Recent advances in thermoregulation

Abstract

Thermoregulation is the maintenance of a relatively constant core body temperature. Humans normally maintain a body temperature at 37°C, and maintenance of this relatively high temperature is critical to human survival. This concept is so important that control of thermoregulation is often the principal example cited when teaching physiological homeostasis. A basic understanding of the processes underpinning temperature regulation is necessary for all undergraduate students studying biology and biology-related disciplines, and a thorough understanding is necessary for those students in clinical training. Our aim in this review is to broadly present the thermoregulatory process taking into account current advances in this area. First, we summarize the basic concepts of thermoregulation and subsequently assess the physiological responses to heat and cold stress, including vasodilation and vasoconstriction, sweating, nonshivering thermogenesis, piloerection, shivering, and altered behavior. Current research is presented concerning the body's detection of thermal challenge, peripheral and central thermoregulatory control mechanisms, including brown adipose tissue in adult humans and temperature transduction by the relatively recently discovered transient receptor potential channels. Finally, we present an updated understanding of the neuroanatomic circuitry supporting thermoregulation.
Copyright © 2015 The American Physiological Society.

Full text

Staying Current
Recent advances in thermoregulation
Etain A. Tansey and Christopher D. Johnson
Centre for Biomedical Sciences Education, Queen’s University, Belfast, Northern Ireland
Submitted 19 September 2014; accepted in final form 17 June 2015
Tansey EA, Johnson CD. Recent advances in thermoregulation. Adv
Physiol Educ 39: 139 –148, 2015; doi:10.1152/advan.00126.2014.—Ther-
moregulation is the maintenance of a relatively constant core body
temperature. Humans normally maintain a body temperature at 37°C,
and maintenance of this relatively high temperature is critical to
human survival. This concept is so important that control of thermo-
regulation is often the principal example cited when teaching physi-
ological homeostasis. A basic understanding of the processes under-
pinning temperature regulation is necessary for all undergraduate
students studying biology and biology-related disciplines, and a thor-
ough understanding is necessary for those students in clinical training.
Our aim in this review is to broadly present the thermoregulatory
process taking into account current advances in this area. First, we
summarize the basic concepts of thermoregulation and subsequently
assess the physiological responses to heat and cold stress, including
vasodilation and vasoconstriction, sweating, nonshivering thermogen-
esis, piloerection, shivering, and altered behavior. Current research is
presented concerning the body’s detection of thermal challenge,
peripheral and central thermoregulatory control mechanisms, includ-
ing brown adipose tissue in adult humans and temperature transduc-
tion by the relatively recently discovered transient receptor potential
channels. Finally, we present an updated understanding of the neuro-
anatomic circuitry supporting thermoregulation.
transient receptor potential channel; preoptic area of the hypothala-
mus; set point; brown adipose tissue; thermoregulation; heat; cold
AN UNDERSTANDING of body temperature regulation is necessary
to learn the basic concept of homeostasis and for a wide variety
of physiological and clinical applications. It is covered in most
elementary physiology courses, but often with a degree of
superficiality and dogma, due to time and content constraints.
As research in this area has progressed over the last few
decades, major advances in our understanding have been made,
particularly in the central circuitry involved in thermoregula-
tory control and in the peripheral sensory mechanisms of
temperature transduction. These advances have not necessarily
filtered through to general textbooks that form the cornerstone
of many medical-related and basic science courses (see Ref.
26). In the present article, we describe the processes of ther-
moregulation, taking these recent advances into account so that
those involved in teaching thermoregulation provide a more
up-to-date representation.
Normal core body temperature is around 37°C and con-
trolled within a narrow range (33.2–38.2°C) and narrowing
further when disregarding oral measurements in favor of rectal,
tympanic, or axillary measurements (68). There are normal
fluctuations that occur throughout the day (circadian rhythm),
throughout a month (menstrual cycle), and throughout a life-
time (aging). Abnormal core temperature deviations of even a
couple of degrees will challenge the body’s thermoregulatory
mechanisms, and swings in temperature outside the normal
range can prove fatal. For example, beyond a body temperature
of 42°C, cytotoxicity occurs with protein denaturation and
impaired DNA synthesis (38), resulting in end-organ failure
and neuronal impairment. If body temperature drops below
27°C (severe hypothermia), the associated neuromuscular, car-
diovascular, hematological, and respiratory changes can
equally prove fatal (40). Despite the need for tight regulation of
core temperature, humans can survive in the most inhospitable
of places and can challenge their thermoregulatory capacity in
the most extreme ways. Humans participate in the Marathon
Des Sables (a 251-km endurance running challenge in the
Sahara desert, a place where day time temperatures can reach
50°C) and ice diving, where water temperatures may only be a
few degrees above freezing. How is it possible that they can do
this and survive?
To ensure optimal physiological function and survival, hu-
mans must be able to preserve core body temperature (within
the head, thorax, and abdomen) in the face of environmental
temperature challenges. Thus, heat gain to the body must equal
heat loss.
As humans are endothermic homeotherms, we produce our
own body heat and can regulate our body temperature. Our
high core temperature is achieved principally through heat
production as a result of metabolism. Heat transfer always
occurs down a thermal gradient (from hot to cold) through the
processes of radiation, conduction, and/or convection. As hu-
mans are often the hottest objects in a given environment, the
normal direction of heat transfer is from the body to the
surroundings. However, as core temperature rises, heat loss
through evaporation becomes the primary mechanism of heat
dissipation.
The following heat balance equation addresses the internal
and external factors that contribute to thermal balance and,
therefore, the maintenance of core temperature:
Heat storage ⫽metabolism ⫺work ⫺evaporation
⫾radiation ⫾conduction ⫾convection
where
•Metabolism refers to the chemical reactions occurring within
the body that produce heat. During exercise, the working
muscle liberates large amounts of heat.
•Work is the external work done.
•Evaporation is the heat loss to environment as water vapor-
ized from the respiratory passages and skin surface. Total
sweat vaporized from skin depends on the following three
factors:
1. The surface area exposed to the environment
2. The temperature and relative humidity of ambient air
3. Convective air currents around the body
Address for reprint requests and other correspondence: C. D. Johnson,
Centre for Biomedical Sciences Education School of Medicine, Dentistry and
Biomedical Science Queen’s Univ., Whitla Medical Bldg., 97 Lisburn Road,
Belfast BT9 7AE, Northern Ireland (e-mail: c.johnson@qub.ac.uk).
Adv Physiol Educ 39: 139–148, 2015;
doi:10.1152/advan.00126.2014.
1391043-4046/15 Copyright © 2015 The American Physiological Society

•Radiation is the electromagnetic radiation (heat) transferred
to bodies not in contact, including the ultraviolet light
radiation from the sun, which penetrates through to the
surface of the earth, and the infrared radiation from the body.
•Conduction is the movement of heat to/from the body
directly to objects in contact with the body. Usually the
amount of heat exchanged in this way is minimal.
•Convection is the transfer of heat to a moving gas or liquid.
When a body is warm, the air molecules that make contact
with the body will be warmed, reducing their density, which
causes the molecules to rise and be replaced with cooler air.
Convective heat exchange is increased by movement of the
body in air or water or movement of air or water across the
skin.
When the heat storage is zero, the body is thermally balanced.
In humans, normal thermoregulation involves a dynamic bal-
ance between heat production/gain and heat loss, thereby
minimalizing any heat exchange with the environment. Thus, a
constant core temperature is maintained.
Temperature Regulation
When discussing body temperature, we usually refer to the
central core and peripheral shell temperatures. The core tem-
perature reflects the temperature within the “deep” body tis-
sues, organs that have a high level of basal metabolism (such
as the brain, heart, and liver). The shell temperature is influ-
enced by blood flow to the skin, which is raised with a high
core temperature, and environmental temperature. It is usually
measured at the skin of hands and feet. The surface area-to-
mass ratio of these sites is high (for example, the surface
area-to-mass ratio of each hand is four to five times greater
than that of the body) (72), and it is known that the surface-
area-to-mass ratio is important to the transfer of thermal
energy. With a high surface-area-to-mass ratio, the hand will
chill faster than the torso, which has a lower surface area-to-
mass ratio. Notwithstanding this, the shell temperature is an
important indicator of the heat exchange requirements of the
body. Shell temperature is usually around 4°C lower than core
temperature. In a warm environment, the difference in temper-
ature between the core and shell decreases as skin blood flow
is increased and skin temperature approaches ambient temper-
ature (see Skin blood vessels below). As humans, we are
generally warmer than the ambient temperature, and so the
general flow of heat is from the shell to the environment.
During cold stress, skin blood flow is reduced, leading to a
decrease in shell temperature and conservation of heat to the
core. Temperature gradients between the core and skin can be
a useful nonspecific monitor of thermal status. For example,
there is an increased gradient between core and peripheral
temperature in shock states, and the gradient is useful in
distinguishing between cardiovascular or respiratory causes of
dyspnea (16).
The hypothalamus is the coordinating or central integration
center for thermoregulation. Evidence suggests that it is the
preoptic anterior hypothamalus that is the most important
region for autonomic temperature control (57). The input to the
hypothalamus comes from peripheral as well as central ther-
moreceptors. Recent experimental work from a number of
laboratories has provided neural substrates for thermoregula-
tory control and is discussed in more detail below. Both
peripheral and central thermoreceptors have two subtypes:
those responding to cold and those responding to warmth.
Peripheral thermoreceptors are located in the skin, where cold
receptors are more abundant than warm receptors. Warm
central thermoreceptors, located in the hypothalamus, spinal
cord, viscera, and great veins, are more numerous than cold
thermoreceptors. The impact of central thermoreceptor activa-
tion is most significant in terms of core temperature, and it
seems that the activation of warm thermoreceptors causes
inhibition of cold receptors (28). Table 1 shows physiological
and behavioral responses to the activation of these thermal
receptors.
Effector Organ Responses to an Increase in Body
Temperature
Skin blood vessels. The skin plays a substantive role in the
thermoregulatory process. In response to increased or de-
creased ambient or internal temperatures, skin blood flow is
modified accordingly through sympathetic vasodilation and
vasoconstriction mechanisms, respectively. Heat is dissipated
from the body when blood is brought in close proximity to the
skin’s surface. This is achieved through vasodilation of skin
blood vessels.
Table 1. Physiological and behavioral responses to the activation of thermoreceptors
Body Temperature
Stimulus Sensors Control Center Effectors Responses
Increase Peripheral and central
thermoreceptors
Hypothalamus 1. Skin blood vessels 1. Arteriolar and arteriovenous anastomosis vasodilation
2. Sweat glands 2. Sweating
3. Endocrine tissue 3. Decreased metabolic rate (adrenal and thyroid
glands)
4. Behavior 4. Reduced activity, stretched body position, and loss of
appetite
Decrease Peripheral and central
thermoreceptors
Hypothalamus 1. Skin blood vessels 1. Arteriolar and arteriovenous anastomosis
vasoconstriction
2. Arrector pili muscles 2. Piloerection and air trapping
3. Skeletal muscles 3. Shivering thermogenesis
4. Endocrine tissue 4. Increased metabolic rate (adrenal and thyroid glands
and brown adipose tissue)
5. Behavior 5. Increased activity, huddled body position, and
increased appetite
6. Brown adipose tissue 6. Nonshivering thermogenesis
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The mechanisms of thermal control for the cutaneous circu-
lation have been thoroughly reviewed recently (29 –31). The
autonomic nervous system plays a major role in the control of
blood flow to the skin (15). Hair-bearing skin (nonglabrous
skin) is innervated by both noradrenergic vasoconstrictor and
cholinergic vasodilator nerves, whereas nonhair-bearing skin
(glaborous skin), present on the palms, soles, and lips, is
innervated solely by vasoconstrictor nerve fibers.
In normothermia, there is a baseline level of vasoconstrictive
tone. In glaborous skin, the principal response to heat is to
increase cutaneous blood flow through passive vasodilation of
blood vessels through sympathetic nervous activity withdrawal
(25, 32). The presence of numerous arteriovenous anastomoses
in glaborous skin can lead to large changes in blood flow to
these regions, for example, in heat, arteriovenous anastomoses
open and blood flows directly from artery to vein, bypassing
high-resistance arterioles and capillary loops (Fig. 1).
In nonglarborous skin, if the convective heat loss resulting
from relaxation of vasoconstrictor tone is insufficient to cool
the core, then a further increase in skin blood flow can occur by
active vasodilatation (31), thus increasing convective heat loss
further. This active vasodilation is, at least in part, in response
to the release of acetylcholine and other cotransmitters from
sympathetic cholinergic nerves and can increase cutaneous
blood flow from 300 ml/min up to or exceeding 8 l/min (31).
Various hypotheses that have been proposed with regard to the
mechanisms involved in cutaneous active vasodilation. Very
little is known for certain about the control processes; however,
the following have been proposed (31):
1. Acetylcholine is the most important chemical for initial-
ising active vasodilator responses to body heating, but cotrans-
mitter(s) appear to be principally responsible for the overall
response. Candidates include vasoactive intestinal peptide,
substance P, histamine, prostaglandins, and transient receptor
potential (TRP)V1 receptor activation.
2. The cholinergic nerves that govern sweating may be the
same as those that control active vasodilation. This hypothesis
originates from the fact that active vasodilation and sweating
seem to occur concurrently.
3. There seems to be a role for nitric oxide in active
vasodilation as the response is attenuated by nitric oxide
synthase inhibition.
Sweat glands. Sweat production and the subsequent evapo-
ration are the principal modes of heat loss in humans when
ambient temperature rises as well as during exercise. In fact,
evaporative cooling is the only mechanism of heat loss once
ambient temperature exceeds body temperature. Exposure to a
hot environment, or exercise, elevates core and skin tempera-
tures, both of which contribute to the increased sweat rate. The
threshold for sweating normally exceeds the threshold for
vasoconstriction by ⬃0.2°C. However, it is known that sweat-
ing begins within seconds of the onset of exercise (74), before
any measureable changes in internal temperature. This is
thought to be mediated by a combination of inputs from central
command and the exercise pressor reflex (61).
Sweat is released by eccrine glands, which are distributed in
large numbers (1.6 – 4 million) over the entire surface of the
body, with regional distributions in density. Sweating is me-
diated by the activation of sympathetic cholinergic fibers (62).
Evaporation of sweat allows heat to be transferred to the
environment as water vapor from respiratory passages and the
skin surface. The major limiting factor in a human’s ability to
maintain body temperature in the face of a thermal challenge is
the availability of water for sweat production. High volumes of
sweat can be produced if a person becomes heat acclimatized,
2–3 l/h (2), compared with 1 l/h in nonacclimatized individuals
(3). Heat acclimatization enhances the sweating mechanism
and has previously been associated with a redistribution of
sweat secretion toward the limbs (28). This could potentially
be desirable as limbs have a relatively large surface area-to-
mass ratio. An elevation in sweating and evaporation at these
sites could therefore enhance thermal homeostasis. However,
more recent evidence suggests that a redistribution of sweating
from the trunk to the limbs does not occur (55, 71).
With heat acclimatization, there is a lower body temperature
threshold for sweating, and sweat gland sensitivity and capac-
ity improves, so for a given core temperature, the sweat rate
increases (8, 17, 37, 56, 58). An increased sweat rate alters the
composition of sweat and is particularly associated with de-
pletion of plasma Na
⫹
and Cl
⫺
concentrations. However,
acclimatization has been shown to attenuate this reduction.
This is likely to be related to the increased renin and aldoste-
rone levels that have been found in acclimatized individuals
producing a lower sweat Na
⫹
concentration (49).
Behavioral adaptations. Physiological thermoregulatory
mechanisms have a finite capacity. Behavioral thermoregula-
tion does not; therefore, changes in human behavior can be
extremely effective in response to a change in body tempera-
ture. Behavioral thermoregulation means that we can con-
sciously and intentionally alter the heat exchange that takes
place with our environments. For example, we can seek shelter
from extreme heat by turning on the heating, grabbing a
sweater, staying in the shade, consume ice-cold drinks, etc. (for
a review, see Ref. 22).
Exercise in heat. Humans usually encounter thermal stress
through adverse weather conditions, but thermal stress can
result from the body’s overproduction of heat (e.g., during
exercise or fever). Exercise of itself will increase body tem-
Epidermis
Dermis
Capillary loop
Venous plexus
Vein
Arteriole Arteriovenous
anastomosis
Postganglionic sympathetic neuron
Oxygenated blood
Deoxygenated blood
Sympathetic varicosities
Precapillary sphincter
Fig. 1. Control of peripheral blood flow to glaborous skin. With permission
from (69). Note the presence of arteriovenous anastomoses, which have a rich
supply of sympathetic vasoconstrictive fibers. The arteriovenous anastomoses
connect arterioles directly to the venous plexus. Increased sympathetic tone in
response to a decrease in core temperature constricts arterioles and reduces
blood flow through arteriovenous anastomoses to almost nothing, thereby
reducing heat loss from the surface of the skin. In response to an increase in
body temperature, the withdrawal of sympathetic tone leads to passive dilation
of arterioles and arteriovenous anastomoses and enables heat loss by increasing
blood flow to the venous plexus. Precapillary sphincters are only sparsely
innervated by sympathetic nerves. At rest, there is a high degree of sympathetic
tone to the skin.
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perature. This may be, in part, due to an initial cutaneous
vasoconstriction, along with vasoconstriction in other nonac-
tive muscle vascular beds (splanchnic, renal, etc.), that results
in more of the cardiac output being available to active skeletal
muscle (6, 33). Thus, exercising in the heat represents a
particular challenge as heat loss is more difficult to maintain. It
is associated with early fatigue and decrements in exercise
capacity (23) and performance (70). If accompanied by a high
relative humidity, the situation is exacerbated. This is princi-
pally due to the fact that less sweat can be evaporated from the
skin’s surface in humid environments (the sweating response to
heat acclimatization is described above).
The development of fatigue during exercise in the heat is not
associated with a single factor but rather involves the interac-
tion of many physiologic processes (52). At high exercise
intensities or during prolonged exercise in the heat, heart rate
increases and stroke volume reduces in parallel with a rise in
core temperature. In addition, cutaneous blood flow plateaus at
a core temperature of ⬃38°C (24). Therefore, beyond this core
temperature, the ability of the athlete to dissipate heat is
reduced. A circulatory conflict is observed between the skin
and skeletal muscle, which contributes to fatigue. This situa-
tion is made all the worse if accompanied by substantial sweat
loss and dehydration.
Training or repeated bouts of exercise have been shown to
improve exercise performance (39) through various physiolog-
ical adaptations; the most important of these are changes that
facilitate increased peripheral blood flow while maintaining
arterial blood pressure. Endurance training and heat acclima-
tization have been shown to improve vasodilatory ability (5, 7).
There are alterations in energy metabolism when exercising
in the heat. Fatigue occurs earlier and is associated with
glycogen depletion (21), whereas carbohydrate supplementa-
tion has been shown to improve exercise capacity in the heat
(11). Exercise in the heat is associated with alterations in
central nervous system function and motor drive, leading to
central fatigue (27, 51). Training and heat acclimatization are
invaluable to athletes who exercise in warm environments.
Knodo and coworkers (35) have described five phenotypic
adaptations to heat: reduced heart rate at a fixed workload,
expanded plasma volume, lower core temperature at an equiv-
alent workload (thus increasing time to fatigue), superior salt
reabsorption from sweat, and an elevated sweat rate. All of
these adaptations contribute to increased exercise performance
in the heat.
Effector Organ Responses to a Decrease in Body
Temperature
Skin blood vessels. When vasoconstriction occurs as a re-
sponse to cold, then blood is shunted away from the skin
surface through the deeper veins. Heat is thus conserved, and
a widening of the gradient between core and peripheral tem-
perature is observed. In response to cold, sympathetic vaso-
constrictor nerves act primarily on ␣-noradrenergic receptors
to cause blood vessel smooth muscle contraction and vasocon-
striction. Other sympathetically released cotransmitters also
contribute to this vasoconstriction, such as ATP and neuropep-
tide Y (see Refs. 9 and 10), the latter of which has been shown
to contribute significantly to cutaneous vascular tone vasocon-
strictor responses to human body cooling (64, 66).
Brown adipose tissue. Brown adipose tissue (BAT) is spe-
cialized for the process of nonshivering thermogenesis, where
oxidative metabolism is uncoupled from ATP production and,
in the process, energy is expended. This tissue is thermogenic
by increasing the metabolic rate. BAT was, until recently,
thought to be only important in small mammals and neonates.
However, evidence for the activation of BAT in adult humans
in response to cold has recently emerged (48, 59, 76), and a
role for BAT in thermoregulation for adults as well as neonates
has become established (75). There is some debate as to
whether this tissue that behaves like BAT is actually true BAT
or is so-called “beige adipose tissue,” which can develop from
white fat cells in response to cold or ␤
3
-adrenergic agonists
(77, 80).
BAT’s potential metabolic role has been recognized to the
extent that it is considered as a potential site for drugs aimed at
altering energy expenditure (73). BAT could potentially be a
therapeutic site for the treatment of obesity. Sympathetic ner-
vous system activity, in response to inputs from peripheral and
central thermoreceptors, can stimulate BAT thermogenesis.
Catecholamines acting on ␤
3
-adrenergic receptors can activate
an uncoupling protein on the inner mitochondrial membrane.
This uncoupling protein, thermogenin, allows H
⫹
to cross the
mitochondrial membrane without ATP production. It is known
that sympathetic nervous system activity is increased in the
cold, and nonshivering thermogenesis increases likewise (34).
In addition, BAT thermogenesis can be modulated by a number
of nonthermal factors, including hypoxia, infection, hypogly-
cemia, and psychological stress (42).
Piloerection (goosebumps). The arrector pili muscle is a
small band of smooth muscle that connects the hair follicle to
the connective tissue of the basement membrane in nongla-
borous skin. It is innervated by the autonomic nervous system.
In response to increased sympathetic nerve discharge, the
arrector pili muscles at the base of tiny hairs in the skin
contract and cause the hairs to become upright, trapping air and
thus increasing the insulating layer of air around the body and
minimizing heat loss. This is known as piloerection. As the
muscle contracts, the epidermis buckles, creating “goose-
bumps.” Piloerection is a known reaction to cold and also
strong emotional stimuli. Piloerection is used as an index of
autonomic sympathetic activity and is thought to be mediated
by ␣
1
-adrenergic receptors (1). As humans possess relatively
little hair and are often clothed, heat conservation through
piloerection is usually regarded as insignificant and rudimen-
tary. However, piloerection may become more important in
conjunction with shivering, potentially enhancing the effec-
tiveness of the shivering response (54).
Shivering. When exposed to mild cold, humans will con-
serve heat through mechanisms such as vasoconstriction and
piloerection, which are energetically inexpensive, and by
changes in behavior. If these adjustments are insufficient to
maintain temperature, shivering occurs. The onset of shivering
has been used as an indicator that maximal vasoconstriction
has already been achieved (19). It is initiated by the hypotha-
lamic preoptic area but mediated by the somatic motor cortex
in response to signals from cold receptors in the skin in
particular; therefore, the normal stimulus for shivering is the
skin temperature rather than the core temperature. Shivering
threshold is normally described as the core temperature at
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which shivering is triggered. This is usually related to a given
skin temperature.
Shivering is involuntary, rapid, oscillating contractions of
skeletal muscle. ATP is hydrolyzed, but no work is done
through the contraction, and so the energy produced is released
as heat. In adults, shivering, at its peak, can elicit heat produc-
tion equivalent to five times the basal metabolic rate (20);
however, in neonates, there is a notable absence of shivering
due to the immaturity of their skeletal muscles, and nonshiv-
ering thermogenesis is the most important means by which heat
is generated (67).
Behavioral adaptions to cold. Behavioral thermoregulation
seems to be particularly important in situations where the body
is exposed to extreme cold, where vasoconstriction and
shivering have a limited effect. Recent research suggests
that behavioral control is influenced by many different areas
of the brain: the medulla oblongata, pons, midbrain, somato-
sensory cortex, amygdala, and thermoregulatory centers in
the hypothalamus as well as the prefrontal cortex (for a
review, see Ref. 22).
Transduction of Temperature
Major advances in the transduction processes in peripheral
thermal sensation have been made since the discovery of the
TRP family of ion channels in the last decade and a half. TRP
channels are a superfamily of proteins that can be expressed in
cell membranes and in membranes of internal structures (see
Ref. 81). Many are polymodal in their activation, all resulting
in cation influx. Nine are established as being sensitive to
temperature, and their roles have been extensively reviewed
(12, 60). The classic notion of activation of a thermoreceptive
neuron might describe a rather vague idea of receptor stimu-
lation resulting from a change in intracellular metabolic chem-
ical reactions in proportion to temperature (26). Yet this may
also describe specific subpopulations of temperature receptors
that discriminate cold noxious, cold, warm, and hot noxious
stimuli with overlap between the stimulatory temperatures (see
Fig. 2). Individual TRP channels have now been identified that
may subserve these specific temperature discrimination roles.
Each has a relatively narrow band of temperature activation,
yet overlapping of these sensitivities allows for a wide range of
temperature discrimination. TRPV1 and TRPV2 were among
the first to be identified with temperature sensitivity (13, 14).
They are activated by temperatures higher than 43 and 52°C,
respectively, and may mediate noxious hot sensation. TRPV4
and TRPV3 are activated by temperatures above 25 and 31°C,
likely mediating innocuous warm sensation (63, 78). TRPM8 is
increasingly activated as temperature drops below 27°C and
is likely to mediate innocuous cold sensation (36). TRPA1 is
activated at temperatures below 17°C and may contribute to
noxious cold sensation, although this role is more controver-
sial, as are the roles of TRPM2, TRPM4, and TRPM5 (12, 60).
The role of these TRP channels can now be effectively mapped
onto textbook figures produced before the knowledge of TRP
channels, describing discharge frequencies at different temper-
atures of neurons from these temperature receptors (see Fig. 2).
However, this must be viewed cautiously at present as few
studies have identified these channels as the transduction
mechanisms on primary thermosensitive afferents (46, 60, 65).
Nevertheless, for many (thousands of) years, we have been
aware of chemical agonist stimulation of these channels. We
may be familiar with the cooling sensation of menthol (a
TRPM8 agonist) as we chew our gum or the warming/burning
sensation we experience when eating food spiced with chili
(capcaisin, a TRPV1 agonist).
It is likely that TRP channels are involved in thermal
sensation. They may contribute by direct activation of sensory
fibers; for example, TRPM8 channels are expressed in primary
somatosensory neurons (4). They may also indirectly stimulate
primary sensory fibers; for example, TRPV3 and TRPV4
channels are expressed in abundance in skin keratinocytes,
which may secrete diffusible factors that stimulate sensory
fibers (81). The molecular mechanisms responsible for temper-
ature transduction in the brain, particularly the hypothalamus,
are largely unknown, although the involvement of TRP chan-
nels has not been found to date (see Ref. 47). With regard to
neurons in the preoptic hypothalamus (POA), it has been
proposed that spontaneous activity in their membranes repre-
sents pacemaker activity capable of generating spontaneous
action potentials, and their temperature sensitivity reflects the
temperature sensitivity of these membrane currents (79, 83). It
has been proposed that thermal sensation in the spinal cord
may reflect the activation of TRP channels in the central end of
sensory neurons located in the spinal dorsal horn (45). Tem-
perature transduction mechanisms for receptive neurons that
exist in the viscera (the abdominal blood vessels, esophagus,
and stomach, among other organs) are also less well elucidated.
However, animal studies have revealed that several TRP chan-
nels, similar to the skin afferent nerves, are expressed in
abdominal vagal afferent nerves (82).
Afferent Pathways
Cool and warm temperature information stimulates separate
populations of primary somatosensory afferents in the skin.
These enter the spinal (or trigeminal) dorsal horn to synapse
with second-order ascending neurons in the lamina 1. There are
subtypes of ascending spinothalamic fibers that relay temper-
ature information from the skin to the central nervous system,
and it is likely that fibers carrying information from innocuous
cool or warm receptors provide the majority of the thermoreg-
Freezing
cold
Indiffer-
ent
Burning
hot
Warm
receptors
Cold-receptors
Cold-pain Heat-pain
(TRPA1)
(TRPM8)
(TRPV4 & TRPV3)
(TRPV1 & TRPV2)
5 10 15 20 25 30 35 40 45 50 55 60
10
8
6
4
2
Temperature (°C)
Impulses per second
HotWarmCoolCold
Fig. 2. Discharge frequencies at different skin temperatures of thermorecep-
tors, along with potential transient receptor potential (TRP) channels associ-
ated with receptor function. [Reproduced with permission from Ref. 26.]
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ulatory information rather than those relaying noxious hot or
cold sensations (18).
More recent experiments by Morrison and Nakamura (43,
44) have incorporated labeling of neurons, to delineate projec-
tions, and electrophysiological recordings from the same neu-
rons to examine their responses to peripheral thermal stimula-
tion. They have provided much more detailed information
regarding central projections from the lateral parabrachial nu-
cleus (LPB) where these second-order neurons synapse. The
LPB receives spinal input from cold-sensitive neurons (exter-
nal lateral subnucleus of the LPB) and warm-sensitive neurons
(the dorsal subnucleus of the LBP). Third-order LPB neurons
arise from these regions, which then project to the median
preoptic nucleus (MnPO) of the POA (45, 47). Activation of
these pathways will initiate either heat gain or heat loss
mechanisms (45, 47). Other second-order neurons travel to the
thalamus and then to the cortex to allow conscious sensation of
temperature (Figs. 3 and 4).
Afferents arising in the viscera travel to the central nervous
system mainly in vagus and splanchnic nerves. The majority of
this sensory information, including temperature, converges at
the level of the nucleus tractus solitarius before passing to the
LPB, so the LPB may integrate both skin and visceral thermal
information (45, 47).
Central Control of Thermoregulatory Responses
Previously, temperature control was taught as involving
integration of central and peripheral thermal signals coor-
dinated in the POA and somehow involving a comparison of
this integrated signal with a “set-point” signal. If an error
between the input temperatures and the set point occurs,
then this would trigger appropriate heat gain or heat loss
mechanisms. Although part of this model was based on the
observation of thermal responses to heating and cooling of
the skin and discrete regions of the hypothalamus (26), evi-
dence of the central circuitry necessary for this model has been
+
+
+
+
+
Cool
skin
receptor
Median preoptic nucleus (MnPO) Medial preoptic area (MPO)
Preoptic area of the hypothalamus (POA)
Cerebral
cortex
Thalamus
Dorso-medial
hypothalamus
(DMH)
Rostral raphae
pallidus nuclei
(rRPa)
BAT
Skin
blood
vessel
Skeletal
muscle
++
Lateral
parabrachial
nucleus
(LBP)
Spinal cord
active or
excited neurone
inactive or
inhibited neurone
KEY
PGE2Arachidonic
acid
COX
NSAIDs
Fig. 3. Central circuitry mediating the re-
sponse to cold. POA, preoptic area of the
hypothalamus; MnPO, median preoptic nu-
cleus; MPO, medial preoptic area; DMH, dor-
somedial hypothalamus; rRPa, rostral raphae
pallidus nucleus; LPB, lateral parabrachial nu-
cleus; BAT, brown adipose tissue (after Ref.
45, which also gives details of putative/known
central neurotransmitters in these pathways);
PGE
2
, prostaglandin E
2
. Nonsteroidal anti-
inflammatory drugs (NSAIDs) have an anti-
pyretic affect by inhibiting the enzyme [cy-
clooxygenase (COX)] responsible for produc-
ing PGE
2
.
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144 THERMOREGULATION UPDATE
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lacking. The application of several techniques has allowed
these concepts to be updated. What appears to be emerging is
a model in which an individual set point within the hypothal-
amus is no longer necessary. Evidence is accumulating that
central and peripheral temperatures influence individual effec-
tor circuits independently (45, 47, 57). Thermoreceptive neu-
rons are activated when the appropriate temperature threshold
for that neuron is reached, and action potentials ascend, via
synaptic relays, to the POA. These signals, along with thermo-
receptive signals arising within the POA, act on several effec-
tor outputs, and the influence of central and peripheral signals
varies between different effectors (47, 57). Cold responses, in
general, are more sensitive to skin temperature (potentially
reflecting the preponderance of cold receptors), whereas hot
responses are more sensitive to core temperature [where warm
receptors are more numerous (57)]. Indeed, there are distin-
guishable variations in the sensitivity of specific effector mech-
anisms to skin and core temperature. For example, the shiver-
ing response and BAT activation are the most responsive to
skin temperature compared with the cutaneous circulation
being influenced more by core temperature changes (41).
There is evidence that the individual effector circuits have
distinctly different threshold temperatures. By carefully simul-
taneously recording the neural drive to individual effector
organs, it has been possible to determine a threshold hierarchy
for the activation of each effector (41). For example, activation
of cutaneous sympathetic vasoconstriction occurs slightly be-
fore (higher core temperature) the activation of BAT in rats
(Ref. 53; not confirmed in humans). Yet the contribution of all
the relatively independent individual effector pathways collec-
tively contributes to a steady core temperature of 37°C. In this
way, the concept of the set point has been updated with a more
nuanced model, and the term “balance point” has been pro-
posed as an alternative (57).
The combination of immunohistochemical identification and
other identification techniques, such as the use of c-Fos, along
with electrophysiological recordings from identified neurons
has allowed the identification of neuronal substrates that cor-
+
+
++
+
+
+
+
Warm
skin
receptor
Cerebral
cortex
Thalamus
Dorso-medial
hypothalamus (DMH)
Rostral raphae
pallidus nuclei (rRPa)
BAT
Skin
blood
vessel
Skeletal
muscle
Lateral
parabrachial
nucleus
(LBP)
active or
excited neurone
inactive or
inhibited neurone
KEY
Median preoptic nucleus (MnPO) Medial preoptic area (MPO)
Preoptic area of the hypothalamus (POA)
Fig. 4. Central circuitry mediating the re-
sponses to warm (after Ref. 45).
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roborate this emerging viewpoint from a number of leading
researcher groups in this area (41, 45, 47, 53). The following is
a summary of the control mechanisms for several of the
temperature effector systems that have been elucidated in
recent years. Cold-sensitive neurons within the MnPO are
activated by cutaneous/visceral afferent activity as well as
direct stimulation of MnPO neurons themselves (see Fig. 3).
These activated inhibitory neurons project to the medial pre-
optic hypothalamus. In the case of neural control of blood
vessels, these activated inhibitory neurons reduce activity in
inhibitory projections to the rostral raphae pallidus. Disinhibi-
tion allows full expression of ongoing activity in the sympa-
thetic vasoconstrictor outflow (via the spinal cord and pregan-
glionic and postganglionic sympathetic nerves). Similarly, dis-
inhibition occurs in outflow to skeletal muscle and BAT but at
the level of the dorsomedial hypothalamus, allowing unim-
peded activity in neurons arising in the dorsomedial hypothal-
amus and projecting to these targets via the rostral raphae
pallidus. This induces heat production by shivering in skeletal
muscle and increased metabolism in BAT.
Warm-sensitive neurons within the MnPO are activated by
cutaneous/visceral afferent activity as well as direct stimulation
of MnPO neurons themselves (see Fig. 4). These neurons
project to the medial preoptic hypothalamus, where they acti-
vate inhibitory input that travels to the rostral raphae pallidus
via the dorsal medial hypothalamus (where there may be one
further synapse in the case of outflow to skeletal muscle and
BAT). Finally, this inhibitory signal slows or stops ongoing
activity arising in neurons that project to the spinal cord to
control output to cutaneous blood vessels, BAT, and skeletal
muscle.
Although the importance of the role of active vasodilatation
has been established and several mechanisms by which it may
be achieved have been found, there is still little or no infor-
mation as to the central pathways responsible for its control.
The role of the POA in coordinating the fever response has
been accepted for many years (26). However, in recent years,
further detail of the mechanism of fever has emerged with the
details of the thermoregulatory circuitry outlined above. It is
likely that fever is induced by production of PGE
2
within the
brain in response to various inflammatory mediators, such as
cytokines, that are released as a result of infection. PGE
2
binds
to receptors specifically on warm-sensitive MnPO and medial
preoptic hypothalamus cells within the POA and inhibits their
activity (see Fig. 3). The resultant disinhibition of several
individual pathways for thermoeffectors causes the activation
of shivering and BAT thermogenesis, along with cutaneous
vasoconstriction (45), so that the raised balance point of these
effectors results in heat gain. This contrasts with a vague
notion of a single set point or thermostat simply being turned
up, with no anatomic substrate. Nonsteroidal anti-inflamma-
tory drugs reduce fever by inhibiting the enzymes that are
responsible for the production of prostaglandins (Fig. 3).
It should be emphasised that the majority of the studies that
have allowed the development of these new models of temper-
ature control have been carried out in animals, particularly rats.
The extent to which these models are applicable in humans
remains to be seen. However, the models of thermoregulation
currently in our textbooks similarly rely on conclusions drawn
from animal experimentation, largely because of the impracti-
cality of examining these models in humans.
Conclusions
The major advances in our understanding of thermoregula-
tion are outlined here as follows:
1. On the sensory side, several membrane channel proteins
(TRPs) have been identified that may transduce specific tem-
perature ranges
2. Elucidation of discrete neuroanatomical circuitry for sev-
eral of the thermoregulatory effectors within the hypothalamic
region that updates the concept of the set point
3. Recognition of a potential role for BAT in thermoregu-
lation and metabolism
4. Advances in the understanding of thermoregulatory con-
trol have been paralleled by advances in the mechanisms that
determine vasomotor tone (dilation and constriction), particu-
larly in the roles played by the myriad of vasoactive neu-
rotransmitters, locally released and systemic factors.
This information can be incorporated into current teaching
of thermoregulation to take into account several of the more
recent advances in the field. We anticipate that the overall
teaching would not differ greatly, but that the factual content
would be more up to date. The main conceptual difference is
the replacement of the set-point model with the balance point.
Although the set point has served as an effective and conve-
nient concept to explain central control of core temperature,
particularly in explaining thermoregulatory responses to fever,
we now have a replacement model that is much more firmly
based on experimental data and yet is conceptually no more
complicated.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: E.A.T. and C.D.J. conception and design of research;
E.A.T. and C.D.J. prepared figures; E.A.T. and C.D.J. drafted manuscript;
E.A.T. and C.D.J. edited and revised manuscript; E.A.T. and C.D.J. approved
final version of manuscript.
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