Biologische en genetische aspecten rondom eetstoornissen

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1 Biologische en genetische aspecten rondom eetstoornissen Prof dr Roger Adan Dept Translational Neuroscience, UMC Utrecht Rintveld eetstoornissen kliniek, Altrecht, Zeist Dept Physiology and Neuroscience, Sahlgrenska Academy, Univ of Gothenborg

2 1950s: lesions in the brain cause obesity and anorexia satiety center hunger center

3 ob/ob wt Leptine deficiente muizen

4 Leptin: the key to a neural circuit underlying energy balance energy expenditure feeding

5 - Food intake + -MSH MC4R Gs AC POMC camp AgRP MC4r MC4r -MSH Leptin Leptin Weight gain Weight loss Vet Adapted from M.W. Schwartz

6 omgevingsinvloeden genen Nutrienten, hormonen en zenuwen informeren de hersenen Badman and Flier, Science 2005:307;5717;

7 plasma level Ghrelin CCK/Insulin/Amylin PYY/GLP-1/oxyntomodulin Meal time hunger satiation satiety

8 plasma level Hedonic feeding behavior Hunger/satiety satiation Je kunt buikpijn hebben van een grote maaltijd maar nog steeds trek hebben Ghrelin CCK/Insulin/Amylin PYY/GLP-1/oxyntomodulin Meal time

9 Honger neuronen in de Arcuate Nucleus POMC AgRP neurons out of total neurons in mouse brain (1 type in 7100) Humans have neurons AgRP neurons are essential for feeding (these neurons are invisible for fmri)

10 Optogenetics: laser light control over neurons

11 Optogenetic activation of AgRP neurons stimulates feeding AgRP neuronen stimuleren met licht met licht eten dieren meer pellets

12 chemogenetics A strategy to bring specific neurons under control of a drug by expressing a DREADD receptor on those neurons CNO only activates DREADDs (not endogenous receptors) DREADDs make target neurons CNO-sensitive

13 Activate AgRP neurons with a drug CNO selectively activates AgRP neurons in these genetically modified mice expressing the hm3d receptor only in AgRP neurons By doing so food intake is increased And consequenty body weight is increased as well

14 AgRP neuronen signaleren honger Activatie van AgRP neuronen leidt tot (over)eten Zou stimulatie met AgRP misschien werken bij anorexia nervosa?

15 Activity-based anorexia removal food scheduled feeding food intake measurement Feeding:

16 Relative body weight (%) AgRP (83-132) (5.6 g/day icv) infusion increases survival in ABA model % survival Cumulative food intake (g) agrp saline Days * agrp saline AgRP rescues rats from starvation Kas et al Mol. Psych Ad lib 1-h fed with wheel AgRP

17 Leptine in het activity-based anorexia model hyperactivity Feeding Thermogenesis leptin How does this work?

18 Suppression of running wheel activity by acute leptin injection in the midbrain dopamine system hyperactivity ** ** ** VTA leptin Leptin suppresses hyperactivity via the VTA (part of the reward system)

19 Er zijn aanwijzingen uit neuropsychologisch en neuroimaging onderzoek dat het dopaminerg systeem bij anorexia nervosa veranderd is. Activatie van dopamine neuronen leidt tot: - Hyperactivitiet - Verstoord eetpatroon

20 Chemogenetics: bringing dopamine neurons under control of drug hyperactivity VTA:Gq+ CNO VTA:Gq+ CNO control control

21 Activation of the VTA dopamine neurons using chemogenetics..and feeding (meal size) is decreased Saline CNO CNO

22 Samenvattend: Diermodellen zijn nodig om de rol van hormonen en genen bij anorexia nervosa te begrijpen Opto- en chemogenetica zijn nieuwe technieken die de rol van neuronen bij anorexia kunnen helpen ontrafelen Kernvraag bij Anorexia Nervosa is hoe (corticale) cognitieve processen (hypothalame) neurale circuits die eetgedrag sturen, beinvloeden Wat is nieuw in genetisch onderzoek?

23 Manhattan plot for GWAS meta-analysis of anorexia nervosa (n = 16,991 cases and n = 56,059 controls of European descent).

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25 Using human genetic data to identify cell types underlying anorexia nervosa

26 Chemogenetics in humans: yes we can!! We have the technology, AAV viral vectors are clinically safe We only need to know which neurons to target: AgRP neurons, dopamine neurons? < Presentatietitel invullen > - # 26

27 Linde Boekhoudt Keith Garner Inge Wolterink Han de Jong Mieneke Luijendijk Rahul Pandit Geoffrey van der Plasse Kathy de Git Ruud van Zessen Azar Omrani Veronne de Vrind Jeroen Verharen Nefeli Kakava Tessa Roelofs Jacques Flores Louk Vanderschuren Geert Ramakers Margriet van Gestel Arjen Boender Annemarie van Elburg Unna Danner Paul Smeets Susanne la Fleur Visiting address: Heidelberglaan CX UTRECHT The Netherlands Postal address: Postbus GA UTRECHT The Netherlands T. +31 (0) E.