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Gestoord eetgedrag Roger Adan. Nature or nurture Genes or environment.

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Presentatie over: "Gestoord eetgedrag Roger Adan. Nature or nurture Genes or environment."— Transcript van de presentatie:

1 Gestoord eetgedrag Roger Adan

2 Nature or nurture Genes or environment

3 Waarom stijgt het aantal obesen? Energy Intake Energy Expenditure Fuels Metabolism Genetic Predisposition Storage WAT +/- Limited capacity Homeostatic Regulator +/- Nutrient Sensing Leptin Physical Activity + - Environment / Lifestyle

4 Een-eiige tweelingen opgegroeid in verschillende leefomgeving

5 DZ Plomin et al. (1994) Science; Gric e et al (2002) Am J Hum Genet. Alcoholism(females) Twin Probandwise concordance Alcoholism(males) Alzheimer’sdisease Autism Major affective disorder Anorexia nervosa nervosa Schizophrenia MZMZMZMZ Obesity Hoe vaak zijn 1 en 2 eiige tweelingen samen aangedaan

6 Linkage analysis for obesity and diabetes

7 Genoom wijde associatie

8 Principle association study obese patients Random population controls SNP variant (yellow) present in ~15 % of the disease population SNP variant (yellow) present in ~5% of the control population

9 GWAS Frayling, nature review genetics 2007

10 Current status obesity/T2D genes

11 Waarom zouden we op zoek gaan naar genen?

12 ob/ob wt Leptin deficiency (1994) Leptinmutation After treatment

13 LEPTIN and OBESITY

14 Leptin-receptors in brain

15 Leptin  POMC  Leptin  AgRP   -MSH MC4r Adipose tissue Weight gain Weight loss Adapted from M.W. Schwartz + Food intake Gs AC MC4R cAMP -  -MSH

16

17 Adapted from M.W. Schwartz  -MSH MC4r AgRP POMC AgRP transgene Ollman et al (1997) Science Viable yellow (A vy ) mouse (ectopic overexpression of Agouti, an AgRP homolog) Miller et al (1993) Genes Dev. MC 4 R - / - mice Huszar et al (1997) Cell POMC mutations Krude H et al (1998) Nat Genet MC system and obesity

18 Many MC4 receptor mutations in human obesity Adan, 2006

19 adipose Weight gain Leptin  Gs AC MC4R + POMC  Leptin receptor Arcuate nucleus MSH Mutations causing Human obesity MC 4 receptor POMC gene Leptin receptor Leptin Mutations causing Human obesity MC 4 receptor POMC gene Leptin receptor Leptin Obese mouse mutants MC4-/- POMC -/- db/db ob/ob Obese mouse mutants MC4-/- POMC -/- db/db ob/ob

20 Genen voor fenotypen genes for stress genes for hunger signalling genes for locomotion omgevingsfactoren satiety locomotion stress hunger signalling obesitas stress locomotion hunger signalling ontrafelen van fenotypen Kas & Van Ree, Trends in Neurosciences, 2004 drug Adrug B drug C

21 Het gebruiken van humaan genetische variatie voor onderzoek Mutation frequency per generation: ~ per nucleotide Thus: 175 new SNPs per diploid genome (birth) there are more people on earth ( ) than nucleotides in the human genome (~ ) Thus every nucleotide gets mutated 500 times per generation of the world population !

22 Human population migration and expansion 8000 B.C B.C B.C B.C B.C A.D A.D Population size (in billions) There have (only) been generations ( years) of humans

23 Nature 2000 Jun 15;405(6788): Risch NJ Threshold for disease Effect on phenotype (e.g.BMI) Number of individuals Heritability: rare allele - strong effect (MC4r) common allele - small effect (AgRP)

24 Two specific patterns Dissect the genetic background of two specific eating patterns: meal size (‘portions’) meal frequency (‘snacking’)

25 (Adapted from Schwartz et al., Nature 2000)

26 Example portion question

27 * Genetic variation of the human CCK gene affects meal size (Genetic variation of the human CCK gene does not affect snacking behavior)

28 Example snack question

29 * * * * Genetic variation of the human leptin (receptor) genes affects snacking behavior

30 Parabrachial N. Caudal Brainstem Sensory Input Outflow autonomic endocrine Skeletal motor Ingest or reject Oro- motor Loco- motor MoN RF we know a lot about neural circuitry of feeding Midcollicular decerebrate rat model (Grill et al.) Berthoud, Physiol & Behav 2004 SNS BAT, WAT, Muscle, Liver Energy Expenditure Spinal Cord RVLM Taste, GI, Liver, Pancreas Energy Assimilation Vagus V, VII, IX Hormones Fuels AP NTS dmnX

31 Parabrachial N. Caudal Brainstem Cortex, Limbic system Sight V1 V4 Smell OLF PIR ACB Thalamus PFC AMY HIP AIC Taste Sensory Input Outflow autonomic endocrine Skeletal motor Ingest or reject Oro- motor Loco- motor MoN RF we know a lot about neural circuitry of feeding AMY PRL Berthoud, Physiol & Behav 2004 PIT SNS BAT, WAT, Muscle, Liver Energy Expenditure Spinal Cord RVLM Taste, GI, Liver, Pancreas Energy Assimilation Vagus V, VII, IX Hormones Fuels AP NTS dmnX LH arcuate DMH VMH HYPOTHALAMUS PVN

32 “Obesity by Choice in Rats” M.Tordoff, AJP 282, bottles sucrose 1 bottle water 1 bottle sucrose 5 bottles water 1 bottle water control 99 kcal 118 kcal 110 kcal “The more sources of a nutrient a rat has, the more it chooses to ingest” “The effect was so powerful it could override physiological controls of intake” “The more sources of a nutrient a rat has, the more it chooses to ingest” “The effect was so powerful it could override physiological controls of intake”

33 Satiety signaling Hunger - signaling

34 progressive ratio of reinforcement (a measure for motivation)

35 PR measure of motivation Westers dieet chow Experimental setup 1 aWAT 4 wks chow Rattenbrokken (chow) group 1: group 2:

36 motivation to press for sucrose predicts (visceral) obesity la Fleur et al, 2007 Int J Obes active lever presses mg WAT/g BW HFHS-choice diet chow diet

37 PR measure of motivation Westers dieet chow Experimental setup 2 3 weeks group 1: group 2:

38 obese rats are more motivated to respond for sucrose rewards obtained * for 4 weeks -choice diet diet la Fleur et al, 2007 Int J Obes

39 lever press speed (presses/sec) reward number **** speed to press per reward is higher in HFHS-choice diet rats HFHS-choice diet chow diet la Fleur et al, 2007 Int J Obes

40 Conclusions de motivatie voor suiker voorspelt wie er dik wordt op een westers dieet het westers dieet verhoogt de motivatie voor suiker er ontstaat zo een vicieuze cirkel waarin het eten van westers voedsel de trek (motivatie) voor die voedsel verder verhoogt

41 Aminergic drug targets in the 20th century Geneesmiddelen tegen overgewicht dopamine noradrenalin amfetamine Sibutramine fenfluramine Fluoxetine serotonin

42 Why are so many drugs acting on aminergic systems? DOPAMINE SEROTONIN ADRENALINE HISTAMINE Because drugs were available in the ’50s that interfered with these transmitters (iproniazide-TBC, Chlorpromazine- antihistaminicum)

43 AMINERGIC LIGANDS ARE CHEMICALLY SIMPLE WE SIMPLY LACKED PHARMACOLOGICAL TOOLS TO IDENTIFY OTHER RECEPTORS AS DRUG TARGET

44 the human genome has more than 400 G protein coupled receptors (neuro)peptide chemokine lipids amines orphan (MC4)

45 Satiety signaling Hunger - signaling rimonabant fenfluramine sibutramine amfetamines

46 Ook je genen spelen een rol bij obesitas De rol van de hersenen op het ontstaan van overgewicht is wat onderschat geweest Honger, verzadiging en snacken: -zitten in verschillende gebieden in de hersenen -worden gereguleerd door verschillende genen

47 Implicaties: Het credo meer bewegen en minder eten behoeft wat meer nuance; de een snackt, de ander schept te veel op zijn bord en weer een ander beweegt vooral te weinig We moeten ons meer bewust zijn van honger en verzadigingssignalen en honger onderscheiden van zin in iets lekkers Het beloningssysteem is vaak al tevreden met kleine beetjes van iets lekkers Succesvolle geneesmiddelen ter bestrijding van overgewicht werken meestal op het zenuwstelsel


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