Minggu, 03 Juli 2016

The Human Sweet Tooth and Its Relationship to Obesity

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1. INTRODUCTION

The term “sweet tooth” has been used widely in both popular culture and in the scientific
literature. But what is meant by the term sweet tooth and how do we measure it? When
we say that a person has a sweet tooth, we may be thinking of a person who usually
prefers to eat a sweet food or beverage rather than one that is savory or salty. Or we
might assume that the sweeter a food or beverage is, the more someone with a sweet
tooth will prefer it. Because to like sweet foods is seen as a prerequisite to eating too
much, the study of the human sweet tooth has usually been undertaken with the goal of
understanding how the perception of or preference for sweet foods contributes to
overeating and obesity. But the underlying assumptions of this hypothesis—that
increased perception of and preference and desire for sugar leads to increased intake of
sweet food and drinks—is rarely directly tested.
This review is divided into two sections. In the first section, we assess the ways in
which human behavior toward sweets is measured, and the factors that influence it. In the
second section, we examine the relationship between the preference for sweet foods, their
intake, and the effect on obesity.

2. SWEET TOOTH: MEASUREMENT AND INFLUENCES
2.1. Sensation, Behavior, or Desire?
Sweet is one of the five primary taste qualities, and there are several measures of human
perception of sweetness. The lowest concentration at which someone can detect sugar or
recognize its sweet quality can be measured. The terms for these measures are detection
and recognition thresholds; the detection threshold usually occurs at lower concentrations
than recognition because subjects can tell that there is something in a solution before they
can identify its quality (1). A second measure of sweetness is how intense abovethreshold
concentrations of sweetness are perceived to be. For instance, some people may
find the sweetness of a commercially available carbonated beverage to be “very strong”
but another person might find it to be “weak”. This concept is referred to as perceived
intensity. The next measure is “liking”—defined as the degree to which the person
perceives it as acceptable and desirable when presented with a single stimulus. This
measure is sometimes also referred to as “acceptability” Sometimes people have a choice
among stimuli and choose the one that is the most acceptable or desirable. These types of
measures are referred to as “preference”. When the degree of the desire to eat a sweet
food or drink is measured, this is referred to as craving. A final and important measure of
human behavior toward sweetness is the amount of sugar someone eats when offered a
choice of foods or drinks, either in the laboratory or in their daily lives.
There is no agreement within the experimental literature upon a definition of sweet
tooth. Sometimes it is assessed using measures of liking or preference (2–9), sometimes
by measures of food intake or food selection, and sometimes by measures of the
motivation to eat sweet foods (10, 11). Most laboratory measures designed to assess
sweet tooth use preference measures rather than measures of food intake or desire and
motivation. Food intake and food selection outside of the laboratory are hard to measure
accurately because of the disinclination of subjects to correctly report the food they eat.
Therefore, proxy indices of sugar intake—such as the number of dental caries or the
amount of oral bacteria per subject—are sometimes substituted as measures to
circumvent report bias (12). Also, asking specific questions about sugar usage, for
instance on cereal or in coffee, may elicit accurate responses regarding sugar intake and
preference (4, 13).
Perhaps one reason that preference is most often measured in human studies is because
these methods detect reliable individual differences among subjects (14). Preference
measures are also desirable because people can be classified into categories. For instance,
some investigators have identified two different response patterns to sucrose solutions, a
type I response whereby subjects increase in the liking for sucrose up to a middle range
of concentration, followed by a breakpoint after which preference decreases with
increasing concentration. This pattern is referred to as an inverted-U shape. The type II
response is characterized by increased liking as the concentration increases, but levels off
(15). Other investigators have reported similar patterns among subjects (5).
Although laboratory measures of sweet preference are commonly used, they may not
predict the preference for other sweeteners (16) or the preference for sweet foods or
beverages. Investigators have tried to bridge the gap between preference measures for
laboratory stimuli and preference measures for real-world foods and drinks by using
The human sweet tooth and its relationship to obesity 45
mixtures of sugar and milk (17, 18) or by adding sugar to simple beverages or foods (9).
Finally, some investigators have compared sweet preference measures inside the
laboratory to self-reported behaviors outside of the laboratory (8, 13).
Human behavior toward sweet may be affected by the degree to which the subjects
can perceive the stimuli. There are individual differences in the detection or recognition
thresholds for sweetness (19, 20), and although rare, there are people who do not perceive
a sweet taste from sucrose (21). Therefore, when measuring preference for sucrose at low
concentrations, it is important to consider that some people will not be able to perceive
the stimulus as well as other people. Thus far in human studies, sweet detection threshold
does not predict either how intense higher concentrations are perceived or how much they
are liked (22–25). Although in mice there is a relationship between peripheral sensitivity
and intake of sweeteners (26), this relationship in humans is unclear, and more focused
study is needed.

2.2. Stable and Variable Aspects of Sweet Taste Perception
Individual differences in the response to sweet are present at birth, with some infants
responding more positively than others to the taste of sucrose (27), and these individual
differences persist as children become young adults (14). However, the same people
measured on two occasions, weeks or months apart, have similar but not identical sweet
preference, suggesting that sweet preference changes over the short term (3, 7, 28).
There are effects of race and sex on sweet preference. Americans of African descent
prefer higher concentrations and Pima Indians prefer lower concentrations of sugar
compared with those of European ancestry (7, 13, 29–33). However, race differences in
sweet preference may be specific to types of foods. For instance,Taiwanese students rate
sucrose solutions as more pleasant but sweetened cookies as less pleasant compared with
students of European descent (34). Studies of sex differences suggest that male and
female infants do not differ in sweet preference (29) but that older boys and men prefer
higher concentrations of sweets compared with women (7, 11, 31, 35, 36). Although men
prefer high concentrations of sweet in their food and drink, studies of food craving in
men show they experience less desire to eat sweet foods compared with women (37, 38).
Sex differences in food craving may be population-specific, however, since women in
Egypt did not show elevations in sweet food craving compared with men (38). Week-toweek
variations in sex hormone concentrations in women predict changes in sucrose
threshold (39) but with equivocal effects on sucrose preference (40, 41), and it is not
clear to what extent sex hormones account for sex differences in human behavior toward
sweet.
In addition to race and sex, age is also a reliable predictor of sweet preference.
Children prefer more highly sweetened solutions compared with adults (31, 35, 42) but
see (36). Children may also have lower detection thresholds (23) and lower perceived
intensity at high-sucrose concentrations (43) compared with adults, but not all studies
agree (35, 36, 44). Younger people also eat more sugar than do older people (45). Dietary
experience alters sweet preference in children; for instance, children fed sweet water like
it more than children not fed sweet water (29). Children are less afraid of sugar than other
nutrients and even neophobic children will accept sweets (46). Sweet craving changes
Genomics and proteomics in nutrition 46
over the life span, and older women report less craving for sweet food compared with
younger women (47).
An immediate but short-lived reduction in the preference for sweet-tasting solutions
can be produced by ingesting a sweet solution (48). The reduction of sugar preference
immediately after the ingestion of sweet solutions may extrapolate to situations outside
the laboratory, such as after a meal. This effect, when measured in the laboratory, is more
pronounced in people who are chronic dieters (49, 50), is not observed in obese subjects
(51), and is influenced by the menstrual cycle (52, 53).

2.3. Genes and Genetics
Because family and twin studies have shown modest heritability for sweet intake, sweet
perception or preference may be partially due to genetic variation (54). Most studies of
sweet preference use sugar or carbohydrate intake as a measure of preference and as
measures of food intake collected through diaries. Family and twin studies using other
measures of sweet perception and preference are needed to assess more specifically the
degree to which these phenotypes are heritable. In considering how and where genetic
differences may influence the human behavior toward sweetness, we now discuss recent
advances in our understanding of sweet taste biology.
The initial events in the perception of sweet taste occur in taste receptor cells in the
tongue, which are found clustered in taste buds in taste papillae. The perception of
sweetness intensity is related to the number of papillae (55). The number of taste papillae
and taste buds varies widely in humans, and these differences among people may be due
to alleles in genes that develop and maintain sensory cells. For at least one genetic
disorder (familial dysautonomia), mutations in a single gene (IKBKAP) (56, 57) are
associated with few or no taste papillae and taste buds (58). It is possible that less
harmful alleles of this gene may influence the density of taste buds in otherwise healthy
people.
Inside the taste papillae, taste receptor cells produce proteins that participate in sweet
taste transduction, and some of these proteins are inserted into the cell membrane to form
taste receptors. Two proteins twist together to create a sweet receptor (Fig. 1) (59, 60).
The names of these proteins are T1R2 and T1R3, for taste receptor family 1, proteins 2
and 3, and the names of the associated genes for these proteins are Tas1r2 and Tas1r3. If
T1R3 pairs with the first member of this family,T1R1, the receptor is sensitive to umami,
the taste quality of monosodium glutamate and an important flavor principle of Asian
cooking.
These sweet and umami receptor genes were discovered through mapping experiments
in mice. Inbred mouse strains differ in their intake of saccharin, and the results of
breeding experiments suggested that an allele of a single gene was partially responsible
for these differences (61). Through positional cloning approaches, this gene was identified and found to be the gene Tas1r3 (60, 62–66). An important advance in our understanding of the behavior of animals toward sweetness was the observation that small changes in the DNA sequence of the
mouse Tas1r3 gene lead to large differences in the consumption of sweetener (67). This
reduction of sweetener preference by mice with certain Tas1r3 alleles is probably due to
their reduced ability to perceive the intensity of the sweeteners. Recordings of their
peripheral taste nerves suggest that mice with the low-preference Tas1r3 alleles exhibit
lower nerve firing in response to saccharin (26). Furthermore, when the Tas1r3 gene is
eliminated by genetic engineering in mice, the peripheral nerve firing is reduced in
response to sweeteners (68).

FIGURE 1 Representation of a human taste bud and taste receptors cells. T1R2 and T1R3 co-localize (and probably dimerize) to create a receptor for sweet stimuli. The receptors are embedded in the apical membrane of the taste receptor cell and stimulate G proteins to initiate a transduction signal inside the cell. Genetic variation in theTas1r3 gene (which codes for T1R3 protein) accounts for differences in sweet intake of mice.

he pairing of T1R2 and T1R3 does not constitute the only receptor for all sweeteners,
however. When the Tas1r3 gene is knocked out in mice, their ability to detect glucose
and maltose is unaffected compared with mice with a normal Tas1r3 gene (68).
Furthermore, the ability to detect other sugars and high-intensity sweeteners is reduced in
Tas1r3 knockout mice, but not absent.Therefore, other receptors or mechanisms exist that
signal sweetness in mice, for instance, the remaining partner (T1R2) could act as a taste
receptor by itself (69).
If DNA sequence variants have a large effect on the intake of saccharin and other
sweeteners in mice, then this may also be true in humans. There is a human counterpart to
each of the mouse sweet receptor genes (TAS1R1, TAS1R2, and TAS1R3*) (70). Because
the peripheral neural responses of humans to sugars predict their verbal reports about the
taste of sugars (71), peripheral differences in taste sensitivity may be an important
component of the human behavior toward sweetness. There is more variation than
appreciated in human perception of sweeteners, and one investigator has even suggested
that there is a “different receptor site for each subject” (72) or, in other words, each
person may perceive sugars slightly differently. Although the differences in the ability to
perceive sweet stimuli has been thought to be of little consequence in human sweet intake
and preference, the relationship in mice may stimulate further study of this topic.
Sweet preference may be influenced by genetic variants in the sensory system in
humans as it is in mice. However, the appreciation of sweet and the pleasure that it brings
to some people may be due to differences in the degree to which they have learned about
its rewarding properties. The genes and genetics involved in the perception of the
pleasure associated with sugar are not known, but several observations provide clues
about which mechanisms may be involved. Sweet preference is increased in opioid
addicts compared with healthy subjects (73), and the opioid antagonist naloxone reduces
the pleasantness of sucrose (74). Studies suggest that the rewarding aspects of alcohol
and sweeteners may also share brain pathways, because alcoholic subjects and their
family members may prefer sweeter solutions compared with nonalcoholic subjects (6,
75). Therefore, the investigation of genes that participate in the shared brain pathways
responsible for the pleasurable effects of drugs and sweeteners is warranted.

3. OBESITY AND SWEET TOOTH
People assume that because increases in sugar consumption in the human diet are
associated with a proportional rise in obesity, eating sugar and foods that are sweet is the
cause. More specifically, people often hypothesize that if someone has a sweet tooth, it
will cause the person to eat sweet food in excess of his or her caloric needs and
consequently gain weight. In other words, the sweet tooth is the cause and obesity is the
effect. However, an alternative hypothesis is that obesity, per se, may change sweet
preference
* The protein name for each of the three receptors has the same name in mice and humans (T1R1,
T1R2, and T1R3). However, the gene names in the mice (Taslr1, Taslr2, and Taslr3) are lowercase
and italic whereas the human gene symbols are in uppercase and italic: TAS1R1, TAS1R2, TAS1R3.
The human sweet tooth and its relationship to obesity 49
and that metabolism and taste may participate in a feedback loop. Pathways that could
influence sweet preferences and contribute to these loops are shown in Fig. 2.
3.1. Do Obese People Have Different Behavior Toward Sweet Food
than Lean People?
Most studies have compared lean and obese subjects for the preference or liking of sweet
stimuli, usually sucrose solutions, or have compared lean and obese subjects for their
intake of sweet foods in the laboratory. These studies have produced mixed results: In
some studies, lean people prefer sweet food or drinks more than do obese people (76–80),
and in one study the reverse was observed (36). However, the most common observation
is that there is no difference in sweet preference between lean and obese people (2, 31,
81– 87). Outside of the laboratory, when food intake is measured in situations where
people choose their own meals, most studies demonstrate that lean subjects eat more of
their calories as sugar compared with obese subjects (88).
Based upon these data, it would appear that there is little evidence that obese people
prefer sweets or eat more sweet food and drink compared with lean people. However,
there are three points that are important to consider before drawing this conclusion. First,
because subjects can and do restrain their intake of foods, especially sweets, when they
are dieting or trying to avoid gaining weight, food intake outside the laboratory may not
correspond with sweet preference (i.e., subjects may choose to not eat their most
preferred foods.) Second, food intake as reported by subjects can be biased, and when
proxy measures of sweet intake such as oral bacteria associated with sucrose
consumption are measured, obese women have higher indices of sweet consumption
compared with lean women (89). Third, none of these studies measures people before
they become obese and therefore does not directly test the hypothesis that a subject’s
behavior toward sweet food and drink is a factor in the development of obesity.
Once someone becomes obese, the preference for sweet may change because of a shift
in the homeostatic mechanisms and feedback loops that regulate hunger and satiety (Fig.
2). To try to understand the behavior of the obese subject in the absence of obesity,
investigators have studied formerly obese people who have reduced their weight and are
no longer obese. These subjects demonstrate a heightened preference for sugar when it is
mixed with high concentrations of fat (18). In another study, diabetic patients measured
during weight loss preferred lower concentrations of sweetness compared to the
preferences before weight loss (90). It is unclear what effect weight loss alone has on
sweet preference, and whether changes in preference after weight loss reflect the
preferences subjects had prior to
becoming obese. Lean people, who restrict their food intake, however, such as ballerinas
and patients with anorexia nervosa, vary in their sweet preference (91–93). There is no
consistent change in sweet preference when people restrict their food intake, regardless of
their starting weight.

3.2. Metabolic Effects of Sugar
For diets with the same caloric content, the macronutrient composition affects the balance
of nutrients stored or burned for energy.When excess calories are eaten as sugar, then
insulin secretion and other endocrine changes convert the excess calories to glycogen and
the body may also increase its overall metabolism temporarily to burn the excess calories.
This process of glycogen storage and increased carbohydrate oxidation avoids the
comparatively costly conversion of carbohydrate to stored lipids. Excess dietary fat,
however, is stored as triglyceride in adipose tissue and is less readily oxidized compared
with glycogen (94).
Extrapolating from this observation, humans who consume calories from sugar should
be leaner than those who consume an equivalent number of calories from dietary fat (88).
In fact, in a rodent study, substituting sucrose for other macronutrients led to a higher rate
The human sweet tooth and its relationship to obesity 51
of metabolism, a lower overall caloric intake, and less body fat compared with a
comparable diet without sugar (95). Consistent with this hypothesis, human patients who
ate a higher proportion of their calories as sugar lost more weight after gastric surgery
compared with those who ate less sugar (96). However, when subjects are asked to add
sugared drinks to their diet, they gain weight (97). In other words, when liquid sugar is
added to the diet, there is poor caloric compensation and subjects gain weight, but when
sugar is added as a solid food (jelly beans), then subjects appear to compensate for the
added calories and do not gain weight (98). The metabolic consequences of eating sugar
would encourage leanness rather than obesity if sugar is replacing calories from other
sources, but not if sugar is added to an already adequate diet. The composition of the
calories (liquid or solid) from sugar might be important in determining whether subjects
will reduce their calories from other sources.

3.3. The Pleasure of Sweet
Sugar is a fuel that provides calories, but it is also a pleasure that is rewarding in the
absence of any other benefit. The pleasure of sweetness soothes crying infants (99–104).
The effects of sugar are partially due to its taste because, although oral sucrose reduces
pain in babies, sugar placed directly into the stomach does not (105). Sugar is soothing to
adults as well as babies. Investigators examined the intake of sweet foods in women and
noted a higher intake of sweets both during the menstrual cycle and in those with more
incidences of psychiatric problems (12). Sweets may alleviate depression and
premenstrual symptoms, and provide relief from the cravings for other drugs because
sweet taste releases opiates into the blood, at least in rodents (106). Human babies
exposed to the distress of cocaine withdrawal suck sweet pacifiers more than do babies
without prior cocaine exposure (107). In addition to the release of opiates, the ability of
sugar to bring pleasure is caused by changes in the neural circuits in specific brain areas
(108, 109). People may differ in their ability to perceive pleasure from sucrose because of
individual differences in these neural circuits. People who derive a greater than average
pleasure from sucrose and who have a greater than average amount of distress may gain
weight if they eat sugar to soothe themselves and do not reduce calories from other
sources.

3.4. Insulin and Leptin
Sweetness in food and drink provides a signal of the number of calories available in the
form of readily digested sugar. Therefore we might expect that sweet taste sensitivity
would change in the face of the metabolic need for glucose. This has proved to be the
case. When metabolic changes occur that reduce glucose availability, such as increases in
plasma insulin concentration, then sweet preference increases (110–112). A similar
response is seen in diabetic animals with high levels of plasma glucose but limited ability
to utilize it because of insulin resistance. This effect, however, may only occur during
dire metabolic states, because moderate levels of hunger (and the concomitant metabolic
consequences of normal food deprivation) do not influence the preference for sweet
solutions (113).

Genomics and proteomics in nutrition 52
In addition to hormones such as insulin that regulate immediate glucose availability,
other hormones regulate long-term energy stores. Investigators have proposed that the
body has a regulatory mechanism that maintains weight at or near a set point, and that
obesity ensues either because people have a high set point or because the set point is
overridden by increased caloric consumption (114, 115). A fall below set point increases
appetite and may increase the preference for energy-dense foods such as sweets and fats
(116, 117). One hormone proposed to provide this signal of long-term energy stores is
leptin. Leptin is secreted by adipose tissue and acts as a signal to the brain to indicate
high or low energy reserves. Receptors for leptin are located in the brain as well as in
other peripheral tissues (118).
Mice with mutations of the leptin receptor have a higher behavioral and neural
response to sugars compared with littermates without mutations, which suggests that
leptin might suppress the peripheral sweet taste system (119). Evidence in support of this
hypothesis comes from the observation that leptin receptors are present on taste receptor
cells in mice, and the administration of exogenous leptin acts directly to suppress the
neuronal activation to sweet—but not salty, sour, or bitter—stimuli (120). Obese mice
that lack a functional leptin receptor (db/db) do not reduce their consumption of sweet
solutions after leptin administration, but their lean littermates, which have normal leptin
receptors, do reduce their consumption (121).
Although exogenous administration of leptin reduces the neural response to sweet in
mice with a functioning leptin receptor, insulin resistance, inability to utilize plasma
glucose, and leptin resistance induced by prolonged obesity or diabetes may override the
normal ability of leptin to reduce the cellular response to sweet taste (122). In obese and
diabetic animals, the increase in plasma leptin concentration does not appear to have an
effect on the neural response to sweet.
To extrapolate from these studies in rodents to human behavior should be approached
cautiously. The only study performed on humans to date found that the plasma leptin
concentration of obese women was not correlated with sucrose preference (123).
However, as demonstrated earlier, in humans, indices of the perceived intensity of a
sucrose concentration do not necessarily correspond to how much that sweet
concentration will be liked. Thus, future studies in humans may examine how the
perceived intensity of a sucrose solution correlates with plasma leptin concentration, and
if leptin is shown to have a direct effect on human taste receptor cell function, then
manipulation of plasma leptin concentrations and the measure of sucrose perception
would be a logical next step for human studies.

3.5. Digestion
Some people are born with an impaired ability to digest specific sugars, such as lactose or
fructose. As a consequence of their inability to digest the sugar, they often do not wish to
eat it and find it repugnant (124, 125). Similarly, there may be cases in which sugar is
more easily digested than other nutrients and therefore is more desired. One such
example of this situation is the high sugar intake of patients with Crohn’s disease (126).
One hypothesis is that sweet preferences and aversions may be learned responses that
depend upon the punishing or rewarding properties of sugar ingestion. In healthy people,
the ability to digest sugars varies from person to person, and this normal variation may
The human sweet tooth and its relationship to obesity 53
affect sweet preference through learning. Differences in the degree of digestive tolerance
for sugars are correlated with geography and genotype. For instance, there are
geographical differences in the ability to digest lactose that reflect the degree of dairy
farming in a region. Therefore, differences in the efficacy of digestive enzymes by
geography and traditional diet may partially account for racial differences in the
preference for sugar (127). Studies designed to assay differences in the digestion of sugar
and its impact on the human sweet tooth in otherwise healthy subjects might prove
useful.

4. CONCLUSIONS
Understanding human behavior toward sweetness and its influence on body weight
requires further study. Longitudinal studies of people before they become obese are
needed to assess the effects of sweet preference on body weight. Experimental results in
mice have taught us two things: Sweet tooth is partially explained by differences in the
DNA sequence of taste receptor genes, and the hormone leptin has a direct effect on taste
receptor cells. Changes in sweet preference may be part of the homeostatic mechanism
that regulates body weight in humans and is worthy of further study.

Author: Amanda H.McDaniel and Danielle R.Reed
Monell Chemical Senses Center, Philadelphia, Pennsylvania, U.S.A.

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