Obezitatea n gene ???

LEP, LEPR, MC4R, POMC , PCSK1, BDNF, NTKR2, SIM1, GLP1, SNRStudiul factorilor genetici ai obezitatii au permis identificarea a peste 70 gene , ale caror variatii predispun la aceasta maladie.Astfel , 70% din variatia IMC sunt de origine genetica , chiar daca impactul genelor poate diminua la indivizii care au adoptat o dieta echilibrata si un regim de sport . Doua idei favorabile se disting: 1)Nu suntem determinati de mediul ambiant sa devenim obezi , mai ales ca unii dintre noi sunt protejati de patrimoniul lor genetic. 2)Chiar daca nu am mostenit lotul bun de gene , noi putem rezista in fata acestui fenomen , dar si a pesimismului ambiant .

Unele forme de obezitate , uneori extreme , sunt legate de prezenta unei mutatii pe o gena . Pina in prezent , opt gene au fost identificate (LEP, LEPR, MC4R, POMC , PCSK1, BDNF, NTKR2, SIM1 ) care conduc la sinteza unor proteine responsabile de cresterea in greutate, dar i de alte neregulariti specifice.

GENELE asociate obezitii

Gena FTO

Cel mai relevant exemplu este gena FTO (descoperita de frnacezi si apoi de englezi ) , despre care s-a aflat ca unele mutatii determina cresterea pina la 67 % a riscului de obezitate ; 137% pentru personale care prezinta mutatii pe ambele copii ale genei . Actualmente , gena FTO este pricipala care predispune cel mai mult in acumularea grasimii. Ea i mpiedic pe oameni s se simt stui i i face s simt frecvent pofta de dulciuri i mncruri grase, spun oamenii de tiin, care au descifrat recent mecanismul prin care gena FTO influeneaz greutatea corporal.

http://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000140718;r=16:53737875-54155853;t=ENST00000464071

Particulariti

Simbol:FTODescriere:fat mass and obesity associated(masa de grasime si obezitatea asociate )Localizare:chr16:53737875-54155853

Promotorul genei

Cromozomul 16 secventa genei (exoni)chromosome:GRCh37:16:53737275:54156453:1

TATGAAGCTAGCAAGTTATGGAGGTAATCACATGATAAACAAATAATATATAATTAAGCAAACAATAGACCACTCAAGGTTTAGGGTCTACCAACCAACTCCTAATCCAGGGCAAATGAGCAAACTGTGTTAGGGACCTACAACTTGCAGGATCTGGATAGAGATGGCAATTAGCAGCATCAACTCTCACCTTCATGGCTGGGATATAACATTTCAAATTGGTCCTGGACGTGGGGATAAAGGGCGGCCTGTGATTCAGGCTGAGGATGTGGAGGTGTCTTGGGCTGGGCTGCTTTCACGCCAGCAGAACTCCAGGGCCAACTCCAGGGCCTTCTCCAGGCGGCAGAGCGGACCCTAGGACCCCGGCCCGCGCTGCAGTGGGGAGGGTCAGCAACCTCCACCCACCCTCATCCTCCCCCATCCTCCCGGGTACTCACCGTGCCACTGGCCCTGCAGCTAGCTACCGTTGCTATAGCGCCGACAGCGTGGCGGGCGGCTGGCCGAGAGGAGCACGGGAGAAACTGCAGGCCCCGTAGCCTCCTGGGAAATGTAGTTCTCCTTGGACTCTAGCCTGTTTGCTCGCGGGGTAGCGGACTACGCTCTTCCAGCTGTCGGACCTGGGAAATTCTCCTGTGCTAAATCCCGTGGCGCTCGCGGGTGTCGCGCGGTGCATCCTGGGAGTTGTAGTTTTTTCTACTCAGAGGGAGAATAGCTCCAGACGGGAGCAGGACGCTGAGAGAACTACATGCAGGAGGCGGGGTCCAGGGCGAGGGATCTACGCAGCTTGCGGTGGCGAAGGCGGCTTTAGTGGCAGCATGAAGCGCACCCCGACTGCCGAGGAACGAGAGCGCGAAGCTAAGGTATGTCGGGCTCCCGGGGCCTGGAGATCTTCGTGCGCTGTGAGCAAGGATCAGGGAACCGGAAGGGCTTGGTTTGATGGCGAGCGGATGCGCGGTGTTAAACTAAGGGATGACAGGGCCTTGTCAGCAAGGGACCTGGAGATATTAGAGGGGATGTTACAAATTCGTGCTCTTCAGGATGCAGGCCGAGTCTTGTTGGATCGGCTCAAAAATGAGAAGCAAGATACCCATTTCCTTGTCCTTCTTCTGCATCTATTCCTTGGTTAAATTTGT..

http://www.ensembl.org/Homo_sapiens/Gene/Sequence?db=core;g=ENSG00000140718;r=16:53737875-54155853;t=ENST00000471389;t1=ENST00000471389;t2=ENST00000460382;t3=ENST00000463855;t4=ENST00000431610;t5=ENST00000268349;t6=ENST00000394647

Secvena codificatoare5' upstream sequence ..........gaaatgtagttctccttggactctagcctgtttgctcgcggggtagcgga 1. ENSE00001407106 CTACGCTCTTCCAGCTGTCGGACCTGGGAAATTCTCCTGTGCTAAATCCCGTGGCGCTCG CGGGTGTCGCCGCGGTGCATCCTGGGAGTTGTAGTTTTTTCTACTCAGAGGGAGAATAGC TCCAGACGGGAGCAGGACGCTGAGAGAACTACATGCAGGAGGCGGGGTCCAGGGCGAGGG ATCTACGCAGCTTGCGGTGGCGAAGGCGGCTTTAGTGGCAGCATGAAGCGCACCCCGACTGCCGAGGAACGAGAGCGCGAAGCTAAG

Intron 1 gtatgtcgggctcccggggcctgga..........atatgtaattattattttcaaacag

2. ENSE00003499057 AAACTGAGGCTTCTTGAAGAGCTTGAAGACACTTGGCTCCCTTATCTGACCCCCAAAGAT GATGAATTCTATCAGCAG

Intron 2 gtaaggtattttaatatttttatca..........tgtttttgctttggttttgttttag

3. ENSE00001319762 TGGCAGCTGAAATATCCTAAACTAATTCTCCGAGAAGCCAGCAGTGTATCTGAGGAGCTC CATAAAGAGGTTCAAGAAGCCTTTCTCACACTGCACAAGCATGGCTGCTTATTTCGGGAC CTGGTTAGGATCCAAGGCAAAGATCTGCTCA... GGCATGGGGAAAATGGCAGTGAGCTGGCATGTGGCAGTGTACAGTTATAGCTGTGAAG Intron 3 gtacagtctgctcttggaaaaagca..........tgatcattttcttctcttttggcag

4. ENSE00003480244 GCCCTGAAGAGGAAAGTGAGGATGACTCTCATCTCGAAGGCAGGGATCCTGATATTTGGC ATGTTGGTTTTAAGATCTCATGGGACATAGAGACACCTGGTTTGGCGATACCCCTTCACC AAGGAGACTGCTATTTCATGCTTG

Intron 4 gtaatctttggaaaatcaaaattat..........tacatttctggtgtttttcctgtag

5. ENSE00003523757 ATGATCTCAATGCCACCCACCAACACTGTGTTTTGGCCGGTTCACAACCTCGGTTTAGTT CCACCCACCGAGTGGCAGAG

Intron 5 gtaagtgtaaataaaaatgtgattc..........gtgattgctggttctgtctcaacag

Intron 5 gtaagtgtaaataaaaatgtgattc..........gtgattgctggttctgtctcaacag

6. ENSE00003575733 TGCTCAACAGGAACCTTGGATTATATTTTACAACGCTGTCAGTTGGCTCTGCAGAATGTC TGTGACGATGTGGACAATGATGATGTCTCTTTGAAATCCTTTGAGCCTGCAGTTTTGAAA CAAGGAGAAGAAATTCATAATGAG

Intron 6 gtaaggactttcttttttttttttt..........accatcttctctttatggtccacag

7. ENSE00003604517 GTCGAGTTTGAGTGGCTGAGGCAGTTTTGGTTTCAAGGCAATCGATACAGAAAGTGCACT GACTGGTGGTGTCAACCCATGGCTCAACTGGAAGCACTGTGGAAGAAGATGGAGGGTG

Intron 7 gtaagtccatcagacctgggaccgt..........ctctgttttggatcatttcttgtag

8. ENSE00003492841 ACAAATGCTGTGCTTCATGAAGTTAAAAGAGAGGGGCTCCCCGTGGAACAAAGGAATGAA ATCTTGACTGCCATCCTTGCCTCGCTCACTGCACGCCAGAACCTGAGGAGAGAATGGCAT GCCAG

Intron 8 gttagttctgttgtgaaatgggatt..........taatttcctatttttactcttccag

9. ENSE00001946879 GTGCCAGTCACGAATTGCCCGAACATTACCTGCTGATCAGAAGCCAGAATGTCGGCCATA CTGGGAAAAGGATGATGCTTCGATGCCTCTGCCGTTTGACCTCACAGACATCGTTTCAGA .....................................................................................................................GGTCCAGGGCAGGCGACAGGAACGAGCCCAGCGTGTGACAAAGCCTAACCTACTTTCCTC TTTCCCAAGCTTTTTCAGAGACTCTGGAGTGGACCCAGCCCTCTGGGGAAAGACAGAACT .. CCAGAAGCCCCGGCTCTTAGAGTTTCTATTAAGATGTACCTCATAAATATATACGCCTCC TATGTACCCACAAAAATTAAAAATAAAAAAATTGAAATCA 3' downstream sequence ctcatttatgcttggtgttatgattgtaactaagaatcctggagtgagct..........

Transcripia genei In acest proces participa mai multi factori de transcriptie care se ataseaza de promotorul genei si permit initierea si reglarea acesteia:

Egr-1, FOXD3 ,NF-AT,MEF-2A,S8,NF-AT2,FOXA2, aMEF-2, NF-AT1, FOXO1, Sp1

USF (upstream stimulatory factor ) factor de stimulare TSS situs de start al trancriptiei

Processing-ul In rezultatul spliceng-ului se formeaza 9 transcripturi (datorita tipurilor de splicing )

Name Transcript ID Length (bp) Protein

FTO-001 ENST00000471389 11766 ENSP00000418823FTO-005 ENST00000463855 3056 ENSP00000417843FTO-008 ENST00000268349 2799 ENSP00000268349FTO-002 ENST00000460382 1517 ENSP00000417422 FTO-201 ENST00000394647 1065 ENSP00000378142FTO-006 ENST00000431610 707 ENSP00000415636 FTO-003 ENST00000464071 1065 ENSP00000418424 FTO-007 ENST00000472835 847 No protein productFTO-009 ENST00000570395 555 No protein product

Transcript: FTO-001 ENST00000471389

Exons: 9 Coding exons: 9 Transcript length: 11,766 bps Translation length: 505 residues (number of amino acids in the protein)

Transcript: FTO-008 ENST00000268349

Exons: 3 Coding exons: 3 Transcript length: 2,799 bps Translation length: 129 residues

Transcript: FTO-007 ENST00000472835

Exons: 2 Coding exons: 0 Transcript length: 847 bps

Transcript: FTO-003 ENST00000464071 (previne expresia proteinelor eronate)

Exons: 8 Coding exons: 3 Transcript length: 1,065 bps Translation length: 70 residues (number of amino acids in the protein)

Rol Biologic :

Niv. molecular : codifica sinteza proteinelor : ENSP00000418823 , ENSP00000417843 , ENSP00000268349 Niv. celular : dezvoltarea si mentinerea tesutului adipos

Niv. de organism : aparitia obezitatii si a altor maladii grave ( diabet , schizofrenie )

Procesele Biologice :

- homeostazia temperaturii - reglementarea de cretere a organismului - reparatia ARN

- reglementarea sistemului respirator - dezvoltarea tesutului adipos - reglementarea proliferarii celulelor adipoase albe - demetilarea oxidativa - demetilarea AND-ului

Studii independente au demonstrat ca lipsa unui fragment din cromozomul 16 (16p11.2 ) mariste cu 50% riscul de a deveni obez . De asemenea , lipsa acestui fragment este asociata cu autism , schizofrenie ,retard mental caracteristici relevate la majoritatea indivizilor obezi in cadrul unui stiudiu . Nucleozide N6-methyladenosine, o modificare n ARN, s-a dovedit a fi un substrat major al genei FTO.

Regiunea defecta a cromozomului 16 implica mai multe gene , printre care SH2B1 , care se manifesta in replicarea fenotipului obezitatii. Acesta gena codifica o proteina care interactioneaza cu un regulator al receptorului pentru leptina . Pacientii care au aceasta gena inactiva , manifesta o reziztenta mare pentru insulina si un exces de leptina hormon produs in straturile de grasime care stimuleaza apetitul .

Colectivul german, a constatat ca in absenta genei FTO, soarecii de laborator nu s-au ingrasat de loc, chiar si dupa ce au primit si consumat hrana in cantitati mari, si in pofida faptului ca au fost lasati sa leneveasca. Concluzia preliminara ar fi aceea ca in celulele soarecilor fara FTO, grasimile sunt transformate in energie mai repede decat in cazul soarecilor care dispun de o gena FTO activa.

Oamenii care au aceast variant (botezat de cercettori gena obezitii sau gena foamei) tind s mnnce mai mult i, cel mai adesea, eueaz n ncercarea de a pierde n greutate prin diet.

Potrivit unui studiu , unii dintre noi, pur i simplu sunt programai biologic s mnnce mai mult. Nu numai c aceste persoane au niveluri mai mari de grelin i de aceea se simt mai flmnde, dar creierele lor reacioneaz diferit la grelin (un hormon secretat de stomac, care stimuleaza apetitul) i la vederea imaginilor cu alimente. Este o dubl problem .

SPORT vs GENOM

Persoanele sedentare care prezint o singur variaie a genei FTO au cu 30% mai multe anse s devin obeze, pe parcursul vieii. n schimb, persoanele cu aceeai caracteristic genetic dar care sunt active fizic i reduc riscurile cu 8%. Exerciiile fizice asociate cu o alimentaie echilibrat ajut i mai mult la "pclirea" genelor, reducnd pericolul ngrrii cu 27%. n cazul persoanelor care au dou variaii ale genei FTO, ce prezint aproape 70% risc de obezitate, exerciiile fizice au reuit s scad acest pericol cu 21%. Oamenii de tiin caut n prezent dovezi care s demonstreze c att stilul de via, ct i genele cauzeaz obezitatea i ncearc s afle modul n care activitatea fizic poate atenua predispoziia genetic."Sportul nu neutralizeaz total predispoziia genetic la ngrare, dar studiul arat c programarea genetic nu este liter de lege i nu conduce neaprat la obezitate", a declarat coordonatorul cercetrii, prof. dr. Ruth Loos.Specialitii n educaie fizic i sport, precum i medicii epidemiologi recomand persoanelor predispuse genetic la obezitate s fac minimum o or de sport pe zi.

O alimentaie sntoas i un regim de soprt

echilibrat contrabalanseaz loteria genetica !!!