The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Nutrition in Medicine
Dan L. Longo, M.D., Editor

Physiological Integration of Taste

and Metabolism
Josephine M. Egan, M.D.​​

“Y
ou don’t know what you’re missing till it’s gone” is a truism From the Diabetes Section, Laboratory of
that certainly applies to taste. It took a pandemic for taste to get attention. Clinical Investigation, National Institute
on Aging, National Institutes of Health,
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections Baltimore. Dr. Egan can be contacted at
can cause acute loss or distortions of taste as a result of infection within taste buds1 ­eganj@​­grc​.­nia​.­nih​.­gov or at the National
and, in some cases, can result in long-term taste dysfunction.2,3 Since chemosensory Institutes of Health, National Institute
on Aging, Biomedical Research Center,
disorders can substantially dampen a person’s enjoyment of life, this is an opportune 251 Bayview Blvd., Ste. 100, Baltimore,
time to appreciate recent advances in our understanding of taste. It is time to let go of MD 21224.
old ideas, such as the myth of the tongue taste map (which persists in the collective N Engl J Med 2024;390:1699-710.
consciousness despite decades of research debunking it) and the notion of taste as DOI: 10.1056/NEJMra2304578
limited to the mouth. Research reveals that downstream signaling of extraoral taste Copyright © 2024 Massachusetts Medical Society.

receptors regulates our physiological balance long after conscious gustation has faded.
In this review, I highlight two important areas of progress. First, I provide an up-
date on taste physiology and biochemistry, the receptors mediating prototypical taste
perception, and taste neurotransmission. Second, I examine taste in the context of
recent press and research reports on the health consequences of added sugars and
nonnutritive sweeteners. This area of research offers delectable “food for thought,”
highlighting the role of extraoral taste receptors and their putative involvement in
food intake, metabolism, and obesity.

Ta s te R ecep t or s a nd Ta s te T r a nsduc t ion Mech a nisms

Taste perception begins when nonvolatile chemicals in food, called tastants, are
placed in the mouth and activate taste receptor cells (TRCs), which recognize all
five primary taste sensory qualities: sweet, umami (savory), bitter, salty, and sour.
There is also evidence for the taste of “fat.”4 Taste is described in affective ways as
being pleasant (appetitive) or aversive (revulsive). TRCs are present in taste buds
buried in taste papillae, which are fleshy protuberances on the tongue (Fig. 1).
Once activated, TRCs send tastant information that the brain integrates with smell
and trigeminal-nerve transduction (registering texture, temperature, and pain) to
craft a complex perception of whatever we consume.
TRCs are morphologically classified into types I, II, and III, which can be subclas-
sified on the basis of differences in TRC function, molecular markers, or both (Fig. 1).
We also acknowledge a fourth cell, type IV, at the base and sides of taste buds.5 Al-
though there was once a belief that taste-sensing cells responsive to each of the basic
taste qualities were concentrated in separate areas, this is not accurate. TRCs sensitive
to each tastant are present in taste buds across the tongue, meaning that there
is no taste map representing regions of the tongue corresponding to specific tastes.5
In taste buds, glial-type type I TRCs support the structure of the buds. On the
plasma membranes of these cells, the enzyme NTPDase2 degrades intragemmal
ATP secreted by type II cells in response to tastants. Type II TRCs detect sweet,

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A
TASTE BUD
Circumvallate papillae (CVP)
Type I cell
Type II cell
Type III cell

Foliate papillae (FLP)

TONGUE

Fungiform papillae (FFP)

Intragemmal
nerve fiber
Type IV cell

B
TYPE II CELL TYPE I CELL TYPE II CELL TYPE III CELL
Sweet/umami/bitter Salt appetitive Sour

Adenosine OTOP1
ENaC
T1R or AMP H+
T2R Na+
ADP

ATP 5-HT
NTPDase2

Mitochondrion

Mitochondrion
ATP
ATP

CALHM1/3
CALHM1/3
P2X2/3 5-HTR
P2X2/3

Intragemmal nerve fiber

umami, and bitter tastants through subfamilies
of G protein–coupled receptors (GPCRs): the
TAS1R (TAS1R1, TAS1R2, and TAS1R3) and
TAS2R classes. These taste receptors initiate in-
tracellular signal transduction by stimulating the
heterotrimeric G protein α-gustducin. The result-
ing cascade follows a common downstream path-
way, involving phospholipase Cβ2, inositol tri-
phosphate (IP3) production, which causes Ca2+
release from the endoplasmic reticulum, followed
by Ca2+-dependent activation of transient receptor
potential melastatin 5 (TRPM5) channels and cul-

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 Physiological Integr ation of Taste and Metabolism
Figure 1 (facing page). Anatomy and Physiology of the
Tongue and Taste Buds.
There are three types of papillae (Panel A): fungiform
(FFP), foliate (FLP), and circumvallate (CVP). CVP, up
to 11 in number, are the largest and are easily visual-
ized on the back of the tongue. FLP are parallel folds on
the sides of the tongue. FFP, several hundred in num-
ber and just visible to the naked eye, are scattered on
the anterior tongue, interspersed with a fourth papilla
type, filiform, that do not contain taste buds; they help
cleanse the mouth, move food around, and serve mech-
anosensory functions by responding to touch, pain, and
temperature. Each taste bud has a pore surrounded
by a bushy network of villi of the taste receptor cells
(TRCs). Humans may have up to 4500 taste buds, but
the number varies greatly, and 50 to 60% of them are
in CVP. Each taste bud, regardless of location, contains
about 60 TRCs (morphologic types I, II, and III) and
precursor cells (type IV). Types I, II, and III can be sub-
classified on the basis of differences in TRC function,
molecular markers, or both (Panel B). Type I TRCs, which
wrap around the other TRCs, contain NTPDase2 on
their plasma membrane, which degrades ATP released
from type II TRCs. The G protein–coupled receptors,
necessary for sweet taste (TAS1R3 and TAS1R2), umami
taste (TAS1R3 and TAS1R1), and bitter taste (TAS2Rs)
are present on type II TRCs. In response to their re-
spective tastants, they release ATP as their signaling
molecule through CALHM1/3 channels onto purinergic
receptors on intragemmal nerve fibers throughout taste
buds. Sodium ions, responsible for a pleasant salty
taste, enter through epithelial sodium channels (ENaCs)
on TRCs, and also use ATP as their signaling molecule.
Type III TRCs, the only TRC type with classical neuronal
synapses, contain a proton channel (OTOP1) that detects
sour or acidic tastants leading to neurotransmitter re-
lease, such as 5-hydroxytryptamine (5-HT).
minating in cell depolarization and ATP release
through specialized channels (CALHM1/3).6 ATP is
a bona fide TRC neurotransmitter that activates
purinergic receptors on nerve fibers, which then
transduce tastant information to the brain.
The sweet and umami type II TRCs express
TAS1R3, a coreceptor that forms heterodimers
with TAS1R2 and TAS1R1 to detect sweet and
umami, respectively. In some situations, TAS1R3
itself is a low-affinity sweet receptor,7 and TAS1R3
homodimers, especially in nontaste tissue, can
function as cell-surface glucose sensors.8 Recently,
researchers discovered that the Cl− ion, found in
table salt (sodium chloride [NaCl] concentration,
<30 mM), is also a ligand for TAS1R3 and evokes
appetitive preferences, adding to the notion that
TAS1R3 transmits pleasant tastes corresponding
to that which is necessary for life (i.e., energy
and salt).9
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Concentrations of NaCl between 30 and 150 mM
rely on the epithelial sodium channel (ENaC) in
a subset of TRCs for salty, appetitive transmis-
sion. In mice, this channel is blocked by amiloride.
ENaCs allow Na+ influx, followed by cell depolar-
ization, action potential generation, and ATP re-
lease through CALHM1/3 channels onto afferent
fibers.10 This process has not been confirmed in
humans, and humans actually seem appetitive-
salty-taste insensitive to amiloride.11 A possible
explanation is that human ENaCs are structurally
dissimilar or that appetitive salty taste in humans
is mediated by a subpopulation of TRCs that is
completely different from the subpopulation in
mice. Very high NaCl concentrations, which are
aversive to both humans and mice, may activate
responses in bitter type II TRCs, as well as type
III cells12 and perhaps also free nerve endings of
the trigeminal nerve. Bitter type II TRCs express
multiple TAS2Rs, and at least 25 TAS2R genes are
known to be expressed in humans.13 These recep-
tors are capable of discerning thousands of bit-
ter tastants, since some receptors are narrowly
tuned to one or a few tastants, whereas others are
broadly tuned to many bitter tastants.13
Type III TRCs have dense synaptic vesicles
containing classic neurotransmitters such as
5-hydroxytryptamine (5-HT), which they release in
response to acid stimulation. These are the only
TRCs that form classical synapses with nearby
nerve fibers. They are also unique in containing the
proton channel OTOP1, which is necessary for
perceiving sour taste (acid sensing, such as citrus
fruits) and ammonium chloride (breakdown prod-
ucts of amino acids and decaying meats).14 For most
species, sour taste is aversive, but humans enjoy
sour taste triggered by acidic foods, up to a certain
concentration that seems to be individually deter-
mined, with higher concentrations becoming aver-
sive, probably because they induce pain.15 Possible
reasons for this affinity to sour taste are that acids
may inhibit harmful microbial growth, signal the
presence of amino acids (which might also trigger
umami perception), or indicate that a food may
have been fermented and may be psychoactive (e.g.,
alcohol). Also, sour taste may have evolutionarily
guided humans toward sources of vitamin C.15
Type III TRCs also respond to carbon dioxide
by means of the enzyme carbonic anhydrase 4,
which integrates with other somatosensory inputs
that are necessary for the taste of carbonation.16
In addition, optogenetic research (i.e., research
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 The n e w e ng l a n d j o u r na l of m e dic i n e

Sensory cortex
(postcentral gyrus)

Gustatory cortex

Ventral
posteromedial
nucleus

Principal nucleus

Trigeminal nerve
(CN V)
Trigeminal ganglion

Ophthalmic nerve
(CN V1)

Maxillary nerve
(CN V2)
Mandibular nerve
(CN V3) Nucleus of the
tractus solitarius
Geniculate ganglion

Petrosal ganglion
Chorda tympani
Nodose ganglion

Facial nerve
(CN VII)
Glossopharyngeal
nerve (CN IX)
Superior laryngeal
nerve (CN X)
Vagus nerve
(CN X)

in which light is used experimentally to influ-
ence cell behavior) in mice suggests that these
cells are involved in recognizing the taste of
water.17 Further research into type III tastant
detection and subsequent signal integration in
the brain should help clarify how we distinguish
among water, sour, and ammonium stimuli. Fi-
nally, a subset of type III TRCs in mice has been
described as responsive to a wide range of taste
stimuli, such as sweet, bitter, and umami.18
At the base and sides of taste buds are type IV
cells, which are precursors for the other three
TRC types. Although mature TRCs differentiate
throughout life, mouse organoid culture studies
suggest that this process changes over time.19
Investigators are working to fully characterize
TRC precursors in humans, a project that is rele-
vant to an understanding of long-term taste loss
and dysfunction as a result, for example, of SARS-
CoV-2 infections.2,5 Despite interest in human taste

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 Physiological Integr ation of Taste and Metabolism
Figure 2 (facing page). Transmission of Taste Information.
Fibers innervating the taste buds transmit signals to
the gustatory region of the nucleus of the tractus soli-
tarius (NTS), then to the thalamus and the gustatory
cortex (pathway depicted in red). Each taste bud is in-
nervated by primary intragemmal gustatory fibers,
which extensively branch and connect with multiple
taste buds, interacting with many TRCs. This results in
electrical activity that reflects the input from numer-
ous TRCs. Taste buds in the fungiform papillae are in-
nervated by sensory neurons of the geniculate gangli-
on, traveling through the chorda tympani branch of the
facial nerve (cranial nerve [CN] VII). Taste buds in the
posterior third of the tongue are innervated by sensory
neurons of the petrosal ganglion, traveling through the
lingual branch of the glossopharyngeal nerve (CN IX).
Isolated taste buds in the palate are innervated by the
greater superficial petrosal branch of CN VII, whereas
those on the epiglottis and esophagus receive innerva-
tion from the superior laryngeal branch of the vagus
nerve (CN X). Sensory fibers from CNs VII, IX, and X
enter the medulla, synapsing on a slender column of
cells within the gustatory region situated in the rostral
and lateral part of the NTS. From there, neurons proj-
ect to the ventral posteromedial nucleus of the thala-
mus. Next, neurons project to the anterior insula and
frontal operculum in the cerebral cortex, which facili-
tates the conscious perception and discrimination of
tastes. Taste sensations often include somatosensory
aspects like texture, temperature, and responses to
spicy and minty foods. This component is transmitted
by the branches of the trigeminal nerve (CN V), origi-
nating in the trigeminal ganglion. From there, informa-
tion goes to the principal nucleus in the caudal pons,
which also projects to the ventral posteromedial nucleus
of the thalamus, and finally to the somatosensory cortex
in the brain’s parietal lobe (pathway depicted in blue).
buds, studies in humans encounter methodologic
constraints. Although mouse studies primarily
use circumvallate papillae because they contain
half the taste buds, most human data come from
fungiform papillae, since it is the only papilla
type proven to regrow and is easily biopsied in
living subjects. There is large variation in the
density of fungiform papillae and the number of
taste buds between persons, and these decrease
as people age, a phenomenon reported in longitu-
dinal20 and cross-sectional21 studies.
Since TRCs undergo rapid turnover, maintaining
neurosensory integrity (i.e., sweet taste receptors
signaling to “sweet” neurons) is essential (Fig. 2).
The labeled-line model of taste transmission con-
nects taste reception and signal integration in the
brain. Using chemogenetic manipulation in ro-
dents to activate intracellular signaling that is
independent of cell surface receptors, researchers
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found that sweet TRCs induce appetitive behav-
iors, whereas bitter and sour TRCs induce aversive
behaviors.22 Since downstream signaling is the
same for sweet, umami, and bitter, a labeled-line
type of transmission to the insula can be inferred,
whereby dedicated nerve fibers and neurons de-
code the three tastants, as well as NaCl. Proof
of this comes from two-photon calcium imaging,
which has shown spatial segregation in the gus-
tatory cortex, with neurons that responded to
each tastant.23
Such strict specificity is hotly debated, how-
ever, and other evidence favors combinatorial
coding, in which taste information is transmitted
through neuronal circuits that have patterns of
impulse firings. (For an in-depth discussion, see
Roper.24) A parsimonious explanation is as fol-
lows. At low concentrations of a single stimulus,
a labeled line of taste transduction is operational
and is exquisitely elegant in separating appetitive
from aversive stimuli (life or death, to be or not
be, to swallow or not to swallow — immediate
decision requirements). But complex food re-
quires a cross-fiber pattern with nerve fibers that
are more broadly responsive and that perhaps
respond maximally only to particular food con-
tents, allowing for comparison of activity across
the whole fiber repertoire so that the brain can
extract information related to total food quality.
Adding to the orchestration of taste percep-
tion are the hormones produced in TRCs that
modulate TRC signaling. Hormones produced by
enteroendocrine cells of the gut (cholecystokinin,
glucagon-like peptide 1 [GLP-1], ghrelin, pep-
tide YY, and vasoactive intestinal peptide) and
islets of Langerhans (glucagon and insulin), as
well as by some central nervous system neurons
(neuropeptide Y and vasoactive intestinal pep-
tide), are also synthesized in TRCs.25 More work
is needed to uncover all their functions in taste
buds, but so far we know that receptors for some
of those hormones, such as GLP-1, are present
on the intragemmal nerve fibers in taste buds
where GLP-1 receptor (GLP-1R) activation in mice
modulates sweet perception (Fig. 3).26
We are also now aware of the presence of tastant
signal transduction machinery in nontaste tissue,
including enteroendocrine cells (Fig. 4). Researchers
have discovered diverse roles for extraoral taste re-
ceptors, such as regulating male fertility27 and pro-
tecting tissue in the pulmonary vasculature.28 The
gut has emerged as a site for exploring the involve-
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 The n e w e ng l a n d j o u r na l of m e dic i n e

ment of taste receptors and their downstream sig- but our innate aversion to such tastants can be
naling pathways in appetite, nutrition, and disease. overcome by acquired preference and masking
with sweet tastants. Mutations in the TAS2R
genes and other genotypes that increase bitter
Rol e of Ta s te in Fo od In ta k e ,
Me ta bol ism, a nd Obe si t y taste thresholds are associated with increased
consumption of bitter beverages, such as alcohol
Obesity and obesity-related noncommunicable and coffee, a behavior that probably also reflects
diseases are at epidemic levels, with one projection a learned liking of their physiological effects.34
forecasting that by 2030, nearly 1 in 2 adults in the Since taste functions to guide what we should
United States will be obese.29 Although there are not ingest as much as what we should, altera-
many contributing factors,30 those relevant to this tions in taste perception can change our dietary
review concern the ways in which the contempo- patterns.35 Our diet also shapes our taste. West-
rary food environment, with its cornucopia of ap- ern diets rich in fat and carbohydrates change
petitive offerings, encourages overeating by stimu- the proteomic landscape of the tongue,36 and
lating our deeply ingrained reward systems. Taste, obese, diabetic mice and their offspring have an
by guiding us toward gastronomic delights (i.e., increased preference for sweet stimuli.37
tasty, energy-containing food) and away from Current observations suggest that obesity is re-
dangerous toxins, functions as an evolutionary lated to disruptions in the neural pathways that
gatekeeper for the substances that enter our body. encourage reward-related eating and suppress ho-
Sweet preference is innate, developed well before meostatic feedback that curbs hunger, although we
birth, and consuming sweet tastants triggers sat- have yet to fully elucidate the precise physiological
isfaction through central reward pathways.31 Stud- mechanisms.38 However, a direct connection be-
ies in humans have shown both immediate and tween obesity and taste perception in humans is
delayed dopamine signaling in response to palat- not proven. Overweight is associated with a pro-
able food, which suggests that reward pathways clivity for energy-dense, ultraprocessed foods39 and
respond to oral sensation and postingestive pro- for sweet tastants and fats. Researchers have pro-
cessing in the gut.32 There is even some evidence posed impaired lipid perception as a reason for
suggesting that sugar can be addictive in the lipid overconsumption in some obese people.40
same way that nicotine is.33 There is also evidence of different taste percep-
On the flip side of sweet and umami, bitter tion in obesity-prone populations,41 with reports
and sour tastes detect potentially toxic substances, that increased weight is associated with decreased

A B GLP-1 C Neuropeptide Y (NPY)

10 µm 50 µm

Figure 3. Immunohistochemical Features and Examples of Hormones in Human FFP.

Two typical-appearing taste buds are present in an FFP (Panel A, hematoxylin and eosin), and GLP-1 and neuropeptide Y (NPY) are pres-
ent in type II TRCs in taste buds (Panels B and C, respectively, immunofluorescence staining). In mice, GLP-1 maintains or enhances
sweet perception through GLP-1 receptors on the intragemmal nerve fibers, and NPY enhances sweet and bitter perception through Y1
receptors. In FFP from humans, there are approximately 60 TRCs in each bud, at least 50% of which are type II. However, as shown in
these examples, the size of the cells varies greatly between persons and even varies among individual taste buds.

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 Physiological Integr ation of Taste and Metabolism
papilla density42 and higher sweetness thresh-
olds.43 Other studies have shown no association
between perceived taste intensity and obesity.44
These variations in study findings are likely to
reflect, at least in part, differences in the meth-
odologies and scales used to characterize taste
intensity and perception, neurophysiological di-
versity among study participants, and population-
level confounding factors. Studies examining
molecular signaling and gene expression have the
potential to provide more clarity. A study in mice
suggested that obesity-related proinflammatory
cascades were responsible for diminished taste
bud abundance and renewal in obese mice,45 and
genomic work in humans has identified increased
inflammatory and decreased taste-associated gene
expression in obese persons.46 Many other factors
can also influence taste perception, including
age,47,48 medications, and disease.1,49
On a broader level, taste transduction machin-
ery affects health through its impact on the
body’s hormone response to food. GLP-1, classi-
cally characterized as an incretin hormone that
enhances glucose-mediated insulin secretion, is
secreted by enteroendocrine cells that are present
from the duodenum to the early colon. (The sec-
ond known incretin is glucose-dependent insuli-
notropic polypeptide [GIP].) Secretion of GLP-1 is
regulated by TAS1Rs; sodium–glucose cotrans-
porter 1 (SGLT1); fatty acids through GPCR40,
GPCR119, and GPCR120; bile acid receptors; en-
dogenous cannabinoids; and microbial products.
GLP-1 inhibits gastric emptying, causing gastric
distention through ileal neurons that connect by
means of celiac ganglia to gastric neurons and
ultimately contribute to food rejection.50 In ad-
dition, long-acting GLP-1R agonists affect re-
ward behavior and food desirability, possibly
decreasing food intake, at least in part by reduc-
ing palatability.51 GLP-1Rs, as stated above, are
present on intragemmal nerve fibers, where
their activation in mice diminishes the percep-
tion of sweetness.26 These findings may help
explain, in addition to gastric and CNS effects,
some other nonpancreatic actions of GLP-1R
agonists, three of which (liraglutide, semaglu-
tide, and tirzepatide) are approved by the Food
and Drug Administration for use in weight man-
agement. Liraglutide and semaglutide have been
found to promote weight loss possibly by damp-
ening a preference for appetitive tastes, such as
sweet and umami.52,53
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Me ta bol ic C onsequence s of
Nonnu t r i t i v e S w ee tener s
As studies implicated added sugars in the rising
incidence of cardiovascular disease,54 diabetes,55
and obesity,56 public health messaging began
recommending restrictions on sugar intake,57,58
and food manufacturers sought sugar substitutes
(Table 1). Despite the subsequent proliferation of
nonnutritive sweeteners,59 however, obesity and
metabolic dysfunction continued their stubborn
upward trajectory. There is ongoing discussion
about whether nonnutritive sweeteners are them-
selves contributing to the rising obesity levels and
related coexisting conditions, but any link be-
tween these sweeteners and long-term morbidity
lacks consensus. In 2023, the World Health Orga-
nization released new guidelines discouraging
the use of nonnutritive sweeteners to lose weight
and reduce the risk of noncommunicable diseas-
es, a recommendation based on a large system-
atic review.60 In brief, the literature suggests that
there may be short-term weight loss associated
with the initiation of nonnutritive sweetener con-
sumption as a result of lower calorie intake, but
more work is needed to understand the possible
consequences of long-term consumption.61 Some
studies have shown an elevated risk of major car-
diovascular events and disease,62 whereas others
have shown no such effect.63 Nonnutritive sweet-
eners may dampen T-cell–mediated immune re-
sponses,64 and their long-term use is implicated
in an increased incidence of type 2 diabetes.55
Long-term, observational studies in humans sug-
gest a link between nonnutritive sweeteners and
obesity,65,66 and although such studies must often
contend with the possibility of reverse causality,
current observations highlight the need for a
better understanding of possible mechanisms.
One proposed mechanism for how consump-
tion of nonnutritive sweeteners induces meta-
bolic dysfunction is an uncoupling of sweet taste
from caloric value. The seminal studies on this
mechanism showed that mice that had been
conditioned to associate sweetness with calories
gained less weight and consumed less food than
mice that could not rely on sweet taste to predict
caloric value.66,67 Researchers proposed that these
results showed how nonnutritive sweeteners alter
Pavlovian associations between sweet taste and
calories, leading to disrupted metabolic regula-
tion and changing eating behavior.67 The first
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 The n e w e ng l a n d j o u r na l of m e dic i n e

TAS1R (sweet/umami) TAS2R (bitter)

Brain Brain

Chemosensory cells Chemosensory cells

Nose, sinuses

Vagus nerve
Thyroid

Trachea

Adipose tissue

Bronchi

Heart Heart

Stomach Stomach

Pancreas

Bile ducts

Kidney Kidney

Small intestine Small intestine

Colon Colon

Bladder

Testis Testis

steps in proving the biologic plausibility of “un-
coupling” would be to uncover the different path-
ways for sensing energy content as compared with
taste qualities and then to determine whether
natural sugars and nonnutritive sweeteners have
differential effects on these pathways.
Recent work has drawn a distinction between
two glucose-sensing pathways: the traditional TAS1R
sweet tasting pathway and the pathway involving
SGLTs, which transport glucose but not nonnutri-
tive sweeteners.68 Studies exploring differential
brain responses in mice have identified distinct

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 Physiological Integr ation of Taste and Metabolism
Figure 4 (facing page). Extraoral Taste Receptors.
TAS1Rs are present not just on the tongue but through-
out the body in tissues such as the gut, brain, pancreas,
bladder, bone, adipose tissue, airway epithelium, skele-
tal muscle, and testes. There are also extraoral TAS2Rs
in the larynx, gut, and brain and on immune cells, as
well as throughout the respiratory and genitourinary
systems. TAS2Rs, along with TAS1R3 and α-gustducin,
are also present in testes. Animals in which TAS2Rs are
used to avoid noxious foods also appear to have highly
efficient spermatogenesis and, as a consequence, may
produce more offspring. OTOP1, the proton channel in
type III TRCs, was first identified in the vestibular sys-
tem, where it is necessary for the formation of calcium
carbonate–based otoconia and otoliths. It is also ex-
pressed in brown adipose cells.
Table 1. Common Sugars, Sweeteners, and Amino Acids
and Proteins Known to Taste Sweet to Humans.
Sugars
Glucose
Fructose
Maltose
Sucrose
Galactose
Nonnutritive and low-calorie sweeteners
Aspartame
Acesulfame potassium (Ace-K)
Sucralose
Neotame
Advantame
Saccharin
Cyclamate
Alitame
Certain steviol glycosides
Mogrosides: extracts from Siraitia grosvenorii (monk fruit,
also known as Swingle fruit or luo han guo)
Sweet-tasting amino acids and proteins
D-phenylalanine
D-serine
D-tryptophan
Monellin
Brazzein
Thaumatin
neural pathways for sweet sensing as compared
with energy sensing69 and have shown how pro-
longed activation of reward pathways in the
brain leads to compulsive sucrose consumption.70
Even in flies, a high-fat, high-sugar diet impairs
central processing of sweet taste, weakening satia-
tion and encouraging overeating.71 Neuroimaging
is helping to corroborate these findings in hu-
mans, and indeed some studies suggest that hu-
mans process sugar differently from nonnutritive
sweeteners. For example, one functional magnetic
n engl j med 390;18
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No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
resonance imaging study showed that as compared
with glucose, sucralose initiated a weakened sati-
ety response in the hypothalamus, as well as a
prolonged hedonic response in the ventral tegmen-
tal area, which plays a key role in the mesolimbic
pathway that drives reward-seeking behavior.72
Although these results support the need to draw
a distinction between the neural effects of sugars
and the neural effects of nonnutritive sweeteners,
most studies have not investigated the possibility of
combined effects. Recent studies examining both
gastrointestinal and neurologic responses to sweet
taste complicate a strict uncoupling model. One
elegant human study showed that pairing sucralose
with carbohydrate intake impaired the central re-
ward response to sugar and induced insulin insen-
sitivity after only 2 weeks.73 These effects were not
observed in the groups consuming carbohydrates
or sucralose independently, and there was no
change in perceptual sensitivity to taste. These re-
sults contradict the theory that nonnutritive sweet-
eners lead to metabolic dysfunction because of the
lack of calories or disturbance of the conditioned
oral sweet sensation response. The authors instead
theorize that the combination of carbohydrate and
sucralose overactivated glucose transport through
binding of both carbohydrate-derived glucose and
sucralose to gut sweet taste receptors. The results
of this study do not contradict the findings in
the uncoupling experiments in animals, although
they elucidate a different mechanism.
More studies of this kind offer a promising
path for understanding the effects of nonnutritive
sweeteners on human physiology. However, many
studies use more than one nonnutritive sweetener,
and it can be hard to compare results across dif-
ferent sweeteners because of variations in such
factors as sweetener intensity and binding affini-
ties and mechanisms. These problems, combined
with the inherent difficulties in performing long-
term human studies, make blanket conclusions
and establishment of causation difficult. Further
work that compares habitual users of nonnutritive
sweeteners with nonhabitual users and investi-
gates the effects of nonnutritive sweeteners paired
with caloric sources will help clarify the neuro-
physiological effects of sweeteners in the context
of typical food consumption patterns. These in-
vestigations will not only strengthen causal and
mechanistic links but will also supply crucial evi-
dence to better inform dietary recommendations
and introduce new therapeutic paths.
nejm.org May 9, 2024 1707
 The n e w e ng l a n d j o u r na l of m e dic i n e

Ta s te , the Vagus, a nd the
En teroend o cr ine S ys tem
Despite the competing mechanistic theories, the
evidence thus far supports the notion that nonnu-
tritive sweeteners and natural sugars elicit distinct
homeostatic and hedonic responses in the body.
Therefore, it is more accurate to call nonnutritive
sweeteners simulacra of sugars, not sugar substi-
tutes. TRC machinery in extraoral tissues, espe-
cially the gut, and physiological mechanisms of
tastant binding have been “sweet” avenues for
exploring the unique effects of sugars as com-
pared with nonnutritive sweeteners. The latter
have been linked to gut epithelial-cell death and
increased gut-wall permeability74 and to altera-
tions in the composition of the gastrointestinal
microbiota (affecting pathways such as those in-
volved in purine metabolism, glycolysis, and fatty
acid synthesis),75 which have potential down-
stream consequences for hormone secretion,
metabolic homeostasis, and obesity. More directly,
rodent studies suggest that activation of the
sweet taste receptors in the gut by sugars and
nonnutritive sweeteners is linked to hormonal
up-regulation and increased SGLT1 expression,76
glucose transporter 2 (GLUT2) induction,77 and
glucose absorption. There may be long-term con-
sequences, as suggested by a recent study in mice
that showed a dose–response effect of increased
glucose absorption in the gut after long-term ex-
posure to sucralose.78 However, these effects and
the role of sweet taste receptors are debated,79 as
is the existence of such a mechanism in humans,
with decades of work providing evidence both for
and against an effect of nonnutritive sweeteners
on incretin release.80
More large-scale clinical studies are necessary
to start resolving these seeming inconsistencies,
which reflect differences in study design and
study populations. Current research is beginning
to address these challenges, which will require
grappling with metabolic diversity among various
population groups (e.g., persons without obesity
vs. persons with obesity and persons who habitu-
ally use nonnutritive sweeteners vs. persons who
do not), the many different types and dose-depen-
dent effects of nonnutritive sweeteners, and the
effect of such sweeteners under typical consump-
tion patterns (with the recognition, for example,
that nonnutritive sweeteners are rarely consumed The physiology of taste provides insight into our
in isolation and that humans are exposed to these relationship with food and our metabolic well-
sweeteners not only in food and drink but also in
products such as toothpaste).
Advances in optogenetic work are enhancing
our understanding of how integrated gut–brain
signaling of taste sensation helps drive behavior
and metabolic outcomes. A spate of work suggests
that long-term energy homeostasis requires signal
integration from nutrient-sensing receptors in the
gut.81-83 In blinded testing, humans and mice prefer
nutritive sugars over noncaloric sweeteners, and
when scientists genetically manipulate mice to be
unable to taste sweetness in their taste buds, the
mice still develop a preference for sugar over non-
nutritive sweeteners. This preference is modulated
by a population of neurons that are activated by the
gut–brain axis to respond to sugar but not to non-
nutritive sweeteners.81 Some enteroendocrine cells
have long, basal extensions, called neuropods,
which synapse with vagal afferent fibers to directly
convey sugar-sensing information to the brain
within milliseconds.81,82 Vagal afferent signals enter
the medulla, and from there the information travels
in a network of many overlapping circuits that are
involved in eating signaling in the hypothalamus.
This homeostatic effect leads to changes in con-
sumption by altering how the brain learns the
value of sugar and controls behavior through
dopaminergic reward circuits in the basal ganglia.
Sugars and nonnutritive sweeteners stimulate
different neurotransmitter responses from cells
containing cholecystokinin and cells containing
GLP-1. Nonnutritive sweeteners stimulate puri-
nergic neurotransmission only through TAS1Rs
(exactly as they stimulate neurotransmission in
TRCs in taste buds), whereas glucose, which also
activates TAS1Rs, has an additional pathway,
dependent on downstream signaling from SGLT1,
that stimulates glutamatergic neurotransmission
from the neuropods.83 The preference for nutritive
sugars over nonnutritive sweeteners is dependent
on the glutamatergic signaling pathway, probably
because it stimulates vagal afferents that function
as appetitive or reward neurons.84 Moreover, the
role of enteroendocrine cells in food preference
conditioning and gastrointestinal control of re-
ward circuits is, in part, how the gut itself influ-
ences food intake.
C onclusions

1708 n engl j med 390;18 nejm.org May 9, 2024

The New England Journal of Medicine

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No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 Physiological Integr ation of Taste and Metabolism

being. Research has long dispelled the taste map
myth and is now venturing into new territory,
providing a complex understanding of how tas-
tants activate hedonic and homeostatic pathways
and a recognition of the gut’s involvement in food
intake. This knowledge may, in turn, inform up-
dates to dietary guidelines and clinical practice
guidelines for what constitutes an ideal diet.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
I thank all the staff of the Diabetes Section, Laboratory of Clini-
cal Investigation, National Institute on Aging, for their input; Dr.
Qin Yao for the original images of human fungiform papillae; Tom
Wynn and Lauren Brick of the visual media core of the Intramural
Research Program, National Institute on Aging, and Dr. Caio Ma-
zucanti, also of the Intramural Research Program, National Insti-
tute on Aging for initial drafts of the figures; and Adeline Choo
for assistance in preparing an earlier version of the manuscript.

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