'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.

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. Nº Genes: 18.000 22.000
Humans
¿How these different organisms are generated?

3. Genome:
5% CODING (proteins)
essentially conserved throughout Metazoans
90-95% REGULATION

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. Irx1 Irx4
Irx3 Irx5 Irx6
Chr
Human 5
mouse 13
Human 16
mouse 8
IrxA
IrxB
Irx2
Genomic organization of Irx genes

6. Irx1 Irx2 Irx4
Many enhancers within the complex may act on different Irx genes

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. Long-range interaction between Irx promoters is detected by
FISH in zebrafish embryos
Irx3a + irx5a

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

10. FTO-IRX3 in human metabolic diseases

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. Collaboration with M. Nobrega and C.C Hui

13. Collaboration with M. Nobrega and C.C Hui

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. 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. 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. Irx5, but not Irx6, deficient mice are leaner and protective from diet-induced obesity
Irx3
WT KO
Irx5
WT KO
Irx6
WT KO

18. Increase Irx3 activity in the hypothalamus causes obesity
M. Nobrega

19. Irx3 and Irx5 are organized in the same 3D domain

20. Expression in adipocytes

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. 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. 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. 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