Effects of on metabolic and disorders

Authors Nestlé’s work in food composition varies and dietary compositions that are bal- Katherine Macé*, Irène Corthésy- Today, consume diets with remark- anced in one metabolic situation might be Theulaz*, Laurent-Bernard Fay*, Heribert ably diverse compositions. Nestlé has spent unbalanced in another. For example, a Watzke*, Peter van Bladeren* and J. >100 years studying the quality and safety that fuels the of a performance Bruce German*† of food , including and athlete for long endurance events4 could be amino acids (from plant and animal sources), deleterious to an overweight sedentary indi- 5 *Nestlé Research Center, CH 1000 Lausanne 26, (glucose, simple , com- vidual who is developing insulin resistance . Switzerland plex polymers of different backbones The problem is yet more complex, as †Department of & Technology, and polysaccharides), (triacylglycer- with the same basic compositions have dif- University of California, Davis, California 95616, USA ides as and oils from plants and animals, ferent metabolic effects depending on their complex membrane lipids and sterols), poly- structures. Although the community nucleotides, nucleic and organic acids, and as a whole is pursuing the role of diet com- and alcohols, as well as the second- position in metabolic health, few researchers ary metabolites of plants and , are establishing the role of food structure in including carotenoids, flavonoids, anthocy- scientific detail. It is clear that this area needs anins, complex polysaccharides, oligosac- more investigation. Nestlé is therefore actively charides and conjugates. However, studying pursuing this goal. these components as isolated ingredients does not necessarily provide the means to Nestlé’s work in food structure understand complex foods. Nestlé is therefore We now know a great deal about the basic applying its world leading scientific expertise biomaterial properties of foods and their in food structure and nutrition to understand complex structures6. Unfortunately, little diet and metabolic health. is known about the relationships between The challenges to understanding the complex food structure and gut . implications of food composition for meta- Food ingredients consist of the molecules of bolic regulation are encyclopaedic, yet agricultural commodities (that is, cultivated some important principles can be discerned. plants and ) and their supramolecular Depending on the dose, all dietary com- structures, both of which can be altered by ponents affect metabolism and metabolic processing (Fig. 1). Nestlé is the world’s largest food company regulation to some extent. Nestlé research Food structures influence metabolic proc- and supplies ~1% of all dietary choices. has found that varying amino acids in dif- esses in the humans who consume them, but Today’s food marketplace is arguably the ferent proteins affects their metabolism and we are only just beginning to understand most complex, dynamic, highly competi- processes as diverse as glucose metabolism, how. The ligands of minerals, associations tive and exciting of endeavours. The insulin sensitivity, adipose regulation and of biopolymers, colloidal states of lipids and food supply is changing. Advances in com- food-intake control, and that varying the integrity of cellular plant materials all affect modity genetics combined with industrial composition affects metabolism, glucose the dynamics of digestion, gut sensing and processing have extended the yield, caloric metabolism and insulin resistance1. Different signalling systems, and the absorption and content, nutritional quality and safety of simple sugars (such as glucose and fructose) bioavailability of nutrients, substrates, fuels agricultural materials used as food ingredi- and their polymers (both digestible, such as and bioactive molecules. ents. As the largest food producer globally, and glycogen, and indigestible, such as Structures that are formed spontaneously Nestlé is committed to ensuring the high- oligosaccharides) produce varying metabolic by the components of food within the intes- SPONSOR est nutritional quality of its ingredients and responses2. Finally, non-essential exogenous tine also affect digestion. Understanding the products. This paper provides an overview plant and microbial metabolites, ranging from molecular processes of self assembly involves of the work Nestlé is doing in the field, illus- simple organic acids, amines and polyamines a practical application of the field of nano- trated by examples of our published work, to flavonoids and pigments, interact with science7. As an example, the basic food and highlights the areas that are actively human metabolic regulation3. polymers, proteins and polysaccharides, are under investigation at the Nestlé Research On the basis of our research, we believe thermodynamically incompatible in aqueous

Center in Lausanne, Switzerland. that no single food component can be solution and spontaneously separate into two FEATURE understood in isolation. The overall balance discrete phases: a -rich aqueous phase 8 This article has not been written or reviewed by of foods within the context of a particular and a -rich aqueous phase . the Nature editorial team and Nature takes no individual (with regards to factors such as How these discrete phases form, guide diges- responsibility for the accuracy or otherwise of lifestyle and age) can be appropriate or del- tion and dissociate within the intestine remain the information provided. eterious to health. Furthermore, health itself poorly understood.

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2 nin . As aresult,theproteinsexit infant inresponsetotheactionofren- into complexcurdswithinthestomach ofan Nevertheless, caseinmicellesself-assemble teases duetoitslack ofsecondarystructure. protein caseiniseasilydigestedby infantpro- in somecasesingeniouslyso. The majormilk the infant’s intestinalabsorptionprocesses— nents aredelivered conspicuouslyslowly by studies have shown thatmostofitscompo- source ofrapidly releasednutrients.Infact, therefore beexpectedtoanon-structured secreted fromthemammarygland,andmight nutrition toinfants.Milkisanobligatefluid winian selective pressuretoprovide complete , which evolved undertheconstantDar- Nestlé hasspentmany years studying human also possibletolookevolution forclues. comparative studiestoanswer. However, itis organized matrix? This couldtakedecadesof geneous fluidorslowly fromacomplex components rapidly fromasimplehomo- words, isitbetter todigestandabsorbfood structure beneficialtohealth?”—inother by aninfant’s lactaseenzyme. The example as quickly asitcanbedigestedandreleased charide. Therefore, glucoseisabsorbedonly as lactose,which isa nonabsorbabledisac- stomach slowly solutions phase-separating behaviours inaqueous their share withsyntheticpolymers example, proteinsandpolysaccharides oftheirpolymerclasses;for properties so on)andtogainthegeneralmaterial biomolecules (, musclefibresand biological functionsofagricultural todissociatethespecific it isnecessary Traditionally,engineers). thismeansthat by individualchefsorindustrialprocess ofcomplexfoodsthe structure (whether The goalofcuisineistogaincontrol dough, pasta, cheeseandicecream. of thevalueproductssuchasbread, foods, andareanindispensablepart and organolepticqualityofthefinal contribute tothestability, shape, texture and preparation.Thesestructures explicitly formed duringfood processing Gels, fibres, emulsionsandfoams are toform variouscomplexstructures. Food interactin ingredientbiopolymers structure 1|ThephysicsFigure offood generic structures. Our goal now is to understand therelationshipsbetween Ourgoalnowistounderstand food andnutritionalfunctions. generic structures. structure This simplifieddiagramshowsthattheprocessofchangingagivenfood composition involves formed from aseriesofstructures heterogeneous compositebiomaterials. arealsodescribableas the structures nature offoods. Insemi-solidsandsolids, the multicomponentandmultiphase orsuspensionsmirroring dispersions water, are thebiopolymerstructures food Infoods structures. thatareprimarily signifying theoverall genericspaceof can berepresentedasatetrahedron (proteins, carbohydrates, lipidsandwater) combinations ofthefood constituents colours, flavours andtexture).Allpossible the product(for example, appearance, assemblies thatcontrolattributesof the ingredientcompositionintodistinct One questionthatbegsaskingis“Isfood 8 . Food processingtransforms 9 . Glucoseispresentinmilk intestine of considerable geneticinvestment alongthe processes requirethecoordinated regulation less ofthestateenergyexcess. All ofthese not downregulated by theintestineregard- carbohydrates, proteinsandeven alcohol)is nonessential components(includinglipids, Interestingly, theabsorptionofcalorierich, sive consideringhow selective thisprocessis. transport andabsorptioniseven moreimpres- logical matrices.Itsquantitative capacityfor nutrients fromeven themostintractable bio- late, enzymaticallydigestandactively absorb to physically propel,mechanically manipu- Additionally, ithasextraordinary capacities in therestofhumanbody combined. times morebacterialcellsthanallthe neurological organinhumans.Itharbours10 est immuneorganandthesecondlargest capacity andmetabolicactivity. Itisthelarg- surface area,cellulardiversity, signalling ing organ(Figs 2,3)withprodigiouslength, The humangastrointestinaltract isaninspir- quality ofhumandiets. that controlsfoodstructureisimportanttothe deliver nutrients. Accordingly, theprocessing availability mightnotbetheoptimalmeansto of humanmilkdemonstrates thatrapid bio- Nestlé’s interestinthegut 10 . SPONSOR RETAINS SOLERESPONSIBILITY FORCONTENT renewed our interest in understanding the role renewed ourinterestinunderstanding therole insulin resistanceanddiabetes). prevent thecomplicationsofobesity(thatis, maintenance, andinindividuals ofallagesto adults toaidweightlossandpromote weight fat gainandtype2diabeteslaterinlife, infants toprevent predispositionstowards research. This knowledge isbeingappliedin type 2diabetes),isafocusofNestlé’s current balance deregulation(such asobesityand healthy conditions,aswellthoseofenergy- standing how energyisstoredandutilizedin tion areaprerequisiteforgoodhealth.Under- Energy metabolismanditsappropriateregula- metabolism. adjust foodintake,andglucoseenergy from thegastrointestinaltract tothebrain that Nutrient ingestiongenerates afferentsignals part ofthephysiology ofenergymetabolism. tract plays aroleinsensingandsignallingas and absorptive functions,thegastrointestinal Not surprisingly, inadditiontoitsdigestive of theoverall signallinginducedby foods. evolution. Yet tasteandsmellareonlyapart ment ofsimpleorganismsearlyincellular metabolism Nestlé’s attentiontoenergy The growing prevalence ofobesityhas The abilitytosensenutrientswas arequire- afusionof 44/12/06 12:16:13 pm / 1 2 / 0 6

1 2 : 1 6 : 1 3 p m of dietary factors (including lipids, proteins Nestlé’s focus on individual variations vary in their responses to diet, we need to and carbohydrates) as early determinants of in metabolic state and dietary know how scientifically. childhood obesity11, as well as the predispo- responses Nutrigenomics is beginning to assign the sition to diet-induced metabolic disorders in Although a disturbingly high percentage of genetic basis of differences in human adulthood. Nestlé research addresses targets the population suffers from metabolic dis- responses to diet15. However, genotype is not including proteins in infants12 and exces- orders, it is notable that many individuals the only way in which individuals within a sive carbohydrate intakes in adults13 using in the same environment do not. Why do population differ with respect to dietary models ranging from healthy humans to cell some people accommodate their metabolic responses. Diet itself, lifestyle, life stage and cultures14. The act of eating promotes energy regulation to variations in diet and lifestyle? health status all influence dietary requirements consumption, and the thermic effects of food We are actively working to combine imaging and metabolic responses to foods. Metabolic itself and energy expenditure are important to and metabolic profiling as the cornerstone disorders cause changes in physiological states overall energy metabolism. for future health assessment (Fig. 4). If people and perturb normal responses to diet, as do SPONSOR FEATURE Figure 2 | Cells within the stomach, proximal small intestine, distal ileum and colon all sample the gut. Complex meals induce the secretion of cocktails of peptides to digest and absorb nutrients. The integration of the various control systems that signal ingested calories, control meal size, signal adiposity and give pertinent input throughout the brain is still far from being understood. The thickness of rows indicates the intensity of peptide secretion. An upward pointing arrow (↑ ) indicates that the release of the gut peptide is increased by the specified food or nutrients. A downward pointing arrow (↓) indicates that secretion of the gut peptide is decreased by the specified food or nutrients. CNS, central nervous system.

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4 hypertension, obesityanddiabetes.Nestlé ceptibility toparticulardiseases,including positions —thatis,induceepigeneticsus- early inlifecanpotentiategeneticpredis- different lifestylesanddiets.Food choices physiological responsesofanindividual to generally, metabolicmemorycanalterthe Genetic imprinting,programming or, more with various high-throughputseparation to nutrition the applicationsofmetabolicprofiling lism directly. Nestléresearch haspioneered health. The alternative istomeasuremetabo- mine existing,orpredictfuture,metabolic guide theirdietaryandlifestylechoices. metabolic statusofhealthy individuals, andto are accurate enoughtomeasurethevarying of diagnosticsormetabolicassessorsthat damage healthwillrequireanewgeneration Preventing metabolicdisordersbeforethey ers relyonthepresenceofadiseasedstate. stone ofdiseasemanagement. Yet such mark- diseases asclinicaldiagnosticsareacorner- ferences andactuponthem?Biomarkersof orders. Isitpossibletomeasurethesedif- to dietsandpredispositionsmetabolicdis- Humans differintheirmetabolism,responses athlete’s uniquemetabolicdemands turn affectsthevalue ofdietstailoredtoan ments, includingathletictraining, which in of adaptive responsestovarious environ- research hasalsodemonstrated thebenefits in somecasesforlongperiodsoftime exposed tocanaltertheexpressionofgenes, sedentary tohighlyactive. physical activity, ranging frombeingrelatively diets andwillinglyengageinextremesof Modern humansareexposedtoavariety of adapt andsurvive indifferingenvironments. humans have shown aremarkableabilityto cise, aswellstress the intensity, duration andfrequency ofexer- metabolic states Nestlé’s visionforassessingindividual cells and G-proteinreceptors, andintegrationofluminalsensing(neuroendocrine achieves sensingofionchannels(directgating), metabolicsignalsorcues cellular sensing;inaddition, aftertranscellularorparacellularpassage, it acidity) sensing, luminal(apicalmembraneofepithelialcells)sensingand cells, achieves bacterialsensing, mechanical(osmoticstimuli, heatand system, whichcomprises>108neuronsand70–80%ofthebody’s immune Theentericnervous enteroendocrine systemsecretes>20hormones. and thegutwall alsosensesthebacterialpopulation.Inresponse, the The gastrointestinaltractrespondstochangesinitsluminalcontents, 3 Figure Measuring genotypealonecannotdeter- The environment thatanindividual is → gutbrainsignallingandimmunecells | 18 Transversal nutrientsensingmechanismsinthegut . Massspectrometrycombined 16 . Throughout history,. Throughout 16 . 17 . → require. The secondistheimportanceofcon- approach tohealthstatusmeasurementwould hundreds ofmetabolitesthateven aminimal insufficient standardstoroutinelyquantifythe accuracy andprecision.Currently, thereare issues. The firstisquantitation—specifically, guide individual healthraises important ing tobuildknowledge thatwillmonitorand sion, reversal andultimate prevention stand metabolicdisorders,andtheirprogres- for datamining,inordertomorefullyunder- assemble largelegacy databasesappropriate gies toenablethescientificcommunity ing much neededhigh-throughputtechnolo- academic andindustrialpartnersaredevelop- tion orenvironmental effects.Nestléandits whether theywerecausedby geneticvaria- ations tobiochemical pathways regardless of to modelsandusedassignindividual alter- ing andmetabolicsignalling,couldbefitted ing thoseresponsibleforgastrointestinalsens- Measures ofmetabolitesandpeptides,includ- the routineassessmentofpersonalhealth thereby achieving afundamentalchange in healthy populationandtheirown history, son’s statuscouldbecomparedtothatofthe measured quantitatively inindividuals, aper- human metabolomics.Ifmetabolitescouldbe lites andcompletenetworks asasteptowards techniques canidentifythousandsofmetabo- this phasereflectthecapacityofanindividual dial phase;thechanges in metabolismduring the fastedstatebutalsoinfedorpostpran- Metabolism mustbeassessednotsimplyin metabolic health,itmustbemeasured. described. Ifresponsetodietiscritical important tometabolichealth,itmustbe third concernsfooditself.Ifstructureis normal individuals) shouldbeincluded. The ioural, cognitive andotherdimensionsin neurological, genetic,anatomical,behav- tiple aspectsofhealth(such asphysiological, eased individuals anddiseaseendpoints,mul- biasing theoutcomeby includingonlydis- the sources ofthemetabolicdata.Ratherthan text —thatis,annotatingthesubjectswho are immunesignalling. We appreciatethatusingmetabolicprofil- 20 . 19 SPONSOR RETAINS SOLERESPONSIBILITY FORCONTENT . tive enterprise. We have thereforeengaged that scienceisbestpursuedasacollabora- Nestlé Research Centerhaslongrecognized about foodandmetabolismislacking. The lism. Yet agreatdealofscientificknowledge bolic disorders—itisthefuelofmetabo- diets. Ofcourse,foodisinvolved inmeta- the devastating consequencesofunbalanced ing allpossiblestrategies thatmightreverse need differentsolutions. diseases. However, metabolicdisorderswill ing thefoodsupplytoprevent deficiency ments, andretaining,enriching andfortify- nutrients, recognizingtheirabsoluterequire- trated by thesuccessesinidentifyingessential processing tosolve healthproblemsisillus- The power ofnutritionresearch andfood measurement ofmetabolicprofiles. the gutwithresearch onmetabolismandthe research onfoodanditsphysical dynamics in medicine holdgreatpromisetocompliment nologies thatarerevolutionizing clinical homeostasis. The molecularimagingtech- signalling, allofwhich areinvolved inenergy lation ofsensing,digestion,absorptionand to processamealthroughthecomplexregu- that humanhealthassessmentwas becoming and H ing thefirstsymposiumon“Personalizing Diet and helpedtoguideresearch visions.Follow- scientific networks, stimulatedcollaborations outcomes ofthesesymposiahave promoted national nutritionsymposiainLausanne. The of nutritionalresearch by hostingannualinter- in basicmetabolismandthoseattheforefront an active roleinbringingtogetherresearchers tutions over thepastdecade.Nestléhastaken than 1,000scientistsand100academicinsti- Nestlé hasactively collaborated withmore address metabolismanditsconsequences, collaborations, consortiaandtaskforces. To the research communitythroughhundredsof tackling metabolicdisordersandconsider- solution tometabolicdisorders Nestlé’s foodasa indetermining work Nestlé’s foodandnutritionresearch is ealth”, scientific consensus concluded ealth”, scientificconsensusconcluded 44/12/06 12:16:15 pm / 1 2 / 0 6

1 2 : 1 6 : 1 5 p m Figure 4 | The dynamics of food and metabolism Metabolic regulation is a continuous process varying from fasted to fed states. Levels of metabolites rise and fall in response to the influx of nutrients from foods, as do the signalling systems that stimulate appetite and mobilize energy in times of need, and inhibit eating and direct energy-rich molecules into storage in times of surplus. The combined molecular- imaging and metabolic- profiling capabilities available today due to revolutionary advances in analytical sciences provide an unprecedented opportunity to accurately monitor these processes. If brought to practice as part of routine health care, these tools would similarly revolutionize the diagnosis, treatment and prevention of metabolic diseases.

necessary. After the second symposium, References 12. Mace, K. et al. Protein quality and quantity in cow’s milk- entitled “The Next Energy Crisis: Metabolic 1. Stettler, R. et al. Interaction between dietary lipids based formula for healthy term infants: past, present and future. Nestlé Nutr. Workshop Ser. Pediatr. Program Health”, it became clear that aggressive steps and physical inactivity on insulin sensitivity and on intramyocellular lipids in healthy men. Care 28, 58, 189–203 (2006). were needed to manage individuals with 1404–1409 (2005). 13. Minehira, K., Vega, N., Vidal, H., Acheson, K. & Tappy, L. existing metabolic disorders. Nestlé is cur- 2. Ferchaud-Roucher, V., Pouteau, E., Piloquet, H., Zair, Y. & Effect of carbohydrate overfeeding on whole body rently working to extend this strategy to pre- Krempf, M. Colonic fermentation from lactulose inhibits macronutrient metabolism and expression of lipogenic lipolysis in overweight subjects. Am. J. Physiol. Endocrinol. vent metabolic disorders before they occur. enzymes in adipose tissue of lean and overweight Metab. 289, E716–E720 (2005). humans. Int. J. Obes. Relat. Metab. Disord. 28, 1291– The implications of metabolic disorders 3. Williamson, G., Barron, D., Shimoi, K. & Terao, J. In vitro 1298 (2004). for long-term health, as identified by scientific biological properties of flavonoid conjugates found in 14. Darimont, C. et al. Reconstitution of telomerase research, confirmed by clinical evidence and vivo. Free Radic. Res. 39, 457–469 (2005). activity combined with HPV-E7 expression allow human interpreted by scientific experts, are alarming. 4. Decombaz, J. et al. Post-exercise replenishment of preadipocytes to preserve their differentiation capacity intramyocellular lipids. Proc. Nutr. Soc. 60, 11 (2001). after immortalization. Cell Death Differ. 10, 1025–1031 Those individuals who are at risk of metabolic 5. Stettler, R. et al. Interaction between dietary lipids (2003). disorders need to know so and early. This is and physical inactivity on insulin sensitivity and on 15. Corthesy-Theulaz, I. et al. Nutrigenomics: the impact the role of . Nestlé is now look- intramyocellular lipids in healthy men. Diabetes Care 28, of biomics technology on nutrition research. Ann. Nutr. 1404–1409 (2005). ing to address the critical challenges raised Metab. 49, 355–365 (2005). 6. Mezzenga, R., Schurtenberger, P., Burbidge, A. & Michel, 16. Schmitt, B. et al. Transcriptional adaptations of lipid by this knowledge. Once assessed, how will M. Understanding foods as soft materials. Nat. Mater. 4, metabolism in tibialis anterior muscle of endurance- 729–740 (2005). individuals choose foods with the dietary trained athletes. Physiol. Genomics 15, 148–157 compositions, structures and quantities that 7. Sagalowicz, L., Leser, M. E., Watzke, H. J. & Michel. M. (2003). SPONSOR are appropriate? How can the complex agri- Monoglyceride self-assembly structures as delivery vehicles. Trends Food Sci. Tech. 17, 204–214 (2006). 17. Ferrer-Martinez, A., Marotta, M, Turini, M., Mace, K. & Gomez-Foix, A. M. Effect of sucrose and saturated-fat cultural and food marketplace change to 8. Tolstoguzov, V. in Functional Properties of Food diets on mRNA levels of genes limiting muscle fatty acid provide them? There will be no simple solu- Macromolecules (eds Mitchell, J. R. & Ledward, D. A.) and glucose supply in rats. Lipids 41, 55–62 (2006). tions. Unquestionably, greater knowledge of 385–415 (Elsevier Applied Science, London, UK, 1986). 18. Roberts, M., Geiger, W. & German, J. B. The revolution in foods, and their compositions and biological 9. Tessari, P. et al. Slow versus fast proteins in the stimulation of b-cell response and the activation of the microanalytic : a macro-opportunity for clinical effects, will be needed. The diversity in the entero-insular axis in . Diabetes Metab. nutrition. Am. J. Clin. Nutr. 71, 434–437 (2000).

marketplace that is available for individual Res. Rev. 16 Nov 2006 (doi:10.1002/dmrr.698). 19. German, J. B., Roberts, M. A., Fay, L. & Watkins, S. M. FEATURE choices in , texture and flavour must 10. Anderle, P. et al. Changes in the transcriptional profile of Metabolomics and individual metabolic assessment: the next great challenge for nutrition. J. Nutr. 132, extend to variables that relate to metabolic transporters in the intestine along the anterior–posterior and crypt–villus axes. BMC Genomics 6, 1–17 (2005). 2486–2487 (2002). health. Nestlé is committed to providing the 11. Mace, K., Shahkhalili, Y., Aprikianm O. & Stan, S. Dietary 20. Grigorov, M. G. Global dynamics of biological systems scientific research and technologies necessary fat and fat types as early determinants of childhood from time-resolved omics experiments. Bioinformatics to meet this challenge. : a reappraisal. Int. J. Obes. (in the press). 22, 1424–1430 (2006).

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