Neurobiologie van eetstoornissen; over muizen en ... - Altrecht
Neurobiologie van eetstoornissen; over muizen en ... - Altrecht
Neurobiologie van eetstoornissen; over muizen en ... - Altrecht
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<strong>Neurobiologie</strong> <strong>van</strong> <strong>eetstoorniss<strong>en</strong></strong>;<br />
<strong>over</strong> <strong>muiz<strong>en</strong></strong> <strong>en</strong> m<strong>en</strong>s<strong>en</strong><br />
Marti<strong>en</strong> Kas<br />
Dept. of Neurosci<strong>en</strong>ce & Pharmacology<br />
Rudolf Magnus Institute of Neurosci<strong>en</strong>ce<br />
University Medical C<strong>en</strong>tre Utrecht<br />
The Netherlands<br />
Voedselinname <strong>en</strong> <strong>en</strong>ergie verbruik<br />
Grams<br />
30<br />
20<br />
10<br />
0<br />
Body weight homeostasis<br />
Lichaamsgewicht homeostasis<br />
with wheel<br />
no wheel<br />
Food intake<br />
(ad libitum)<br />
1 2 3 4 5 6 7<br />
Time [days]<br />
1
Grams<br />
8<br />
6<br />
4<br />
2<br />
0<br />
Food intake<br />
-2 -1 0 1 2 3 4 refeeding<br />
Time [days]<br />
Registered yearly incid<strong>en</strong>ce of anorexia nervosa<br />
in m<strong>en</strong>tal healthcare in northern Europe in the 20th c<strong>en</strong>tury<br />
Hoek, Curr Opin Psychiatry, 2006<br />
Lichaamsgewicht uit balans<br />
Adult obesity preval<strong>en</strong>ce in the UK<br />
2
Hoe kunn<strong>en</strong> deze verstoring<strong>en</strong><br />
in lichaamsgewicht ontstaan?<br />
1950s: lesions in the brain cause obesity and anorexia<br />
satiety c<strong>en</strong>ter hunger c<strong>en</strong>ter<br />
+/-<br />
Storage<br />
WAT<br />
Energy<br />
Intake<br />
Homeostatic<br />
Regulator<br />
Energie balans<br />
omgeving / Lifestyle<br />
Physical<br />
+ Activity -<br />
Fuels<br />
Nutri<strong>en</strong>t<br />
S<strong>en</strong>sing<br />
Energy<br />
Exp<strong>en</strong>diture<br />
Metabolism<br />
+/-<br />
Limited<br />
capacity<br />
Cholecystokinin (CCK) – korte termijn<br />
G<strong>en</strong>etic Predisposition<br />
3
Leptine defici<strong>en</strong>tie<br />
Leptine receptor<strong>en</strong> in het brein<br />
Halaas et al., Sci<strong>en</strong>ce, 1995<br />
hypothalamus<br />
Leptine – lange termijn<br />
-<br />
+<br />
4
LEPTIN and OBESITY<br />
Nature g<strong>en</strong>etics, 2009<br />
Respons op leptin farmacotherapie<br />
3yrs old - weight = 40kg 6yrs old - weight = 29kg (Farooqi et al)<br />
Van vetweefsel naar<br />
melanocortine 4 receptor<strong>en</strong> (MC4R) in het brein<br />
5
α-MSH<br />
POMC ↑<br />
-<br />
Food intake<br />
MC4R<br />
Leptin ↑ Leptin ↓<br />
Weight gain Weight loss<br />
Vet<br />
+<br />
AgRP ↑<br />
Melanocortine signalering<br />
MC4r<br />
MC4r<br />
α-MSH<br />
Adan and Kas, Tr<strong>en</strong>ds in Pharmcol. Sci., 2003<br />
The yellow mouse obesity syndrome<br />
Ubiquitously expression of Agouti<br />
Melanocortin-3 and 4 receptor<strong>en</strong> in het brein<br />
6
Hers<strong>en</strong> regio specificiteit<br />
Hers<strong>en</strong> regio specificiteit<br />
Kas et al., Journal of Neurosci<strong>en</strong>ce, 2004<br />
Kas et al., Journal of Neurosci<strong>en</strong>ce, 2004<br />
PVN LH<br />
Hers<strong>en</strong> regio specificiteit<br />
DMH<br />
Kas et al., Journal of Neurosci<strong>en</strong>ce, 2004<br />
Melanocortine 4 receptor<strong>en</strong> drag<strong>en</strong> bij aan obesitas,<br />
maar do<strong>en</strong> dit op verschill<strong>en</strong>de manier<strong>en</strong> (afhankelijk <strong>van</strong><br />
het hers<strong>en</strong>gebied waar ze voor kom<strong>en</strong>)<br />
7
Lichaamsgewicht uit balans<br />
CHANGING TIMES: HISTORY OF THE FEMALE "IMAGE IDEAL"<br />
Familie <strong>en</strong> tweeling<strong>en</strong> studies ton<strong>en</strong> aan dat<br />
anorexia nervosa voor >50% <strong>over</strong>erft.<br />
Ontwikkeling <strong>van</strong> anorexia nervosa<br />
Kaye et al., 2009<br />
8
Heterog<strong>en</strong>iteit in de anorexia nervosa<br />
pati<strong>en</strong>t<strong>en</strong> populatie!<br />
Dynamiek in leptine in AN<br />
discharge<br />
Hebebrand et al., Mol Psychiatry, 1997<br />
Co-morbiditeit <strong>van</strong> anorexia nervosa met,<br />
bijvoorbeeld:<br />
- OCD (31 % - 68 %)<br />
- Angst stoorniss<strong>en</strong> (23 % - 75 %)<br />
Swinbourne and Touyz, 2007<br />
Kas et al, Mol Psychiatry, 2007<br />
9
Heterog<strong>en</strong>iteit in de eetstoornis populatie<br />
Hyperactiviteit in anorexia nervosa<br />
Kas et al., Eur. J. Pharmacol. 2003<br />
Het ‘activity-based anorexia model’<br />
bij knaagdier<strong>en</strong><br />
Day<br />
1<br />
2<br />
3<br />
4<br />
5<br />
6<br />
7<br />
8<br />
Kas et al, Mol Psychiatry, 2003<br />
Verminderd lichaamsgewicht <strong>en</strong> voedsel inname Leptine nivo’s <strong>en</strong> hyperactiviteit in anorexia<br />
Kas et al., Molecular Psychiatry, 2003<br />
Human<br />
Holtkamp et al., J Clin Endocrinol Metab 2003<br />
Elburg et al., J. Neural Transmission, 2007<br />
Rod<strong>en</strong>t<br />
Exner et al., Mol Psychiatry, 2000<br />
Hillebrand et al., Biol Psychiatry, 2005<br />
10
“of mice and m<strong>en</strong>…...”<br />
g<strong>en</strong>es developm<strong>en</strong>t life ev<strong>en</strong>ts behavior<br />
Muis inteelstam verschill<strong>en</strong> in hyperactief gedrag<br />
Kas, Kaye, Foulds Mathes & Bulik, Am J Med G<strong>en</strong>et, 2009<br />
Muis inteeltstamm<strong>en</strong><br />
G<strong>en</strong><strong>en</strong> Gedrag<br />
G<strong>en</strong><strong>en</strong> Gedrag<br />
11
Inbred mouse strain behavioral differ<strong>en</strong>ces<br />
C57BL/6J mice<br />
A/J mice<br />
G<strong>en</strong>etische dissectie <strong>van</strong> complex gedrag<br />
- <strong>van</strong> f<strong>en</strong>otype naar g<strong>en</strong>otype -<br />
Singer et al., Sci<strong>en</strong>ce, 2004<br />
GENETIC CONSORTIUM FOR ANOREXIA NERVOSA (GCAN)<br />
USA, The Netherlands, France, Germany<br />
United Kingdom, Italy, Spain, Austria, Poland, Norway<br />
DNA samples of > 4000 cases<br />
Funded by the Wellcome Trust<br />
12
Integratie <strong>van</strong> disciplines:<br />
Fundam<strong>en</strong>tal<br />
Neurosci<strong>en</strong>ce<br />
Translational<br />
research<br />
G<strong>en</strong>etics<br />
Clinical<br />
Neurosci<strong>en</strong>ce<br />
Definitie <strong>van</strong> kerneig<strong>en</strong>schapp<strong>en</strong> <strong>van</strong> ziekte: Met<strong>en</strong> <strong>van</strong> kerneig<strong>en</strong>schapp<strong>en</strong>:<br />
13
Complem<strong>en</strong>taire onderzoeksmethod<strong>en</strong>:<br />
G<strong>en</strong>es Behaviour<br />
G<strong>en</strong>es Behaviour<br />
14
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