José Luis Gómez-Skarmeta-Lo último en obesidad

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New obesity genes: insights from the 3D architecture of the genome

Jos Luis Gmez-Skarmeta

Centro Andaluz de Biologa del DesarrolloSevilla, Spain

N Genes: 18.000 22.000HumansHow these different organisms are generated?

Genome:

5% CODING (proteins)essentially conserved throughout Metazoans90-95%REGULATION

Iroquois genesTranscription factors from the homeoprotein familyConserved during evolutionMany functions during during different developmental stageComplex expression patternsAre associated to diseases

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Irx1Irx4Irx3Irx5Irx6

ChrHuman 5mouse 13

Human 16mouse 8

IrxAIrxBIrx2Genomic organization of Irx genes

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Irx1Irx2Irx4

Many enhancers within the complex may act on different Irx genes

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The enhancers within the Irx clusters are shared among the different promoters and the promoters of the first two genes in the Irx clusters interact with each other

Irx1Irx2Irx4

J. J. Tena, M. E. Alonso, E. de la Calle-Mustienes, E. Splinter, W. de Laat, M. Manzanares, J. L. Gmez-Skarmeta. An evolutionarily conserved three-dimensional structure in the vertebrate Irx clusters facilitates enhancer sharing and co-regulation.Nat. Commun. 2, 310 (2011)

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Long-range interaction between Irx promoters is detected by FISH in zebrafish embryos

Irx3a + irx5a

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How deciphering long range regulation can help revealing genes involved in human diseases?

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FTO-IRX3 in human metabolic diseases

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Ragvin A, Moro E, Fredman D, Navratilova P, Drivenes , Engstrm PG, Alonso ME, de la Calle Mustienes E, Gmez-Skarmeta JL, Tavares MJ, Casares F, Manzanares M, van Heyningen V, Molven A, Njlstad PR, Argenton F, Lenhard B, Becker TS. Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proc Natl Acad Sci U S A. 107:775-80 (2010).

*

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Collaboration with M. Nobrega and C.C Hui

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Collaboration with M. Nobrega and C.C Hui

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BMI-associated SNPs are eQTLs for IRX3, not FTO. They associate with increase IRX3 expression in human brain but not in adipose tissueCollaboration with M. Nobrega and C.C Hui

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Irx3 deficient mice are leaner and protective from diet-induced obesity, have reduce white adipocyte tissue, higher energy expenditure, are glucose tolerant and not insuline resistant and show increase expression of brown fat markers Collaboration with M. Nobrega and C.C Hui

Fat mass

Adipocyte size

Body weight

Energy expediture

Brown adipocyte genes

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Irx3 is expressed and required in the hypothalamus and may control peripheral metabolic regulation and energy homeostasis

S. Smemo#, J. J. Tena#, K-H. Kim#, E. R. Gamazon, N. J. Sakabe, C. Gmez-Marn, I. Aneas, F. L. Credidio, D. R. Sobreira, N. F. Wasserman, J. H. Lee, V. Puviindran, D. Tam, M. Shen, J. E. Son, N. A. Vakili, H-K. Sung, S. Naranjo, R.D. Acemel, M. Manzanares, A. Nagy, N. J. Cox, C-C. Hui*, J. L. Gomez-Skarmeta* and M. A. Nbrega*. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507:371-375 (2014).

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Irx5, but not Irx6, deficient mice are leaner and protective from diet-induced obesity

Irx3 WT KOIrx5 WT KOIrx6 WT KO

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Increase Irx3 activity in the hypothalamus causes obesity

M. Nobrega

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Irx3 and Irx5 are organized in the same 3D domain

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Expression in adipocytes

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Non-risk T AlelleIRX3 IRX5IRX3 IRX5Risk C Alelle

ARIDB5IRX5FTOIRX3

IRX5FTOIRX3

ENERGY EXPENDITUREFOOD INTAKEHypothalamus

BROWN ADIPOCYTEWHITE ADIPOCYTEMesenchymal adipocyte precursor

ENERGY EXPENDITUREFOOD INTAKEHypothalamus

BROWN ADIPOCYTEWHITE ADIPOCYTEMesenchymal adipocyte precursorAdapted from Preview by Herman and Rosen at Cell Metabolism (2015)

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AuthorAnthony Goldstone, MD, Imperial College of LondonAbstractEnergy density influences interaction between FTO and DRD2 gene variants in brain reward system responses to food evaluationResultsFTO A carriers had greater BOLD signal to high-energy foods in OFC in whole brain analysis, and greater high-energy food appeal rating and external eating behaviour (independent of age, gender and percentage body fat). DRD2 A1 carriers had greater reward system responses to low-energy foods, particularly in caudate and nucleus accumbens. In gene-gene-food interaction analysis, FTO A carrier status increased reward system responses to high-energy, but not low-energy foods, but only in DRD2 A1 non-carriers. Similarly DRD2 A1 carriers had greater reward system responses only to high-energy foods and only in FTO A non-carriers. Similar interactions were seen in an expanded mixed ethnicity cohort of 75 adults.ConclusionThese results support a role for the FTO gene in regulation of body weight by altering human food reward processing through influences on dopaminergic neuronal function.CitationGoldstone A. Imperial College of London. Oral abstract presentation at: The Obesity Society Annual Meeting at ObesityWeekSM 2015; November 2-6, 2015; Los Angeles, CA.

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Irx3 and Irx5 genes, acting both at the level of the the hypothalamus and in the adipocytes, control the balance between energy expenditure (and adipocyte browning) and lipid storage.Irx3 and Irx5 genes are co-regulated through a 3D chromatin structure that favor enhancer sharing.Take home messageThe risk allele in SNP rs1421085 disrupts a binding site for the repressor Arid5B increassing the activity of an Irx enhancer that promotes Irx3 and Irx5 expression in the hypothalamus and the adipocytes, togetherwith the reduction of energy expediture and the increase of lipid storage.

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Laboratory membersElisa de la Calle-MustienesJuan TenaRafa D. AcemelCarlos GmezNacho MaesoPanos FrimpasEnsieh FarahaniSandra JimnezSergio GonzlezMarta Magri

ACKNOWLEDGMENTSFundingMinisterio de Ciencia y Tecnologa (Spain)Junta de AndalucaMarie Curie Initial Training NetworkCollaboratorsTom BeckerMiguel ManzanaresMarcelo NobregaC.C. Hui