesity to diabetes.
CC -!- SUBUNIT: Homodimer; disulfide-linked (By similarity).
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed only in fatty tissues.
CC -!- SIMILARITY: Belongs to the resistin/FIZZ family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/retn/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF205952; AAG02144.1; -; mRNA.
DR EMBL; AF323081; AAG59824.1; -; mRNA.
DR EMBL; AF352730; AAK18621.1; -; Genomic_DNA.
DR EMBL; AF290874; AAK83106.1; -; mRNA.
DR EMBL; AY207314; AAO38860.1; -; mRNA.
DR EMBL; AY359066; AAQ89425.1; -; mRNA.
DR EMBL; DQ301958; ABB96251.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW69015.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW69016.1; -; Genomic_DNA.
DR EMBL; BC069302; AAH69302.1; -; mRNA.
DR EMBL; BC101554; AAI01555.1; -; mRNA.
DR EMBL; BC101560; AAI01561.1; -; mRNA.
DR RefSeq; NP_001180303.1; NM_001193374.1.
DR RefSeq; NP_065148.1; NM_020415.3.
DR UniGene; Hs.283091; -.
DR PDB; 1LV6; Model; -; A=1-108.
DR PDBsum; 1LV6; -.
DR ProteinModelPortal; Q9HD89; -.
DR SMR; Q9HD89; 17-107.
DR STRING; 9606.ENSP00000221515; -.
DR DMDM; 18202962; -.
DR PaxDb; Q9HD89; -.
DR PRIDE; Q9HD89; -.
DR DNASU; 56729; -.
DR Ensembl; ENST00000221515; ENSP00000221515; ENSG00000104918.
DR GeneID; 56729; -.
DR KEGG; hsa:56729; -.
DR UCSC; uc002mhf.1; human.
DR CTD; 56729; -.
DR GeneCards; GC19P007733; -.
DR HGNC; HGNC:20389; RETN.
DR MIM; 605565; gene.
DR neXtProt; NX_Q9HD89; -.
DR PharmGKB; PA422; -.
DR eggNOG; NOG46608; -.
DR HOGENOM; HOG000137607; -.
DR HOVERGEN; HBG018297; -.
DR InParanoid; Q9HD89; -.
DR KO; K13438; -.
DR OMA; CQSVTSR; -.
DR OrthoDB; EOG7CVQ14; -.
DR PhylomeDB; Q9HD89; -.
DR GeneWiki; Resistin; -.
DR GenomeRNAi; 56729; -.
DR NextBio; 62204; -.
DR PRO; PR:Q9HD89; -.
DR ArrayExpress; Q9HD89; -.
DR Bgee; Q9HD89; -.
DR CleanEx; HS_RETN; -.
DR Genevestigator; Q9HD89; -.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005179; F:hormone activity; NAS:UniProtKB.
DR GO; GO:0045444; P:fat cell differentiation; IEA:Ensembl.
DR GO; GO:0032868; P:response to insulin stimulus; IEA:Ensembl.
DR InterPro; IPR009714; Resistin.
DR PANTHER; PTHR21101; PTHR21101; 1.
DR Pfam; PF06954; Resistin; 1.
DR SUPFAM; SSF111423; SSF111423; 1.
PE 2: Evidence at transcript level;
KW 3D-structure; Complete proteome; Diabetes mellitus; Disulfide bond;
KW Hormone; Obesity; Reference proteome; Secreted; Signal.
FT SIGNAL 1 18 Potential.
FT CHAIN 19 108 Resistin.
FT /FTId=PRO_0000030341.
FT DISULFID 22 22 Interchain (Probable).
FT DISULFID 51 104 By similarity.
FT DISULFID 63 103 By similarity.
FT DISULFID 72 89 By similarity.
FT DISULFID 74 91 By similarity.
FT DISULFID 78 93 By similarity.
FT HELIX 9 18
FT HELIX 30 39
FT STRAND 46 48
FT HELIX 58 61
FT STRAND 68 70
FT TURN 75 78
FT HELIX 81 89
FT STRAND 90 92
FT HELIX 96 99
FT STRAND 102 105
SQ SEQUENCE 108 AA; 11419 MW; 9B127DFE1699B4F1 CRC64;
MKALCLLLLP VLGLLVSSKT LCSMEEAINE RIQEVAGSLI FRAISSIGLE CQSVTSRGDL
ATCPRGFAVT GCTCGSACGS WDVRAETTCH CQCAGMDWTG ARCCRVQP
//
ID RETN_HUMAN Reviewed; 108 AA.
AC Q9HD89; D6W649; Q540D9;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 100.
DE RecName: Full=Resistin;
DE AltName: Full=Adipose tissue-specific secretory factor;
DE Short=ADSF;
DE AltName: Full=C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein;
DE AltName: Full=Cysteine-rich secreted protein A12-alpha-like 2;
DE AltName: Full=Cysteine-rich secreted protein FIZZ3;
DE Flags: Precursor;
GN Name=RETN; Synonyms=FIZZ3, HXCP1, RSTN; ORFNames=UNQ407/PRO1199;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10921885; DOI=10.1093/emboj/19.15.4046;
RA Holcomb I.N., Kabakoff R.C., Chan B., Baker T.W., Gurney A.,
RA Henzel W., Nelson C., Lowman H.B., Wright B.D., Skelton N.J.,
RA Frantz G.D., Tumas D.B., Peale F.V. Jr., Shelton D.L., Hebert C.C.;
RT "FIZZ1, a novel cysteine-rich secreted protein associated with
RT pulmonary inflammation, defines a new gene family.";
RL EMBO J. 19:4046-4055(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11201732; DOI=10.1038/35053000;
RA Steppan C.M., Bailey S.T., Bhat S., Brown E.J., Banerjee R.R.,
RA Wright C.M., Patel H.R., Ahima R.S., Lazar M.A.;
RT "The hormone resistin links obesity to diabetes.";
RL Nature 409:307-312(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11090083;
RA Kubota T., Kawano S., Chih D.Y., Hisatake Y., Chumakov A.M.,
RA Taguchi H., Koeffler H.P.;
RT "Representational difference analysis using myeloid cells from C/EBP
RT epsilon deletional mice.";
RL Blood 96:3953-3957(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Rajala M.W., Scherer P.E.;
RT "Identification of a novel cysteine-rich secreted A12-alpha related
RT protein.";
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Li M., Wu Y.C., Deng Y.J., Yang J.;
RT "Homo sapiens resistin mRNA found in lymphocytes.";
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
CC -!- FUNCTION: Hormone that seems to suppress insulin ability to
CC stimulate glucose uptake into adipose cells. Potentially links
CC obesity to diabetes.
CC -!- SUBUNIT: Homodimer; disulfide-linked (By similarity).
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed only in fatty tissues.
CC -!- SIMILARITY: Belongs to the resistin/FIZZ family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/retn/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF205952; AAG02144.1; -; mRNA.
DR EMBL; AF323081; AAG59824.1; -; mRNA.
DR EMBL; AF352730; AAK18621.1; -; Genomic_DNA.
DR EMBL; AF290874; AAK83106.1; -; mRNA.
DR EMBL; AY207314; AAO38860.1; -; mRNA.
DR EMBL; AY359066; AAQ89425.1; -; mRNA.
DR EMBL; DQ301958; ABB96251.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW69015.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW69016.1; -; Genomic_DNA.
DR EMBL; BC069302; AAH69302.1; -; mRNA.
DR EMBL; BC101554; AAI01555.1; -; mRNA.
DR EMBL; BC101560; AAI01561.1; -; mRNA.
DR RefSeq; NP_001180303.1; NM_001193374.1.
DR RefSeq; NP_065148.1; NM_020415.3.
DR UniGene; Hs.283091; -.
DR PDB; 1LV6; Model; -; A=1-108.
DR PDBsum; 1LV6; -.
DR ProteinModelPortal; Q9HD89; -.
DR SMR; Q9HD89; 17-107.
DR STRING; 9606.ENSP00000221515; -.
DR DMDM; 18202962; -.
DR PaxDb; Q9HD89; -.
DR PRIDE; Q9HD89; -.
DR DNASU; 56729; -.
DR Ensembl; ENST00000221515; ENSP00000221515; ENSG00000104918.
DR GeneID; 56729; -.
DR KEGG; hsa:56729; -.
DR UCSC; uc002mhf.1; human.
DR CTD; 56729; -.
DR GeneCards; GC19P007733; -.
DR HGNC; HGNC:20389; RETN.
DR MIM; 605565; gene.
DR neXtProt; NX_Q9HD89; -.
DR PharmGKB; PA422; -.
DR eggNOG; NOG46608; -.
DR HOGENOM; HOG000137607; -.
DR HOVERGEN; HBG018297; -.
DR InParanoid; Q9HD89; -.
DR KO; K13438; -.
DR OMA; CQSVTSR; -.
DR OrthoDB; EOG7CVQ14; -.
DR PhylomeDB; Q9HD89; -.
DR GeneWiki; Resistin; -.
DR GenomeRNAi; 56729; -.
DR NextBio; 62204; -.
DR PRO; PR:Q9HD89; -.
DR ArrayExpress; Q9HD89; -.
DR Bgee; Q9HD89; -.
DR CleanEx; HS_RETN; -.
DR Genevestigator; Q9HD89; -.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005179; F:hormone activity; NAS:UniProtKB.
DR GO; GO:0045444; P:fat cell differentiation; IEA:Ensembl.
DR GO; GO:0032868; P:response to insulin stimulus; IEA:Ensembl.
DR InterPro; IPR009714; Resistin.
DR PANTHER; PTHR21101; PTHR21101; 1.
DR Pfam; PF06954; Resistin; 1.
DR SUPFAM; SSF111423; SSF111423; 1.
PE 2: Evidence at transcript level;
KW 3D-structure; Complete proteome; Diabetes mellitus; Disulfide bond;
KW Hormone; Obesity; Reference proteome; Secreted; Signal.
FT SIGNAL 1 18 Potential.
FT CHAIN 19 108 Resistin.
FT /FTId=PRO_0000030341.
FT DISULFID 22 22 Interchain (Probable).
FT DISULFID 51 104 By similarity.
FT DISULFID 63 103 By similarity.
FT DISULFID 72 89 By similarity.
FT DISULFID 74 91 By similarity.
FT DISULFID 78 93 By similarity.
FT HELIX 9 18
FT HELIX 30 39
FT STRAND 46 48
FT HELIX 58 61
FT STRAND 68 70
FT TURN 75 78
FT HELIX 81 89
FT STRAND 90 92
FT HELIX 96 99
FT STRAND 102 105
SQ SEQUENCE 108 AA; 11419 MW; 9B127DFE1699B4F1 CRC64;
MKALCLLLLP VLGLLVSSKT LCSMEEAINE RIQEVAGSLI FRAISSIGLE CQSVTSRGDL
ATCPRGFAVT GCTCGSACGS WDVRAETTCH CQCAGMDWTG ARCCRVQP
//
MIM
605565
*RECORD*
*FIELD* NO
605565
*FIELD* TI
*605565 RESISTIN; RETN
;;RSTN;;
FOUND IN INFLAMMATORY ZONE 3; FIZZ3
*FIELD* TX
CLONING
read more
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.
GENE FUNCTION
Type II diabetes (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).
GENE STRUCTURE
Wang et al. (2002) determined that the resistin gene comprises 4 exons,
the first of which is untranslated, and spans approximately 1,750 bp.
BIOCHEMICAL FEATURES
- 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.
MOLECULAR GENETICS
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.
MAPPING
Steppan et al. (2001) localized the human resistin gene to a cloned
fragment of human chromosome 19 (GenBank GENBANK AC008763).
ANIMAL MODEL
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.
*FIELD* AV
.0001
DIABETES MELLITUS, NONINSULIN-DEPENDENT, SUSCEPTIBILITY TO
HYPERTENSION, INSULIN RESISTANCE-RELATED, SUSCEPTIBILITY TO, INCLUDED
RETN, +62G-A
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 II diabetes (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.
*FIELD* RF
1. 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.
2. Cao, H.; Hegele, R. A.: Single nucleotide polymorphisms of the
resistin (RSTN) gene. J. Hum. Genet. 46: 553-555, 2001.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
*FIELD* CN
Marla J. F. O'Neill - updated: 4/18/2005
John A. Phillips, III - updated: 1/11/2005
Marla J. F. O'Neill - updated: 10/22/2004
Denise L. M. Goh - updated: 10/18/2004
Victor A. McKusick - updated: 9/15/2004
Victor A. McKusick - updated: 9/9/2004
John A. Phillips, III - updated: 8/19/2004
Ada Hamosh - updated: 6/11/2004
Ada Hamosh - updated: 6/9/2004
John A. Phillips, III - updated: 4/8/2003
Victor A. McKusick - updated: 3/3/2003
John A. Phillips, III - updated: 1/30/2003
John A. Phillips, III - updated: 1/6/2003
Victor A. McKusick - updated: 10/11/2001
Paul J. Converse - updated: 2/14/2001
*FIELD* CD
Ada Hamosh: 1/19/2001
*FIELD* ED
wwang: 04/27/2007
wwang: 10/27/2005
carol: 10/21/2005
wwang: 4/27/2005
wwang: 4/19/2005
terry: 4/18/2005
terry: 4/5/2005
wwang: 1/11/2005
terry: 10/28/2004
carol: 10/22/2004
carol: 10/21/2004
carol: 10/18/2004
tkritzer: 9/17/2004
terry: 9/15/2004
tkritzer: 9/9/2004
terry: 9/9/2004
alopez: 8/19/2004
alopez: 6/15/2004
terry: 6/11/2004
alopez: 6/10/2004
terry: 6/9/2004
tkritzer: 4/14/2003
mgross: 4/14/2003
tkritzer: 4/9/2003
terry: 4/8/2003
carol: 3/10/2003
tkritzer: 3/6/2003
terry: 3/3/2003
alopez: 1/30/2003
alopez: 1/6/2003
mcapotos: 10/11/2001
mgross: 2/14/2001
carol: 1/19/2001
*RECORD*
*FIELD* NO
605565
*FIELD* TI
*605565 RESISTIN; RETN
;;RSTN;;
FOUND IN INFLAMMATORY ZONE 3; FIZZ3
*FIELD* TX
CLONING
read more
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.
GENE FUNCTION
Type II diabetes (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).
GENE STRUCTURE
Wang et al. (2002) determined that the resistin gene comprises 4 exons,
the first of which is untranslated, and spans approximately 1,750 bp.
BIOCHEMICAL FEATURES
- 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.
MOLECULAR GENETICS
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.
MAPPING
Steppan et al. (2001) localized the human resistin gene to a cloned
fragment of human chromosome 19 (GenBank GENBANK AC008763).
ANIMAL MODEL
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.
*FIELD* AV
.0001
DIABETES MELLITUS, NONINSULIN-DEPENDENT, SUSCEPTIBILITY TO
HYPERTENSION, INSULIN RESISTANCE-RELATED, SUSCEPTIBILITY TO, INCLUDED
RETN, +62G-A
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 II diabetes (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.
*FIELD* RF
1. 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.
2. Cao, H.; Hegele, R. A.: Single nucleotide polymorphisms of the
resistin (RSTN) gene. J. Hum. Genet. 46: 553-555, 2001.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
*FIELD* CN
Marla J. F. O'Neill - updated: 4/18/2005
John A. Phillips, III - updated: 1/11/2005
Marla J. F. O'Neill - updated: 10/22/2004
Denise L. M. Goh - updated: 10/18/2004
Victor A. McKusick - updated: 9/15/2004
Victor A. McKusick - updated: 9/9/2004
John A. Phillips, III - updated: 8/19/2004
Ada Hamosh - updated: 6/11/2004
Ada Hamosh - updated: 6/9/2004
John A. Phillips, III - updated: 4/8/2003
Victor A. McKusick - updated: 3/3/2003
John A. Phillips, III - updated: 1/30/2003
John A. Phillips, III - updated: 1/6/2003
Victor A. McKusick - updated: 10/11/2001
Paul J. Converse - updated: 2/14/2001
*FIELD* CD
Ada Hamosh: 1/19/2001
*FIELD* ED
wwang: 04/27/2007
wwang: 10/27/2005
carol: 10/21/2005
wwang: 4/27/2005
wwang: 4/19/2005
terry: 4/18/2005
terry: 4/5/2005
wwang: 1/11/2005
terry: 10/28/2004
carol: 10/22/2004
carol: 10/21/2004
carol: 10/18/2004
tkritzer: 9/17/2004
terry: 9/15/2004
tkritzer: 9/9/2004
terry: 9/9/2004
alopez: 8/19/2004
alopez: 6/15/2004
terry: 6/11/2004
alopez: 6/10/2004
terry: 6/9/2004
tkritzer: 4/14/2003
mgross: 4/14/2003
tkritzer: 4/9/2003
terry: 4/8/2003
carol: 3/10/2003
tkritzer: 3/6/2003
terry: 3/3/2003
alopez: 1/30/2003
alopez: 1/6/2003
mcapotos: 10/11/2001
mgross: 2/14/2001
carol: 1/19/2001