Genetics and Dietary Preferences - jifsan

Presenter disclaimer• The research described here has beenfunded mainly by the NIH.• The presenter obtains no personal fundsof any sort from any private company.• Many private companies provideunrestricted and research support to theMonell Center.• The current list of these companies:

Monell Corporate SponsorsAFB International Inc.Altria GroupAjinomoto Co., Inc.Avon Products, Inc.Beiersdorf AGCadburyCampbell Soup CompanyThe Coca-Cola CompanyColgate-Palmolive CompanyCoty Inc.Diana IngredientsDiageo, plcDow Advanced MaterialsEstée Lauder Companies, Inc.Firmenich IncorporatedGeneral MillsGivaudan SAGlaxo Smith KlineHeng Yuan Xiang China (Group) Co., Ltd.International Flavors & Fragrances Inc.Japan Tobacco Inc.Johnson & JohnsonKao CorporationKellogg CompanyKerry Ingredients and FlavoursKikkoman USA R&D LaboratoryKimberly-Clark CorporationKirin Holdings Company, Ltd.Kraft FoodsL’OrealMarsMcCormick & Company, Inc.Mead Johnson NutritionalsNational StarchNestlé ResearchOgawa & Co. Ltd.PanasonicPepsiCo, Inc.Philip Morris Products S.A.Procter & GambleReckitt Benckiser, plcR.J. ReynoldsRoyal Friesland CampinaSenomyx, Inc.Schering-PloughThe Sugar Association, Inc.Suntory Holdings Ltd.SymriseTaisho Pharmaceutical Co., Ltd.Takasago International CorporationUnilever Research & DevelopmentWm. Wrigley Jr. Company

Overview of Presentation:Why care about flavorWhat is flavorFlavor dissectedSmell - AndrostenoneTaste - SaltChemesthesis - OleocanthalFlavor expandedFuture research directions

Flavor and the ChemicalSenses

The SensesVisionHearingTouchSmellTaste

The Senses: Impact of LossVisionHearingTouchSmellTaste

The Senses: Health ImpactVisionHearingTouchSmellTaste

The Senses: Health ImpactVisionHearingTouchSmellFoodTaste

Diseases related to excess food intake• Obesity• Diabetes• Hypertension• Some cancers• Probably many others

What is flavor?SmellTasteChemesthesis – irritation (tingle, burn, cool)

OdorPERCEPTIONareaOdorantsRetronasalTastesTastePERCEPTIONareaIrritants- allskin surfaceMonell Chemical Senses Center

Flavor Drives BehaviorIf it doesn’t “taste” good, people won’t eat it.If it does “taste” good, you can’t stop people fromeating it.

SmellFunctions: Sex, food, warningNobel Prize for ~1000 receptors. Combinatorialcode: each receptor responds to multipleodorants and each odorant can activate multiplereceptorsMany different qualities; claim – there arethousands of different smellsDifficult to name – it smells like…Learning relatively more important for liking thantaste

Outside the cell: MucusOlfactoryreceptorsInside the cellBuck & Axel, 1991

OdorantsOdor CodingOdor receptors: In humans ~350 distinct variantsOlfactoryepitheliumGlomeruliMitral cellsLateral olfactorytractHuman: ~ 350Mouse: ~ 1000Olfactory bulbto olfactorycortex2004OlfactoryreceptorsBuck & Axel (1991) Cell. 65:175 - 187

OdorantsOdor CodingOlfactoryepitheliumGlomeruliMitral cellsLateral olfactorytractto olfactorycortexOlfactory bulbOlfactoryreceptors

OdorantsOdor CodingOlfactoryepitheliumGlomeruliMitral cellsLateral olfactorytractto olfactorycortexOlfactory bulbOlfactoryreceptors

Androstenone

Wysocki & Beauchamp, PNAS, 1987

Malnick et al., 2004, red = intact ORF.

Putative androstenone receptorOR7D4Keller et al., Nature, 2007

A fly in the ointment: Effects of experienceWysocki, Dorries & Beauchamp, PNAS

TasteDedicated to food choice: accept or rejectFive basic tastes:Sour - acids: Ripeness?Salty - NaCl, LiCl: Sodium, minerals?Bitter - Alkaloids, peptides, toxins: Poisonavoidance?Umami - Glutamate, aspartate, nucleotides:Protein? Calories?Sweet - sugars, high intensity sweeteners: Caloriesfor plant eating animalsOthers? – fat, calcium, starchInnate responses to many taste stimuli but learningalso occurs

TasteBeginning in 1999 with a paper from Zucker and Rybagroup, a series of taste receptors have beenidentified:Sweet: GPCRs – heterodimer T1R2+T1R3Umami: GPCRs – heterodimer T1R1+T1R3Bitter GPCRs - ~25 in humans; dimerize?Sour: Ion channel(s) – PDK, ASIC, others?Salt: Ion channel(s) – ENaC, TRP, others?

Major Discoveries in Taste ReceptorsLi et al, 2002;Nelson et al., 2002.

Multiple Regions of T1R2+T1R3 are Required forEffective Interaction with Different Sweet CompoundsThe sweet receptor has six distinct ligand binding sitesT1r2 & T1r3 Amino Terminal DomainsSugars, aspartame,small molecule sweetenersT1r3 C-Rich RegionBrazzein, monellinT1r3 Transmembrane Regioncyclamate, lactisoleT1r2 Transmembrane RegionperillartineATDsT1r2+T1r3 HeterodimerR. Margolskee

Salt

Salt, … the primordial narcotic**Multhauf, RP, Neptune’s Gift, Baltimore: The Johns Hopkins University Press, 1978, p. 4.

Too much?

The Problem: Once Americans reach theirfifties, the risk of developing high bloodpressure over the remainder of the lifespanis estimated to be 90% even for those withhealthy blood pressures. It has beenestimated that reducing sodium intakescould prevent more than 100,000 deathsannually and save billions in medical costs.

Recommendations in the past:1969: The first statement from the U.S.government:First: at risk populationsLater: all U.S. populationSince 1968, more than 18 national andinternational government and medical bodieshave concurred.Results to date: NO EFFECT!

Salt is everywhere in the U.S. food supply andmost is added by others

Two potential strategies:Change the stimulus – or – Change the person

Salt taste mechanismsThe identity of the human salt receptor - newinformation and remaining puzzles• Stimulus specificity:– NaCl and LiCl only purely salty substances known.– This suggests a very specific mechanism.• Animal models:– Neural responses to NaCl are inhibited by the diureticamiloride.– In 2010 two research groups proved that one component ofthe salt receptor mechanism involves an epithelial Nachannel (ENaC).

Epithelial Na channel (ENaC)

Salt taste mechanisms• One component is an ENaC*• Implications:- Salt taste substitute through thismechanism unlikely due to specificity- Salt taste enhancer possible*Bosak et al., 2010; Chandrashekar et al., 2010

Salt taste mechanisms• An ENaC is not the entire answer.• A second less specific salt taste mechanismalso exists.• This may account for several of the othertaste attributes of salt such as mouthfeel,fullness, lowered bitterness and overallbalance.• This mechanism is unknown.

Vilhjalmur Stefansson

Decreasing Na intake is followed bydecreased salt preferenceExperimentalPre dietLow Na dietNaCl Concentration in crackers (%)Bertino , Beauchamp & Engelman, AJCN

Recommendation of the IOM Committeeon Strategies to Reduce Sodium Intake:FDA set mandatory standards to requirefood and restaurant industries togradually reduce the salt content of theirproducts.

Stepwise process for achieving final standards for the addition of salt to foods

Salt intake across cultureshypertension % prevalence403020100.1YanomamaXingu1Rambugu& NdoriAsaro1065 mmol1008 gr NaCl3200 mg Na1000sodium excretion mmol/dayFrom Beard, 2004

Human adults do not compensateBeauchamp et al., JAMA

Chemesthesis/IrritationChemical skin senseStimuli: CO 2 , menthol, hot peppersPain, heat, cooling, tingle, itch etcReceptors: TRP ion channels - originallydiscovered as temperature sensitiveWhy do people like these in foods and beverages?

The Ion Channels of NociceptionNeuronalmembraneNTransient ReceptorPotential Channels(TRPs)CNCAcid SensingIon Channels(ASICs)Acid - TRPV1Heat - TRPV1, TRPV2Cold - TRPA1Capsaicin - TRPV1Mustard oil - TRPA1Membrane stretch - TRPV2Acid - DRASIC

Oleocanthal

IbuprofenA widely used anti-inflammatory drugRelieves painIn some ways mimics aspirin withoutall of the side effectsLong-term consumption has beenreported to reduce the risk of heartdisease and some forms of cancerand to delay the onset ofAlzheimer’s disease“Tastes bad” – Exclusive throat irritant

Profile sheet used for sensory assessment of olive oil

Throat stinging compound(-)-decarbomethoxy-dialdehydic ligstroside aglyconeHOO1OCHOCHOOleocanthal(oleo = olive; canth = sting; al = aldehyde)

OleocanthalA potent anti-inflammatory compoundfound in many extra virgin olive oilsActivates receptors in throat onlythrough TRPA1; very specific.In humans TRPA1 is expressed inthroat but not the mouth, hence thespecificityIn vitro, is effective against severalcancer cell models and pathwaysinvolved in Alzheimer’s disease

Health-beneficial effects of the Mediterranean dietMediterranean dietOlive oilPolyphenolsOleocanthalOleocanthal

Flavor Expanded:“Taste” throughout thebody

The Tongue’s Taste Cells are the InitialChemosensors of the Alimentary TractThere are also Taste Cells in the Gut!• Multiple taste signaling proteins are found in the gut• And the pancreas• In specific gut endocrine cells and brush cells• Integrate physiological responses to digestionR. Margolskee

The Tongue’s Taste Cells are the InitialChemosensors of the Alimentary TractThere are also Taste Cells in the Gut!R. Margolskee

ProspectsTargeting gut taste cellsNew secretagogues to promote GLP-1releasePotential new targets for treatment ofobesityPotential new targets for modulatinggut motilityR. Margolskee

Flavor Receptors Elsewhere:Functions?Bitter taste receptors in the upper noseBitter taste receptors in the smooth muscle of the lungSweet taste receptors in the brain and pituitary gland

Flavor Receptors Elsewhere:Functions?Bitter taste receptors in the upper noseBitter taste receptors in the smooth muscle of the lungSweet taste receptors in the brain and pituitary glandSweet taste and olfactory receptors in sperm

Sperm and egg meet“Smell”Smell receptors: Spehr et al., Mol CellEndocrinol. 2006, 250.Taste receptors: Kiuchi et al., Cytogenet.Genome Res. 2006, 115.“Taste”

Some Research Needs- What is the nutritional importance of genetic variationin flavor receptors?- What nutritional roles are played by flavor receptorsoutside the nasal and oral cavities?- How does genetic variation interact withenvironmental variation to influence nutritionalphenotyes?- Are epigenetic modifications in flavor receptors ofnutritional significance?- How can our new and growing knowledge of flavorperception mechanisms and functions be translatedinto practical applications to reduce incidence andconsequence of human diseases?

Thank youMonellChemicalSensesCenterwww.monell.org