Why No Calorie makes No Sense

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1 Why No Calorie makes No Sense Nancy E. Rawson, M.Sc., Ph.D. Associate Director Monell Chemical Senses Center 3500 Market St. Philadelphia PA

2 Outline Defining the problem How sweet taste works What we don t know Complications & Opportunities 2

3 Understanding Sweet Taste Highly positive taste quality Stimulus molecules structurally diverse Added sugars associated with risk for obesity, diabetes and cardiovascular disease Children have high proclivity for sweet taste 3

4 Sweet Taste Enhancement Tool Box: Non-nutritive sweeteners High potency sweeteners Sugar alternatives polyols Sensory interactions: Salt enhancement Odor taste interactions Unmasking of intrinsic sugar Physical approaches e.g., particle size 4

5 Why do we taste? Each species must solve the fundamental problem of obtaining sufficient nutrients and avoiding being poisoned. A species taste sensitivity and preference is co-adapted to its ecological niche.

6 Real taste [in] the mouth, according to my theory must be acquired by certain foods being habitual [and] hence become hereditary; Charles Darwin, circa 1839 (aged about 30).

7 different sweeten T1R Sweet and Umami Taste Receptors Outside taste cell Lipid bilayer Inside taste cell T1R2 T1R3 T1R3 T1R1 Sweet Amino acid (Umami) Discovered by multiple research groups in

8 Evolution of T1R genes These three genes are the result of an ancient case of duplication and divergence that occurred more than 400 million years ago, before any vertebrate set foot on dry land! ry/news/140903_hummingbirds 8

9 Tas1R2 is inactivated in many carnivorans Li et al., 2005 Jiang et al., 2012, 2014

10 Implications Evolution matches sensory apparatus to nutritional requirements Carnivores not designed to choose foods high in sugar/carbohydrates Omnivores must choose wisely! Omnivores must select a diet that provides all of their nutritional needs from among an array of choices. In nature, nutritional value can be learned by taste Sugars provide a rapidly accessed source of calories essential for survival

11 We aren t good at fooling mother nature! Brain response distinguishes caloric from the non-caloric sweetener even when the sensory experience is similar. Reward areas differentially activated Smeets et al., 2011 Frank et al., 2008 Challenging paradigm Doesn t explain why We need to look at the detectors to begin to understand the why 11

12 The Tongue s Taste Cells are the Initial Chemosensors of the Alimentary Tract

13 Taste cell types Type I Type II Type III Chaudhari and Roper,

14 How Sweet Taste Works How do taste cells detect sweet compounds? T1r2+T1r3 is the primary detector for sweeteners. Functional expression in heterologous cells Mouse genetic manipulations Pharmacological blocking Humans with genetic variations affecting T1R2 expression exhibit altered sensitivity

15 T1r2+T1r3 Heterodimer Multimer of Two Seven Transmembrane Helix Receptors The T1r2+T1r3 sweet receptor uses multiple binding sites T1r2 & T1r3 Amino Terminal Domains sugars, aspartame, small molecule sweeteners T1r3 C-Rich Region brazzein T1r3 Transmembrane Region cyclamate, lactisole T1r2 Transmembrane Region perillartine

16 T1r2+T1r3 Heterodimer What We Don t Know No Crystal Structure: - Limits ability to: - Model receptor - Design better sweeteners Molecular basis for adaptation - Phosphorylation? Potential for cross-talk with other taste detection pathways?

17 How Sweet Taste Works How do taste cells detect sweet compounds? T1r2+T1r3 is the primary detector for sweeteners. Is the T1r2+T1r3 receptor the only sweet detector? Some sugars are also detected by other means: sugars. Mice lacking T1r3 respond to caloric sweeteners: Behavioral preference Nerve recordings

18 1.4 T1r3 Knockout Mice: Sugars Nerve recording 1.2 Relative response (NH 4Cl = 1) NaCl HCl QHCl Glucose Maltose Fructose Sorbitol Saccharin Sucrose SC45647 Sucralose D-Tryp MSG MSG+IMP Control T1r3 KO T1r3 KO mice lose all nerve responses to noncaloric sweeteners but NOT to sugars Damak et al., Science 301: (2003)

19 T1r3-Independent Sweet Taste Working model: metabolic pathway for sugar detection: Sugar transporters (GLUTs & SGLTs) take up glucose Glucose is metabolized to generate ATP ATP binds to & closes the metabolic sensor (K ATP channel) KO pancreatic b cell

20 T1r3 Knockout Mice: Sugars Nerve recording Relative response (NH 4Cl = 1) Control T1r3 KO The sucrose response is not eliminated 0 NaCl HCl QHCl Glucose Maltose Fructose Sorbitol Saccharin Sucrose SC45647 Sucralose D-Tryp MSG MSG+IMP Damak et al., Science 301: (2003)

21 T1r3-Independent Sweet Taste How to explain the T1r3-independent detection of the disaccharide sucrose? Margolskee

22 T1r3-Independent Sweet Taste Hypothesis: Taste Cells have Brush Border Digestive Enzymes BBE KO BBE Margolskee

23 Brush Border Enzyme Functions Present in Taste tissue Sukumaran et al., 2016.

24 Brush Border Enzymes & Disaccharides Taste nerve recording Brush Border Enzymes Function in the Taste Detection of Disaccharides Before Voglibose After Voglibose After Washout Sukumaran et al., 2016.

25 Brush Border Enzymes & Disaccharides Taste nerve recording Knockout of T1r3 plus Enzyme Inhibitor completely abolish responses to dissacharides Sukumaran et al., 2016.

26 How Does Sweet Taste Work? Enzymatic activity enables detection of polysaccharides as sweet. Pharmacological blocking of enzymatic activity reduces response to disaccharides Variations in amylase expression alters sensory response to polysaccharides

27 Current Sweet-Taste Model Two Pathways for Detecting Sugars Oral Enzymes begin polysaccharide and starch digestion Second metabolic pathway for sugar sensing Margolskee

28 Current Sweet-Taste Model Two Pathways for Detecting Sugars Non-nutritive sweeteners only act on the first pathway Nutritive sweeteners act on both pathways Margolskee

29 Implications Taste cells provide information on both perceptual quality and nutritional quality. Neither pathway alone is sufficient to elicit the full response observed to sugar. Assays to identify sweetener alternatives relying only on T1R2/T1R3 are inadequate. 29

30 A new definition? Our target definition of SWEET needs to encompass the ability of taste cells to detect caloric content. 30

31 Opportunities New targets for sweetness enhancement Metabolic pathway Enzymatic contribution Well understood pathways Experimentally addressable In vitro tools available: Human taste cells in culture express both pathways (Ozdener and Rawson, 2013) Gut and pancreatic cell lines 31

32 A FEW COMPLICATIONS 32

33 Can we shift preference? Reducing sugar intake by 40% for 3 months shifted perceived intensity of a sweet pudding (Wise et al., 2016) However, this effect did not persistno ef following return to free diet Month NO EFFECT ON PREFERRED LEVEL OF SUGAR IN PUDDING! Wise et al., 2016

34 We aren t all the same Genetic variation: Accounts for 23 30% of the total phenotypic variation in perceived intensity across a set of sweeteners (Hwang et al., 2015). SNP in promoter region for T1R3 results in lower receptor expression and is correlated with lower sensitivity to sucrose in humans (Fushan et al., 2009). 34

35 Sweet receptors do more than taste

36 Metabolic effects Release of glucagonlike peptide Modulates insulin release Laffitte et al.,

37 Sensing sweet in the gut T1Rs expressed on cells which release neuroactive peptides involved in control of: Hunger/Satiety Gut motility Blood glucose Depoortere I. Taste receptors of the gut: emerging roles in health and disease Gut 2014;63:

38 Take-home points Evolutionary, in-born drive for sources of energy Shifting preference more difficult than salt Second pathway in taste cells that is not activated by sugar alternatives neural signal resulting from ATP synthesis that is not tasted but may contribute to the neural recognition of sweetness. Impact of alternatives on sweet taste receptors participating in metabolic processes and regulation of energy balance need to be considered. 38

39 I hope I ve convinced you The true target for a sweetener needs to include a caloric component. Sugar reduction, not elimination. 39

40 Thank You! MonellCenter Monell Chemical Senses 40

CHAPTER 1 INTRODUCTION

CHAPTER 1 INTRODUCTION Understanding the mechanism of sweetness has been a challenging problem. It is necessary to understand this in order to design safer sweet molecules, for in many diseases (like diabetes,