Gestoord eetgedrag Roger Adan

Genes or environment Nature or nurture

Waarom stijgt het aantal obesen? Physical Activity + - Environment / Lifestyle Genetic Predisposition Energy Intake Energy Expenditure +/- Limited capacity Homeostatic Regulator Nutrient Sensing Leptin Obesity results when over a longer period of time Energy Intake exceeds Energy Expenditure. Both processes are controlled by a number of factors. Although there is a non-neural component, the neural controls and coordination are the most important Fuels Metabolism Storage WAT

Een-eiige tweelingen opgegroeid in verschillende leefomgeving

Hoe vaak zijn 1 en 2 eiige tweelingen samen aangedaan 1.0 MZ DZ 0.8 Twin Probandwise concordance 0.6 0.4 0.2 0.0 Alcoholism (females) Alcoholism (males) Alzheimer’s disease Anorexia nervosa Autism Obesity Schizophrenia Major affective disorder Plomin et al. (1994) Science; Gric e et al (2002) Am J Hum Genet.

Linkage analysis for obesity and diabetes

Genoom wijde associatie

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

GWAS Frayling, nature review genetics 2007

Current status obesity/T2D genes

Waarom zouden we op zoek gaan naar genen?

ob/ob wt Leptin mutation After treatment Leptin deficiency (1994)

LEPTIN and OBESITY

Leptin-receptors in brain

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

MC system and obesity AgRP transgene MC4R -/- mice Ollman et al (1997) Science MC4R -/- mice Huszar et al (1997) Cell -MSH MC4r AgRP POMC Viable yellow (Avy) mouse (ectopic overexpression of Agouti, an AgRP homolog) Miller et al (1993) Genes Dev. POMC mutations Krude H et al (1998) Nat Genet Adapted from M.W. Schwartz

Many MC4 receptor mutations in human obesity Adan, 2006

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

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

Het gebruiken van humaan genetische variatie voor onderzoek Mutation frequency per generation: ~2.10-8 per nucleotide Thus: 175 new SNPs per diploid genome (birth) there are more people on earth (7.109 ) than nucleotides in the human genome (~3.109) Thus every nucleotide gets mutated 500 times per generation of the world population !

Human population migration and expansion 6 5 4 Population size (in billions) 3 There have (only) been 5-8.000 generations (175.000 years) of humans 2 1 8000 B.C. 4000 B.C. 3000 B.C. 2000 B.C. 1000 B.C. 1000 A.D. 2000 A.D.

rare allele - strong effect (MC4r) Heritability: rare allele - strong effect (MC4r) common allele - small effect (AgRP) Threshold for disease Number of individuals Threshold for disease Risch NJ Nature 2000 Jun 15;405(6788):847-56 Effect on phenotype (e.g.BMI)

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

(Adapted from Schwartz et al., Nature 2000)

Example portion question

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

Example snack question

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

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

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

“Obesity by Choice in Rats” M.Tordoff, AJP 282, 2002 5 bottles sucrose 1 bottle water 1 bottle sucrose 5 bottles water 1 bottle water control “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” 118 kcal In this rat study, Carb, Fat, and Protein was served in separate jars. When an additional jar with Carb or Fat was offered, rats ingested more energy. Similarly, when rats had access to five bottles of 32% sucrose and 1 bottle of water, they ingested more sucrose, more total energy, and gained more weight over 30 days, than when they had 5 bottles of water and 21 bottle of sucrose. 110 kcal 99 kcal

Hunger - signaling Satiety signaling

progressive ratio of reinforcement (a measure for motivation)

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

motivation to press for sucrose predicts (visceral) obesity 1500 2500 3500 4500 200 400 600 800 1000 1200 1400 active lever presses mg WAT/g BW HFHS-choice diet chow diet la Fleur et al, 2007 Int J Obes

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

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

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

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

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

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)

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

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

amfetamines rimonabant fenfluramine sibutramine Hunger - signaling sibutramine Satiety signaling

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

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