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José Luis Gómez-Skarmeta-Lo último en obesidad

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'Lo último en obesidad'. Este es el título del Simposio Internacional que organizamos en la Fundación Ramón Areces los días 1 y 2 de diciembre de 2015. En colaboración con la Fundación General CSIC, reunió a algunos de los mayores expertos en la materia para analizar cómo reducir este grave problema de salud pública.

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José Luis Gómez-Skarmeta-Lo último en obesidad

  1. 1. New obesity genes: insights from the 3D architecture of the genome José Luis Gómez-Skarmeta Centro Andaluz de Biología del Desarrollo Sevilla, Spain
  2. 2. Nº Genes: 18.000 22.000 Humans ¿How these different organisms are generated?
  3. 3. Genome: 5% CODING (proteins) essentially conserved throughout Metazoans 90-95% REGULATION
  4. 4. Iroquois genes Transcription factors from the homeoprotein family Conserved during evolution Many functions during during different developmental stage Complex expression patterns Are associated to diseases
  5. 5. Irx1 Irx4 Irx3 Irx5 Irx6 Chr Human 5 mouse 13 Human 16 mouse 8 IrxA IrxB Irx2 Genomic organization of Irx genes
  6. 6. Irx1 Irx2 Irx4 Many enhancers within the complex may act on different Irx genes
  7. 7. 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 Irx1 Irx2 Irx4 J. J. Tena, M. E. Alonso, E. de la Calle-Mustienes, E. Splinter, W. de Laat, M. Manzanares, J. L. Gómez-Skarmeta. An evolutionarily conserved three- dimensional structure in the vertebrate Irx clusters facilitates enhancer sharing and co-regulation.Nat. Commun. 2, 310 (2011)
  8. 8. Long-range interaction between Irx promoters is detected by FISH in zebrafish embryos Irx3a + irx5a
  9. 9. How deciphering long range regulation can help revealing genes involved in human diseases?
  10. 10. FTO-IRX3 in human metabolic diseases
  11. 11. Ragvin A, Moro E, Fredman D, Navratilova P, Drivenes Ø, Engström PG, Alonso ME, de la Calle Mustienes E, Gómez-Skarmeta JL, Tavares MJ, Casares F, Manzanares M, van Heyningen V, Molven A, Njølstad 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). *
  12. 12. Collaboration with M. Nobrega and C.C Hui
  13. 13. Collaboration with M. Nobrega and C.C Hui
  14. 14. BMI-associated SNPs are eQTLs for IRX3, not FTO. They associate with increase IRX3 expression in human brain but not in adipose tissue Collaboration with M. Nobrega and C.C Hui
  15. 15. 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 sizeBody weight Energy expediture Brown adipocyte genes
  16. 16. 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. Gómez-Marín, 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. Nóbrega*. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507:371- 375 (2014).
  17. 17. Irx5, but not Irx6, deficient mice are leaner and protective from diet-induced obesity Irx3 WT KO Irx5 WT KO Irx6 WT KO
  18. 18. Increase Irx3 activity in the hypothalamus causes obesity M. Nobrega
  19. 19. Irx3 and Irx5 are organized in the same 3D domain
  20. 20. Expression in adipocytes
  21. 21. Non-risk T Alelle IRX3 IRX5 IRX3 IRX5Risk C Alelle ARIDB5 IRX5 FTO IRX3 IRX5 FTO IRX3 ENERGY EXPENDITURE FOOD INTAKE Hypothalamus BROWN ADIPOCYTE WHITE ADIPOCYTE Mesenchymal adipocyte precursor ENERGY EXPENDITURE FOOD INTAKE Hypothalamus BROWN ADIPOCYTE WHITE ADIPOCYTE Mesenchymal adipocyte precursor Adapted from Preview by Herman and Rosen at Cell Metabolism (2015)
  22. 22. Author Anthony Goldstone, MD, Imperial College of London Abstract Energy density influences interaction between FTO and DRD2 gene variants in brain reward system responses to food evaluation Results FTO 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. Conclusion These 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. Citation Goldstone A. Imperial College of London. Oral abstract presentation at: The Obesity Society Annual Meeting at ObesityWeekSM 2015; November 2-6, 2015; Los Angeles, CA.
  23. 23. Irx3 and Irx5 genes, acting both at the level of the the hypothalamus and in the adipocytes, control the balance between energy expenditure (and a dipocyte browning) and lipid storage. Irx3 and Irx5 genes are co-regulated through a 3D chromatin structure that favor enhancer sharing. Take home message The 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, together with the reduction of energy expediture and the increase of lipid storage.
  24. 24. Laboratory members Elisa de la Calle-Mustienes Juan Tena Rafa D. Acemel Carlos Gómez Nacho Maeso Panos Frimpas Ensieh Farahani Sandra Jiménez Sergio González Marta Magri ACKNOWLEDGMENTS Funding Ministerio de Ciencia y Tecnología (Spain) Junta de Andalucía Marie Curie Initial Training Network Collaborators Tom Becker Miguel Manzanares Marcelo Nobrega C.C. Hui

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