Adiponektin (sa skraćenicama GBP-28, apM1, AdipoQ and Acrp30) je proteinski hormon i adipokin, koji je uključen u regulaciju razine glukoze, kao i razgradnje masnih kiselina. Kod ljudi ga kodira gen ADIPOQ, a proizvodi se prvenstveno u masnom tkivu, ali i u mišićima, pa čak i u mozgu.[5][6]

ADIPOQ
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

4DOU

Identifikatori
AliasiADIPOQ
Vanjski ID-jeviOMIM: 605441 MGI: 106675 HomoloGene: 3525 GeneCards: ADIPOQ
Lokacija gena (čovjek)
Hromosom 3 (čovjek)
Hrom.Hromosom 3 (čovjek)[1]
Hromosom 3 (čovjek)
Genomska lokacija za ADIPOQ
Genomska lokacija za ADIPOQ
Bend3q27.3Početak186,842,704 bp[1]
Kraj186,858,463 bp[1]
Lokacija gena (miš)
Hromosom 16 (miš)
Hrom.Hromosom 16 (miš)[2]
Hromosom 16 (miš)
Genomska lokacija za ADIPOQ
Genomska lokacija za ADIPOQ
Bend16 B1|16 13.96 cMPočetak22,965,286 bp[2]
Kraj22,976,778 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija hormone activity
signaling receptor binding
cytokine activity
sialic acid binding
protein homodimerization activity
GO:0001948, GO:0016582 vezivanje za proteine
vezivanje identičnih proteina
extracellular matrix structural constituent
Ćelijska komponenta cell surface
Endoplazmatski retikulum
collagen
Vanćelijsko
extracellular region
GO:0009327 makromolekulani kompleks
collagen-containing extracellular matrix
Biološki proces positive regulation of glucose import
positive regulation of protein phosphorylation
negative regulation of receptor binding
low-density lipoprotein particle clearance
negative regulation of blood pressure
negative regulation of macrophage differentiation
negative regulation of synaptic transmission
generation of precursor metabolites and energy
cellular response to epinephrine stimulus
negative regulation of gluconeogenesis
regulation of glucose metabolic process
Jednodnevni biološki ritam
fatty acid oxidation
positive regulation of interleukin-8 production
glucose metabolic process
protein heterotrimerization
negative regulation of heterotypic cell-cell adhesion
response to ethanol
negative regulation of inflammatory response
cellular response to cAMP
positive regulation of protein kinase A signaling
negative regulation of platelet-derived growth factor receptor signaling pathway
positive regulation of signal transduction
GO:0051247, GO:0051200 positive regulation of protein metabolic process
negative regulation of fat cell differentiation
response to linoleic acid
detection of oxidative stress
glucose homeostasis
adiponectin-activated signaling pathway
response to tumor necrosis factor
positive regulation of blood pressure
response to nutrient levels
positive regulation of cholesterol efflux
negative regulation of MAP kinase activity
cellular response to insulin stimulus
positive regulation of peptidyl-tyrosine phosphorylation
fatty acid beta-oxidation
negative regulation of tumor necrosis factor production
protein localization to plasma membrane
negative regulation of hormone secretion
protein homooligomerization
response to sucrose
positive regulation of metanephric glomerular visceral epithelial cell development
positive regulation of renal albumin absorption
negative regulation of granulocyte differentiation
response to nutrient
negative regulation of protein autophosphorylation
negative regulation of intracellular protein transport
membrane depolarization
response to glucose
positive regulation of myeloid cell apoptotic process
negative regulation of I-kappaB kinase/NF-kappaB signaling
negative regulation of metanephric mesenchymal cell migration
negative regulation of cell migration
positive regulation of fatty acid metabolic process
brown fat cell differentiation
positive regulation of cAMP-dependent protein kinase activity
positive regulation of glycogen (starch) synthase activity
GO:0045996 negative regulation of transcription, DNA-templated
negative regulation of DNA biosynthetic process
positive regulation of protein kinase activity
response to hypoxia
negative regulation of phagocytosis
membrane hyperpolarization
negative regulation of tumor necrosis factor-mediated signaling pathway
positive regulation of monocyte chemotactic protein-1 production
response to glucocorticoid
response to activity
negative regulation of platelet-derived growth factor receptor-alpha signaling pathway
positive regulation of I-kappaB kinase/NF-kappaB signaling
negative regulation of ERK1 and ERK2 cascade
negative regulation of macrophage derived foam cell differentiation
regulation of fatty acid biosynthetic process
regulation of signaling receptor activity
negative regulation of vascular associated smooth muscle cell proliferation
negative regulation of vascular associated smooth muscle cell migration
response to bacterium
positive regulation of cold-induced thermogenesis
negative regulation of cold-induced thermogenesis
GO:0072468 Transdukcija signala
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_001177800
NM_004797

NM_009605

RefSeq (bjelančevina)

NP_001171271
NP_004788

NP_033735

Lokacija (UCSC)Chr 3: 186.84 – 186.86 MbChr 16: 22.97 – 22.98 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Struktura uredi

Adiponektin je polipeptid dug 244 aminokiseline. Postoje četiri različita područja adiponektina. Prva je kratka signalna sekvenca koja usmjerava sekreciju hormona izvan ćelije; sljedeća je kratka regija koja se razlikuje od vrste do vrste; treća je 65-aminokiselinska regija sa sličnošću s kolagenim proteinima; posljednja je globuloidni (loptasti) domen. Sve u svemu, ovaj protein ispoljava sličnost sa faktorima komplementa 1Q (C1Q). Međutim, kada je utvrđena trodimenzijska struktura globulske regije, uočena je zapanjujuća sličnost sa TNFα, unatoč nepovezanim proteinskim.[7]

Funkcija uredi

Adiponektin je proteinski hormon koji modulira brojne metaboličke procese, uključujući regulaciju glukoze i oksidaciju masnih kiselina.[8] Adiponektin se izlučuje iz masnog tkiva (a također i iz placente u trudnoći[9]) u krvotok i vrlo je bogat plazmom u odnosu na mnoge hormone. Mnoge studije su pokazale da je adiponektin u obrnutoj korelaciji s indeksom tjelesne mase u populaciji pacijenata.[10] Međutim, metaanaliza nije uspjela potvrditi ovu povezanost kod zdravih odraslih osoba.[11] Koncentracije adiponektina u cirkulaciji povećavaju se tokom kalorijskih ograničenja kod životinja i ljudi, kao što su pacijenti sa anorexia nervosa. Ovo zapažanje je iznenađujuće, s obzirom na to da je adiponektin proizvod masnog tkiva. Međutim, nedavna studija sugerira da masno tkivo u kostnoj srži, koje se povećava tokom ograničenja kalorija, doprinosi povišenom razinom adiponektina u cirkulaciji, u ovom kontekstu.[12]

Transgeni miševi sa povećanim adiponektinom pokazuju smanjen broj diferenciranih adipocita i povećani utrošak energije, povezan sa mitohondrijskim neuparivanjem.[13] Hormon ima ulogu u suzbijanju metaboličkih poremećaja koji mogu rezultirati dijabetesom tipa 2,[10] gojaznošću, aterosklerozom,[8] a i bolesti zvane bezalkoholna masnoća u jetri (NAFLD) i neovisni faktor rizika za metabolički sindrom.[14] Pokazalo se da adiponektin u kombinaciji s leptinom u potpunosti preokreće otpornost na insulin kod miševa.[15]

Adiponektin se izlučuje u krvotok, gdje na njega otpada približno 0,01% svih proteina u plazmi, sa oko 5-10 μg/mL (mg / L). U odraslih je koncentracija u plazmi veća kod žena nego kod muškaraca, a kod dijabetičara je smanjena u odnosu na one koji nisu dijabetičari. Smanjenje težine značajno povećava koncentraciju u cirkulaciji.[16]

Adiponektin se automatski povezuje u veće strukture. U početku se vežu tri molekule, da bi stvorile homotrimer. Proteinski trimeri nastavljaju se samostalno udruživati i formirati heksamere ili dodekamere. Poput koncentracije u plazmi, relativni nivoi struktura višeg reda su spolno dimorfni, gdje ženke imaju veći udio oblika visoke molekularne težine. Nedavna istraživanja pokazala su da je oblik visoke molekularne težine možda biološki najaktivniji oblik glukozne homeostaze.[17] Nadalje je utvrđeno da je adiponektin velike molekulske težine povezan sa manjim rizikom od dijabetesa, slične veličine povezivanja kao i ukupni.[18] Međutim, utvrđeno je da je bolest koronarnih arterija pozitivno povezana sa adiponektinom velike, ali ne i sa adiponektinom male molekulske težine.[19]

Adiponektin obavlja neke od svojih efekata smanjenja težine putem mozga. Ovo je slično djelovanju leptina;[20] > adiponektin i leptin mogu djelovati sinergijski.

Adiponektin promovira sinapsnu i memorijsku funkciju u mozgu.[21] Ljudi sa nižim nivoima adiponektina imaju smanjenu kognitivnu funkciju.[21]

Receptori uredi

Adiponektin se veže za brojne receptore. Do sada su dentificirana dva receptora i sa homologijom sa G-protein sppregnutim receptorom, a jedan receptor sličan je porodici kaderina:[22][23]

Oni imaju različite tkivne specifičnosti u tijelu i različite afinitete prema različitim oblicima adiponektina. AdipoR1 je bogato zastupljen u skeletnim mišićima, dok je AdipoR2 takav u jetri.[6] Pokazano je da šest mjeseci vježbanja kod pacova udvostruči mišić AdipoR1.[6]

Receptori utiču na nizvodni cilj AMP kinaze, važne kontrolne tačke ćelijskog metabolizma. Ekspresija receptora korelira sa nivoom insulina, kao i sa smanjenim u mišjim modelima dijabetesa, posebno u skeletnim mišićima i masnom tkivu.[24][25] Univerzitet u Tokiju je, 2016. godine objavio da pokreće istragu o anonimnim tvrdnjama o izmišljenim i falsifikovanim podacima o identifikaciji AdipoR1 i AdipoR2.[26]

Otkriće uredi

Adiponektin je prvi put okarakteriziran 1995. godine u razlikovanju adipocita 3T3-L1 (Scherer PE et al.).[27] U 1996., nađeno je da je kod miševa iRNK transkript najjače izražen u adipocitima,[5] a 2007. adiponektin je identificiran kao iRNK transkript koji je visoko eksprimiran u preadipocitima,[28] > (prekursori masnih ćelija) koji se diferenciraju u adipocite.[28][29]

Ljudski homolog je identificiran kao najzastupljeniji transkript u masnom tkivu. Suprotno očekivanjima, utvrđeno je da je adiponektin, iako se proizvodi u masnom tkivu, smanjen u gojaznih osoba.[8][10][20] Ova podregulacije nije u potpunosti objašnjena. Gen je lokaliziran u hromosomu, pozicija 3q27, regiji koja je istaknuta kao ona koja utiče na genetičku osjetljivost na dijabetes tipa 2 i gojaznost. Suplementacija različitim oblicima adiponektina uspjela je poboljšati kontrolu insulina, razinu glukoze u krvi i triglicerida na modelima miša.

Gen je istražen za varijante koje predisponiraju za dijabetes tipa 2.[20][28][30][31][32][33] Nekoliko jednonukleotidnih polimorfizama u kodnom regionu i okolnoj sekvenci identificirano je iz nekoliko različitih populacija, sa različitim prevalencijama, stepenom povezanosti i snagom efekta na dijabetes tipa 2. Pokazalo se da berberin, izohinolinski alkaloid, povećava ekspresiju adiponektina,[34] što delimično objašnjava njegove blagotvorne efekte na metaboličke poremećaje. Miševi koji su se hranili omega-3 masnom kiselinom eikosapentaenojskom (EPA) i dokozaheksaenojsko kiselinom  (DHA) pokazali su povišen adiponektin u plazmi.[35] Također je utvrđeno da kurkumin, kapsaicin, gingerol i katehini povećavaju ekspresiju adiponektina.[36]

Filogenetska distribucija uključuje ekspresiju kod ptica[37] i riba.[38]

Metabolički efekti uredi

Efekti adiponektina:
Promet glukoze
katabolizam lipida[31]
Zaštita od disfunkcije endotela

Adiponektinska regulacija

  • Gojaznost je povezana sa smanjenim adiponektinom.
    • Tačan mehanizam regulacije je nepoznat, ali adiponektin se može regulirati posttranslacijskim mehanizmima u ćelijama.[40]

Hipoadiponektinemija uredi

Nizak nivo adiponektina je nezavisni faktor rizika za razvoj:

Ostalo uredi

Niži nivoi adiponektina povezani su sa ADHD kod odraslih osoba.[41]

Utvrđeno je da je nivo adiponektina povišen kod reumatoidnog artritisa, pacijenata koji reaguju na terapiju DMARD ili TNF inhibitor.[42]

Oslobađanje adiponektina izazvano vježbama povećalo je rast hipokampusa i dovelo do antidepresivnih simptoma kod miševa.[43]

Kao cilj lijekova

Nivoi adiponektina u cirkulaciji mogu se indirektno povećati putem modifikacija načina života i određenih lijekova kao što su statini.[44]

Ojavljeni su podaci o malim molekulanma receptora adiponektina AdipoR1 i AdipoR2 agonista, AdipoRon.[45] Univerzitet u Tokiju je, 2016. godine objavio da pokreće istragu protiv anonimnih tvrdnji o izmišljenim i krivotvorenim podacima o AdipoR1, AdipoR2 i AdipoRon. .[26]

Izviješteno je da ekstrakti slatkog krompira povećavaju nivo adiponektina i time poboljšavaju kontrolu glikemije kod ljudi.[46] Međutim, sistematski pregled zaključio je da nema dovoljno dokaza koji podržavaju konzumaciju slatkog krompira za liječenje dijabetes melitus tipa 2.[47]

Adiponektin je očigledno u stanju da pređe krvno-moždanu barijeru.[43] Međutim, o ovom pitanju postoje neusaglašeni podaci.[48] Kod čovjeka, poluživot adiponektina traje 2,5 sata.[49]

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