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OBESITY -IS IT ALL IN THE BRAIN?
Genetic aspects of appetite regulation


Signe Torekov  


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Accepted by: Health Science Copenhagen
Defended on: September 24, 2009
Official opponents: Professor Sten Madsbad , As. Professor, Steen Bønløkke Pedersen , Professor Tim Frayling
Tutors: Professor Ole Madsen , Professor Oluf Pedersen , Professor Torben Hansen

Published in the PhD Database: October 12, 2009


English abstract
Obesity is a major public health challenge,
resulting in severe co-morbidities, premature
mortality and enormous economic burdens on
the health care system. According to the
World Health Organisation almost half a billion
people are obese. Excessive energy intake
and diminished physical activity contribute
to the increasing prevalence of obesity.
However, the sensitivity of the individual to a
westernized lifestyle appears to be much dependent
on his or her genetic risk factors.
Strong evidence from family, twin and adoption
studies has shown that common forms of
obesity are complex polygenic diseases with
genetic factors accounting for 40-70% of the
variation of BMI. Until recently only few
validated obesity genes were discovered.
However, at present 18 common obesity loci
have been validated. Most genes appear to be
expressed in the hypothalamus suggesting a
role in appetite regulation. However, the observed
genetic variation explains only about
1% of the total inheritance of obesity. Hence,
a large part of the inherited component of
obesity awaits discovery.
In this PhD thesis aspects of the molecular
genetics of obesity in relation to appetite
regulation have been investigated with an experimental
focus on variation in PYY, NPY2R,
NMU and GCG.
In summary, the outcome of the experimental
studies integrated in my thesis contributes to
the ongoing exploration of the genetics of
obesity and related phenotypes and may provide
further basis for the improvement of diagnosis,
treatment and ultimately prevention
of this common disorder and associated complications.



Danish abstract
Fedme er et stort sundhedsproblem, som resulterer
i alvorlige følgesygdomme og overdødelighed,
og som dermed er en kæmpe
økonomisk byrde for sundhedsvæsnet. Ifølge
World Health Organisation er der i dag op i
mod en halv milliard mennesker i verden,
som lider af fedme. Denne globale fedmeepidemi
skyldes overspisning og mangel på motion,
men individets tilbøjelighed til at overspise
og ikke dyrke motion syntes til dels at
være genetisk nedarvet. Studier af familier,
tvillinger og adopterede har således vist at
fedme delvist er nedarvet og genetiske faktorer
udgør 40-70% af variationen i body mass
index (BMI). Indtil for 2 år siden havde man
kun opdaget ganske få fedmegener, men i dag
kendes 18 fedme genloci. De fleste af de
kendte fedmegener er udtrykt i hypothalamus
i hjernen, hvilket indikerer at de er involveret
i appetitregulering. Denne observerede genetiske
variation forklarer dog kun omkring 1 %
af den totale arvelighed af fedme, hvilket betyder,
at en stor del af den nedarvede komponent
af fedme stadig ikke er kortlagt.
Denne ph.d.-afhandling fokuserer på den genetiske
baggrund for fedme i relation til appetitregulering
med en eksperimental fokus på
variation i PYY, NPY2R, NMU og GCG.
Overordnet bidrager studierne foretaget i
ph.d. projektet til en større forståelse for den
genetiske komponent, der ligger til grund for
fedmeudvikling. Studierne kan på sigt være
med til at øge muligheden for at forbedre diagnosen,
samt forebyggelse og behandling af
denne udbredte sygdom.