Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. VIEW ALL HISTORY. Hypothermia is a condition that occurs when your body temperature drops below 95°F. Major complications can result from this drop in temperature….

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A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect. Medically reviewed by Carissa Stephens, R. Body temperature Process Takeaway. What is thermoregulation? Internal body temperature. How does thermoregulation work?

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Medically reviewed by George Krucik, MD, MBA. What Is Neurapraxia? Medically reviewed by Suzanne Falck, MD. What Is the Normal Body Temperature Range? TRP channels that are located in the central endings of primary somatosensory fibers in the spinal dorsal horn Tominaga et al.

Thus, rather than responding directly to changes in environmental temperature, core body thermosensation could play a role a in setting the basal tone of thermoregulatory effector efferents including BAT thermogenesis, b in enhancing thermoregulatory responses in situations of extreme thermal environments when the feedforward thermoregulatory responses driven by changes in skin temperature have proven inadequate to prevent changes in brain or body core temperature, and c in responding to challenges to thermal homeostasis involving shifts in internal body temperature brought about by changes in metabolism e.

or by changes in internal temperature e. Primary thermal somatosensory fibers deliver thermal information to lamina I neurons in the spinal or trigeminal dorsal horn Craig, ; Figure 1.

Craig and colleagues have described thermoreceptor-specific cells responding linearly to graded, innocuous cooling or warming stimuli, and not being activated further in the noxious temperature range Andrew and Craig, ; Craig et al.

The spinothalamocortical pathway, in which second-order thermosensory neurons in lamina I ascend to synapse on thalamic neurons that, in turn, project to the primary somatosensory cortex, is responsible for conscious perception and discrimination of cutaneous temperature information Craig et al.

However, the spinothalamocortical pathway is not required to initiate or sustain involuntary thermoregulatory responses to environmental cold challenges, since thalamic lesions have no effect on sympathetic thermogenic responses to skin cooling Nakamura and Morrison, b. However, spinothalamic and trigeminothalamic lamina I neurons do send collateral axons to the lateral parabrachial nucleus LPB Hylden et al.

Another group of afferents likely to influence BAT thermogenesis Niijima, arise from both BAT Bartness et al. What these afferents sense, the pathways through which this information is relayed centrally and how these adipose afferent signals might influence BAT thermogenesis remain interesting questions.

Neurons in the external lateral subnucleus LPBel of the LPB and projecting to the median subnucleus MnPO of the POA are activated following cold exposure Bratincsak and Palkovits, ; Nakamura and Morrison, b , while those in the dorsal subnucleus LPBd are activated in response to skin warming Bratincsak and Palkovits, ; Nakamura and Morrison, The discharge rate of single, MnPO-projecting LPBel neurons recorded in vivo increased markedly in response to skin cooling in a manner paralleling the skin cooling-evoked increases in BAT SNA Nakamura and Morrison, b.

In contrast, single, MnPO-projecting LPBd neurons were excited by skin warming in parallel with the simultaneous inhibition of BAT SNA Nakamura and Morrison, The critical role of LPB neurons in transmitting cutaneous, and possibly visceral, thermal sensory information to the hypothalamus to drive BAT thermogenic responses is demonstrated by the elimination of BAT responses to alterations in skin temperature following experimental inactivation of local neurons or blockade of local glutamate receptors in the LPB Kobayashi and Osaka, ; Nakamura and Morrison, b.

Similarly, glutamate or other stimulations of LPBel or LPBd neurons can evoke BAT sympathetic and thermogenic responses that parallel those evoked during decreases or increases, respectively, in skin temperature Nakamura and Morrison, b , Thus, both cool and warm cutaneous thermosensory signals that are transmitted from spinal dorsal horn or trigeminal neurons to the POA by separate populations of LPB neurons Figure 1 are essential for eliciting rapid responses in BAT thermogenesis to defend body temperature from a variety of thermal challenges.

Although nociceptive inputs play only a minor role Nakamura and Morrison, b , we do not know what other signals are integrated with cutaneous cold afferent inputs to LPBel neurons in the feedforward pathway contributing to drive BAT thermogenesis during environmental cold challenges.

Within the neural circuits regulating body temperature, the hypothalamus, including the POA, occupies a pivotal position between the cutaneous sensation of ambient temperature and the motor pathways controlling the engagement of thermal effectors Figure 1. Befitting its function as a central integrator of the many dimensions of homeostatic space, the hypothalamus is composed of several interconnected populations of neurons, receives a variety of signals relating to behavioral and emotional state, as well as the condition of the body and the interstitial fluid, and has outputs influencing emotional, behavioral, somatic, and autonomic responses.

Control of body temperature is but one of a myriad of interrelated homeostatic functions embedded in the hypothalamic matrix. Despite the anatomical and neurochemical complexity of this brain region, and the many factors that can influence body temperature regulation, considerable progress has been made in understanding the functional organization of the hypothalamic network that controls BAT thermogenesis.

Within the POA, feedforward, cutaneous cool signaling driving BAT thermogenesis is mediated by glutamatergic inputs from LPBel neurons to neurons in MnPO Figure 1. Stimulation of BAT thermogenesis by activation of LPBel neurons or by skin cooling is blocked by inhibiting neuronal activity in the MnPO Figure 2 or by antagonizing glutamate receptors in the MnPO Nakamura and Morrison, a , b , and glutamatergic stimulation of MnPO neurons evokes increases in BAT SNA and BAT thermogenesis that are similar to cold-defensive BAT responses Nakamura and Morrison, a.

That the POA subregion receiving thermosensory cold signals is confined to the MnPO is supported by the findings that the projections from LPBel neurons activated by skin cooling terminate mainly in a median part of the POA Nakamura and Morrison, b and that glutamatergic stimulation or disinhibition of the MnPO with nanoinjections of NMDA or bicuculline, respectively, evokes physiological responses mimicking cold-defensive responses, while the same stimulation of the MPO or LPO does not Nakamura and Morrison, a.

Thus, activation of MnPO neurons is an essential step in the central mechanism for eliciting cold-defensive BAT thermogenesis to environmental cold challenges Figure 1.

MnPO neurons receiving cutaneous thermal signals from LPB neurons also presumably receive other synaptic inputs that could influence the cutaneous thermal afferent regulation of BAT thermogenesis, although the sources of such inputs to these MnPO neurons are unknown.

The strong activation of BAT thermogenesis by local nanoinjections of bicuculline into MnPO Nakamura and Morrison, a suggests that one such input, at least in anesthetized rats, provides a tonic inhibition of skin cooling-responsive neurons in MnPO.

Figure 2. Inhibition of neurons in the median preoptic nucleus MnPO or blockade of GABA A receptors in the medial preoptic nucleus MPO prevents skin cooling-evoked BAT thermogenesis. A Before and after injection of saline SAL vehicle into the MnPO [inset: typical injection site arrow in the MnPO; 3v, third ventricle; ox, optic chiasm; ac, anterior commissure], episodes of skin cooling evoke increases in BAT sympathetic nerve activity SNA , BAT temperature TBAT , expired CO 2 Exp CO 2 , and heart rate HR , with no change in arterial pressure AP.

Following nanoinjection of the inhibitory transmitter, glycine GLY , into the MnPO, skin cooling no longer increases these thermoregulatory parameters.

Modified with permission from Nakamura and Morrison a. B The skin cooling-evoked increases in thermoregulatory parameters, including BAT SNA and TBAT, are unaffected by nanoinjection of saline vehicle into the MPO, but these increases are reversed by blockade of GABA A receptors in MPO with nanoinjection of bicuculline BIC.

Modified with permission from Nakamura and Morrison Stimulation of BAT thermogenesis in response to skin cooling is postulated to occur via a disinhibitory mechanism in which MnPO neurons receiving cutaneous cool signals from LPBel neurons provide a GABA input to the warm-sensitive, inhibitory projection neurons in the MPO Figure 1 to reduce their tonic activity, resulting in disinhibition of neurons in caudal brain regions whose excitation stimulates BAT thermogenesis for cold defense.

Consistent with this hypothesis, increases in BAT thermogenesis evoked by skin cooling Figure 2 or by stimulation of MnPO neurons are reversed completely by antagonizing GABA A receptors in the MPO Nakamura and Morrison, a. The existence of GABAergic interneurons in the MnPO that innervate the MPO projection neurons is supported by the anatomical observations a that some MnPO neurons innervate the MPO Uschakov et al.

The conceptual foundation of our current understanding of the role of the hypothalamus in normal body temperature regulation and in the elevated body temperature during fever is the existence of a class of hypothalamic neurons which have intrinsic temperature sensitivity: in the absence of synaptic inputs, their discharge frequency increases as the temperature of their local environment increases.

The neurophysiological mechanism underlying the thermosensitivity of warm-sensitive neurons in the POA is thought to reside in a warming-dependent facilitation of the rate of rise of a depolarizing prepotential, due to an heat-induced increase in the inactivation rate of an A-type potassium current, which shortens the intervals between action potentials and thereby increases their firing rates Boulant, a.

Warm-sensitivity could also arise from a heat-induced membrane depolarization that allows warm-sensitive neurons to reach their discharge threshold potential and then determines their discharge frequency Kobayashi et al. Although neurons whose spontaneous discharge frequency is altered by changing the temperature of their local environment exist throughout the CNS, those in the POA and anterior hypothalamus have been most intensely studied because thermoregulatory responses, perhaps with the exception of certain thermoregulatory behaviors Almeida et al.

The preeminent importance of central warm-sensitive neurons for the maintenance of normal body temperature can also be appreciated from the relative position of mammalian resting body temperatures well above the freezing point of water, but only a few degrees below the temperature at which proteins begin irreversible denaturation Romanovsky, Initial, in vivo recordings in the POA identified neurons with spontaneous discharge at thermoneutral temperatures that increased their discharge during local hypothalamic warming i.

The POA contains warm-sensitive neurons whose tonic discharge is also reduced by skin cooling and whose thermosensitivity to preoptic temperature is increased when the skin is cooled Boulant and Hardy, In subsequent recordings in the POA in hypothalamic slices, the majority of thermosensitive neurons were warm-sensitive Boulant and Dean, and the majority of these were GABAergic Lundius et al.

Further, either skin cooling or direct cooling of the local environment of POA neurons evokes sympathetic thermogenesis in BAT Imai-Matsumura et al. These findings are consistent with a model Figure 1 in which warm-sensitive POA neurons that are tonically active at thermoneutral temperatures, integrate cutaneous and local thermal information, and send inhibitory projections from the MPO to suppress BAT thermogenesis.

The observation that transection of the neuraxis immediately caudal to the POA increases BAT SNA and BAT thermogenesis Chen et al. However, transections made just caudal to the hypothalamus do not increase basal levels of BAT thermogenesis in normothermic animals Rothwell et al.

Thus, although a long inhibitory pathway from POA warm-sensitive neurons to medullary BAT sympathetic premotor neurons may contribute to the regulation of BAT thermogenesis, a source of excitatory drive to BAT thermogenesis must exist between the POA and the rostral midbrain.

Figure 3. Disinhibition of neurons in the dorsomedial hypothalamus DMH increases brown adipose tissue BAT thermogenesis and inhibition of neurons in the DMH reverses febrile-evoked BAT sympathetic nerve activity SNA and thermogenesis.

A Nanoinjection of the GABA A antagonist, bicuculline BIC , into the DMH, white arrowhead in inset histological section through the DMH increased BAT SNA, BAT temperature BAT Temp , and expired CO 2.

Modified with permission from Morrison et al. B Nanoinjection of prostaglandin E 2 PGE 2 into the medial preoptic area MPO increased BAT SNA, BAT Temp, Exp CO 2 , heart rate HR , and arterial pressure AP.

Subsequent bilateral nanoinjection of the glutamate receptor antagonist, kynurenate KYN , into the DMH completely reversed these PGE 2 -evoked responses.

Modified with permission from Madden and Morrison Neurons in the cPAG express Fos in response to cold Cano et al. Excitation of neurons in cPAG increases BAT temperature, without a concomitant increase in core temperature Chen et al.

In contrast, in anesthetized and paralyzed rats, skin cooling-evoked stimulation of BAT thermogenesis was unaffected by muscimol injections into the cPAG Nakamura and Morrison, Clearly, there is a need for further investigation of the pathways transmitting the sympathetic drive for BAT thermogenesis from the hypothalamus to medullary BAT premotor neurons, and of the roles of various regions of the PAG in regulating BAT thermogenesis.

Within the hierarchical organization of the central thermoregulatory network, neurons in the rostral ventromedial medulla, centered in the rRPa and extending into nearby raphe magnus nucleus and over the pyramids to the parapyramidal area PaPy; Bamshad et al.

A comparison of the localization of Fos induced by cold exposure which activates BAT thermogenesis with the locations of retrogradely labeled neurons following virus inoculations of BAT provided function-based evidence that the rRPa Figure 4 A and the ventromedial parvicellular subdivision of the paraventricular hypothalamic PVH nucleus are the two potential premotor populations having principal roles in mediating the descending regulation of the spinal sympathetic circuit controlling BAT thermogenesis during cold defense Cano et al.

Further functional studies have clearly identified the preeminent role of BAT sympathetic premotor neurons in rRPa in the cold-defense activation of BAT thermogenesis; however, the role of the Fos-expressing neurons in PVH remains unknown.

Figure 4. Effects of disinhibition and inhibition of rostral raphe pallidus rRPa neurons on brown adipose tissue BAT thermogenesis. A Coronal histological section through the rostral medulla at the level of the facial nucleus and the rRPa, containing immunohistochemically labeled neurons that were trans-synaptically infected following inoculations of BAT with pseudorabies virus red , that contain the serotonin synthesizing enzyme, tryptophan hydroxylase green , or that contain both markers yellow.

Py, pyramidal tract. Modified with permission from Cano et al. B Disinhibition of neurons in the rRPa [arrowhead in inset histological section through rRPa at the level of the facial nucleus 7n ] with nanoinjections of bicuculline BIC elicits dramatic increases in BAT sympathetic nerve activity SNA , BAT temperature TBAT , expired CO 2 Exp CO 2 , and heart rate HR , with little change ion arterial pressure AP.

C Inhibition of local neurons in the rRPa with a nanoinjection of the inhibitory serotonin 1A receptor agonist, 8-OH-DPAT, produces a rapid and complete reversal of the skin cooling-evoked increases in BAT SNA and an immediate waning of the accompanying metabolic and cardiac responses, despite the sustained reduction in skin temperature TSKIN.

Brown adipose tissue sympathetic premotor neurons in the rRPa receive a potent glutamatergic excitation, as well as GABAergic inhibitory inputs, with the latter predominating under warm conditions to reduce BAT thermogenesis. Relief of this tonically active, GABAergic inhibition as well as an increase in glutamate-mediated excitation, including that from the DMH Cao and Morrison, , contributes to the cold-evoked and febrile increases in BAT premotor neuronal discharge that drives BAT SNA and BAT heat production.

Nanoinjections into rRPa of agonists for either NMDA or non-NMDA glutamate receptors evoke brief, but intense activations of BAT SNA Madden and Morrison, , indicating that neurons in rRPa capable of increasing the sympathetic drive to BAT express NMDA and non-NMDA subtypes of glutamate receptors.

That nanoinjections of bicuculline into the rRPa evoke intense activations of BAT SNA Figure 4 B and BAT energy expenditure Morrison et al. Conversely, inhibition of neuronal activity or blockade of glutamate receptors in the rRPa reverses the increases in BAT SNA and BAT thermogenesis elicited by a variety of thermogenic stimuli, including skin cooling Figure 4 C and fever Nakamura et al.

Inhibition of rostral ventromedial medullary neurons produces dramatic falls in body temperature in conscious rats Zaretsky et al. Other thermogenic stimuli whose activation of BAT thermogenesis is reversed or prevented by inhibition of neural activity in the rRPa include disinhibition of neurons in the DMH Cao et al.

Thus, the rRPa and PaPy regions of the ventromedial medulla contain the principal populations of BAT sympathetic premotor neurons that provide the final common medullospinal pathway Figure 1 for the BAT sympathoexcitatory drive to the spinal network controlling BAT SNA and that are both necessary and sufficient for the BAT thermogenic responses to thermoregulatory Figure 1 and febrile stimuli and to a variety of neurochemical mediators that influence body temperature.

That vesicular glutamate transporter 3 VGLUT3 -expressing and serotonin-containing neurons in the rostral ventromedial medulla are functionally related to the activation of cold-defensive, BAT thermogenesis is indicated by the findings that a significant percentage of VGLUT3-containing neurons in the rRPa express Fos in response to cold exposure or intracerebroventricular ICV PGE 2 Nakamura et al.

Rats maintained with a brainstem transection just rostral to the superior colliculus Nautiyal et al. Why the pathways proposed by these investigators to explain these effects in transected rats are ineffective in intact rats following neuronal inhibition of hypothalamic sites in intact animals Zaretskaia et al.

These results may point to an effect of anesthesia or to a response to the transection injury, since they could not be repeated acutely following nearly identical transections rostral to the colliculi in anesthetized rats Osaka, Thermally sensitive neurons have been recognized in several sites caudal to the POA and these neurons, rather than cutaneous thermal receptors, may be engaged in eliciting cold-defense responses in rats with transections caudal to the POA.

Overall, while these occasional data derived from transected preparations are curious, their relevance to normal thermoregulatory mechanisms in intact animals remains unknown. The discharge of BAT SPNs that determines the level of BAT SNA and BAT thermogenesis, as well as the rhythmic bursting characteristic of BAT SNA, is governed by their supraspinal and segmental inputs as well as those to the network of spinal interneurons that influence BAT SPN excitability.

Spinally projecting neurons in the rRPa region can contain phenotypic markers for a the VGLUT3, potentially indicative of glutamatergic neurons Nakamura et al. Consistent with these findings, 5-HT-containing Bacon and Smith, ; Vera et al. In addition, IML-projecting neurons located in the rRPa and the PaPy can contain thyrotropin-releasing hormone TRH and substance P Sasek et al.

Glutamate and 5-HT play critical roles in the descending excitation of BAT SPNs by their antecedent premotor neurons in the rRPa. The majority of VGLUT3-containing neurons in the rRPa express Fos in response to cold exposure or ICV PGE 2 Nakamura et al.

Putative serotonergic neurons in the rRPa increase their firing rate in response to cold Martin-Cora et al. Serotonin in the IML can activate BAT SNA and BAT thermogenesis and potentiates the BAT SNA response to NMDA injections into the IML Madden and Morrison, , such that prior application of serotonin into the IML allows a subsequent subthreshold dose of NMDA to evoke a marked increase in BAT SNA Madden and Morrison, The significant role of serotonin-containing neurons in normal cold-defense responses is also supported by the finding that mice that lack almost all central serotonergic neurons show blunted BAT thermogenesis during cold exposure Hodges et al.

The mechanisms of the interaction between glutamatergic and serotonergic neurotransmission in the IML remain to be elucidated.

Viral inoculations of interscapular BAT Cano et al. Spinal GABAergic interneurons would appear to be among this population since they influence the discharge of SPNs Deuchars et al. That such interneurons could receive inputs from the BAT premotor area in the rostral ventromedial medulla is suggested by the demonstration that VGLUT3- and GADcontaining terminals synapse on GABAergic neurons in the IML Stornetta et al.

Spinal catecholamine release may also modulate the activity of BAT SPNs, considering the excitatory and inhibitory effects of catecholamines on functionally unidentified SPNs Coote et al.

Fever is a defended elevation in body temperature that plays a significant role in the acute phase reaction stimulated by endogenous pyrogens released during infection or inflammation.

PGE 2 , which is synthesized in the brain vasculature and in peripheral tissues in response to immune signals Elmquist et al. Intravenous PGE 2 is also effective in eliciting the BAT thermogenic component of the febrile response Ootsuka et al. Although we have only a rudimentary understanding of the microcircuitry of the POA thermoregulatory network, we have proposed Nakamura et al.

As described above for cold-defense responses, under normal conditions, EP3 receptor-expressing POA neurons, potentially including the population of warm-sensitive POA neurons that controls BAT thermogenesis, maintain a tonic GABAergic inhibition of sympathoexcitatory, BAT thermogenesis-promoting neurons in the DMH, and potentially in the rRPa.

Although the resulting increase in the local temperature of the POA would normally elicit more rapidly rising prepotentials in POA warm-sensitive neurons to inhibit BAT activation, this is offset by the membrane hyperpolarization elicited by EP3 receptor occupancy, thereby allowing a sustained activation of BAT thermogenesis and a maintained fever.

Several experimental findings are consistent with such a model. Binding of PGE 2 to EP3 receptors can inhibit neuronal activity by coupling to inhibitory GTP-binding proteins Narumiya et al.

A population of EP3 receptor-expressing POA neurons multisynaptically innervates BAT Yoshida et al. Interestingly, this subpopulation is separate from the subpopulation of EP3 receptor-expressing POA neurons projecting to the rRPa, although a population of POA neurons that do not express EP3 receptors does send bifurcating axonal projections to both DMH and the rRPa Nakamura et al.

The majority of EP3 receptor-expressing POA neurons are GABAergic Nakamura et al. Antagonizing GABA A receptors in the DMH evokes a fever-like stimulation of BAT thermogenesis Morrison, ; Morrison et al. Inhibition of POA neurons with a muscimol nanoinjection elicits hyperthermic, cardiovascular, and neuroendocrine responses similar to those evoked by a PGE 2 nanoinjection into the same site Zaretsky et al.

In addition, ICV PGE 2 application reduces cAMP level in the POA and ICV administration of an inhibitor of phosphodiesterase, a degradation enzyme for cAMP, blunts fever evoked by intra-POA PGE 2 application Steiner et al.

A marked increase in core temperature and a tachycardia can be elicited by injection of PGE 2 into the paraventricular nucleus of the hypothalamus PVH or into the pontine parabrachial nucleus PBN; Skibicka et al. In this regard, the demonstration that elimination of EP3-R selectively in the POA is sufficient to prevent LPS fever Lazarus et al.

Orexins hypocretins; de Lecea et al. Orexin neurons influence a variety of functions, including the regulation of food intake Sakurai et al.

ICV administration of orexin also increases activity and body temperature Monda et al. Loss of orexin neurons leads to the disordered sleep patterns of narcolepsy, which is often accompanied by defective energy and metabolic homeostasis, including a high risk for obesity Kok et al.

Interestingly, systemic orexin, perhaps secreted from the placenta, is required for BAT differentiation and its absence during early development leads to obesity arising from inadequate BAT energy expenditure Sellayah et al.

A role for orexin neurons in the PeF-LH in the regulation of BAT thermogenesis has recently been described Tupone et al. An anatomical substrate for the influence of orexinergic neurons on BAT thermogenesis is provided by the demonstration that the PeF-LH contains orexinergic neurons that are synaptically coupled to BAT, as shown with viral, trans-synaptic retrograde tracing Oldfield et al.

In anesthetized rats, both injections of orexin into rRPa Figure 5 C and glutamatergic activation of orexinergic neurons by nanoinjections of NMDA into the PeF-LH Figure 5 C produced long lasting activations of BAT SNA and BAT thermogenesis, accompanied by marked increases in energy expenditure, indicated by sustained increases in expired CO 2 that paralleled the increases in BAT heat production Figure 5 A.

Curiously, the strong stimulation of BAT SNA and BAT thermogenesis elicited by injection of orexin into the rRPa or by activation of neurons in the PeF-LH required an ongoing, basal level of BAT SNA, generated in this case by maintaining the rats at a slightly cooled core body temperature.

When the rats were warmed to eliminate any basal discharge on the sympathetic nerves to BAT, neither injection of orexin into rRPa nor activation of PeF-LH neurons elicited increases in BAT SNA Tupone et al. Figure 5. Orexin in the rostral raphe pallidus rRPa or activation of neurons in the perifornical lateral hypothalamus PeF-LH produces a prolonged increase in BAT sympathetic nerve activity SNA and BAT thermogenesis in cool, but not warm rats.

C Representative histological sections illustrating nanoinjection sites in the rRPa left panel, white arrowhead and in the PeF-LH right panel, white arrowhead. Note that the NMDA injection sites in the PeF-LH were located in the midst of many neurons immunohistochemically labeled for Orexin-A red.

Modified with permission from Tupone et al. These anatomical data demonstrate not only an orexinergic projection from neurons in the PeF-LH to the site of BAT sympathetic premotor neurons in the rRPa, but also a synaptic connection between orexin-containing neurons in PeF-LH and BAT sympathetic premotor neurons.

Physiologically, the requirement for an ongoing level of BAT SNA, and thus an activation of BAT sympathetic premotor neurons in rRPa, in order for orexin in rRPa to evoke large and sustained increases in BAT SNA and BAT thermogenesis is consistent with a role for orexin in rRPa to change the gain of the response of BAT sympathetic premotor neurons to their activating, presumably glutamatergic excitatory inputs.

The physiological conditions which activate the orexin neurons in PeF-LH that project to rRPa to modulate the gain of the synaptic drive to BAT sympathetic premotor neurons and facilitate BAT thermogenic responses remains to be determined. Also unknown are the other potential projection targets of the orexin neurons that influence BAT thermogenesis.

However, a potential role of orexin neurons in feeding could suggest a simultaneous increase in energy consumption in BAT under conditions of a high level of stored calories. Alternatively, the activation of orexin neurons in awake or aroused states could suggest an accompanying facilitation of BAT thermogenesis to increase brain and core temperatures to optimize performance.

In this regard, it would be of interest to determine if the level of activity in orexin neurons parallels the ultradian oscillations in the BAT thermogenesis Ootsuka et al.

Conversely, a reduction in the activity of the orexinergic input to rRPa may contribute to the reductions in BAT thermogenesis, energy consumption, and body temperature under conditions of sleep, hibernation or starvation.

The seminal study of Hetherington and Ranson initiated the interest in the ventromedial hypothalamus VMH in energy homeostasis and several succeeding studies have suggested that the VMH affects energy expenditure via sympathetic activation of BAT thermogenesis.

Electrical stimulation of the VMH increases BAT thermogenesis Perkins et al. Conversely, lesions of the VMH attenuate BAT SNA Niijima et al. However, the methodologies used in these studies, including electrical stimulation, electrolytic lesions, and large injection volumes i.

Furthermore, the close proximity of the VMH to other regions involved in the sympathetic regulation of BAT thermogenesis, including the DMH, the arcuate nucleus and the lateral hypothalamus, and the frequent absence of histological data in these previous studies precludes any conclusions on the role of neurons in the VMH in the control of BAT thermogenesis and BAT energy expenditure.

An additional confound is that trans-synaptic retrograde tracing studies have consistently failed to identify any significant population of neurons in the VMH following injection of pseudorabies virus in BAT, even at long post-inoculation times Bamshad et al. Nonetheless, a recent study found impaired diet-induced thermogenesis and lower levels of UCP1 in BAT in mice lacking PI3K specifically in the SF-1 containing neurons of the VMH Klockener et al.

Whether this alteration in BAT UCP1 expression is mediated by a direct effect of altered VMH neuronal discharge on the sympathetic input to BAT, and if so, how this observation might be reconciled with the lack of viral tracer labeling of VMH neurons following inoculation of BAT, remain interesting areas for future study.

The brainstem contains the pathways mediating the inhibition of BAT thermogenesis in response to arterial hypoxia, a reflex to restrict oxygen consumption in the face of reduced oxygen availability or compromised oxygen diffusion and transport in the blood.

Systemic hypoxia or bolus systemic injections of sodium cyanide produce a prompt and complete reversal of the BAT SNA activations evoked by hypothermia and by PGE 2 in the POA and this response to hypoxia is eliminated by section of the carotid sinus nerves or by inhibition of second-order arterial chemoreceptor sensory neurons in the commissural region of the nucleus of the tractus solitarius NTS; Madden and Morrison, Interestingly, hypoxia also eliminates the BAT SNA activation resulting from bicuculline nanoinjection into the rRPa, suggesting that activation of a GABAergic input to BAT sympathetic premotor neurons in rRPa is unlikely to mediate the hypoxic inhibition of BAT thermogenesis.

Indirect evidence points to a possible role for a spinal inhibitory mechanism. Similar to arterial hypoxia, disinhibition of neurons in the rostral ventrolateral medulla RVLM reduces the BAT SNA activation following bicuculline into the rRPa Morrison et al.

The pathway for the hypoxic inhibition of BAT metabolism between the NTS and the BAT SPNs remains to be investigated. Similar to the hypoxia-evoked inhibition of thermogenesis, hypoglycemia and glucoprivation cause hypothermia Freinkel et al. This neurally regulated decrease in metabolism reduces cellular oxidative demands during conditions of reduced availability of metabolic fuel.

The importance of this adaptive response, which spares scarce glucose resources for use by critical tissues such as the brain, at the expense of thermoregulation, is demonstrated by the observation that prevention of hypothermia during severe hypoglycemia results in increased mortality rates Buchanan et al.

More recently we have demonstrated not only that the glucoprivic agent, 2-deoxy- D -glucose 2-DG , reversed the cooling-evoked activation of BAT SNA, but that selective glucoprivation with local nanoinjection of 5-thio-D-glucose 5-TG within the ventrolateral medulla VLM also completely reversed the cooling-evoked activation of BAT SNA Madden, Interestingly, intravenous administration of 2-DG did not attenuate the activation of BAT SNA following pontomedullary transection, suggesting that the hypoglycemia-evoked inhibition of BAT SNA is not mediated solely by circuits within the medulla Madden, Identifying the respective contributions of hypothalamic and medullary regions to the reduced BAT thermogenesis during conditions of reduced availability of metabolic fuel, as well as the characterization of the specific neural pathways by which hypoglycemia influences thermoregulatory neural circuits await further research.

The PVH plays a major role in energy homeostasis, influencing both food intake and energy expenditure. Although the pauci-synaptic connection of neurons in the PVH to BAT Bamshad et al.

Initially, neurons in the PVH were thought to play a role in the excitation of BAT SNA, since neurons in the dorsal PVH with direct projections to the spinal sympathetic preganglionic cell column are activated during fever Zhang et al.

Curiously, cold-evoked BAT thermogenesis was unaffected by lesions of the PVH Lu et al. In contrast, activation of neurons in the PVH has recently been demonstrated to inhibit BAT SNA and BAT thermogenesis Madden and Morrison, Although activation of PVH neurons could attenuate the increases in BAT SNA and BAT thermogenesis evoked by injections of NMDA into the rRPa, those resulting from bicuculline injections into rRPa were unaffected by disinhibition of PVH neurons Figure 6 B , consistent with the PVH-evoked inhibition of BAT SNA being mediated by GABA A receptors in the rRPa.

That neurons in the PVH provide an inhibitory influence on BAT SNA is also supported by the observations that NPY presynaptically inhibits GABA release onto PVH neurons Cowley et al. These apparent controversies in the relation of PVH neurons to BAT thermogenesis, particularly during fever, might be explained by the presence of subpopulations of PVH neurons mediating contrasting effects or by a role of PVH neurons during fever that involves the stimulation of other fever-supporting effector systems such as the cutaneous vasculature or hormone release, whereas the inhibition of BAT thermogenesis by PVH neurons contributes to a non-febrile homeostatic function.

Figure 6. Disinhibition of neurons in the paraventricular hypothalamic PVH nucleus inhibits the increases in BAT sympathetic nerve activity SNA evoked by cooling, but not those evoked by disinhibition of neurons in the rostral raphe pallidus rRPa.

A Nanoinjection of bicuculline BIC into the PVH completely reversed the increases in BAT SNA, BAT temperature TBAT , expired CO 2 Exp CO 2 produced by whole body cooling. Core body temperature TCORE was also reduced; heart rate HR and arterial pressure AP were increased by BIC in PVH.

B The increases in BAT SNA, TBAT, expired CO 2 , TCORE, HR, and AP evoked by nanoinjection of BIC into the rRPa are not affected by nanoinjection of BIC into the PVH.

Controversy also exists concerning the role of melanocortin receptor activation in the PVH in energy expenditure and activation of BAT thermogenesis.

Selective rescue of melanocortin-4 receptor MC4R expression in neurons of the PVH and the medial amygdala in mice lacking expression of MC4R failed to normalize elevate their oxygen consumption to wild-type levels Balthasar et al.

Based on these data it was suggested that PVH MC4Rs do not mediate the energy expenditure effects of melanocortins. In contrast, other groups have demonstrated that microinjection of melanocortin receptor agonists into the PVH increases core and BAT temperatures Song et al.

These effects of melanocortin receptor activation could be mediated by activation of presynaptic MC4Rs, which have been shown to potentiate GABAergic inputs to PVH neurons Cowley et al.

Indeed, this explanation would reconcile this controversy, since the rescue of MC4R in the study of Balthasar et al. would only rescue the postsynaptic MC4R in PVH neurons and not those located presynaptically and potentially responsible for the effects of exogenously administered melanocortin receptor agonists.

This explanation is also consistent with our data indicating that the activity of neurons in the PVH is inhibitory to BAT SNA. The physiological conditions which would stimulate the BAT sympathoinhibitory output from the PVH are unknown, but may include hypoglycemia and chronic intermittent hypoxia.

Another interesting possibility is that neurons in the PVH provide a tonic inhibition of BAT thermogenesis and release from this inhibition under specific conditions, such as changes in dietary composition, may activate BAT SNA and BAT energy expenditure.

Inactivation of neurons in the vicinity of the pontine retrorubral field produced a similar stimulation of BAT thermogenesis Shibata et al. Neither the exact location of the neurons mediating this inhibition nor the physiological basis for its control has been determined.

The VLM and the NTS contain neurons that comprise fundamental cardiovascular and respiratory regulatory circuits, including the baroreceptor and arterial chemoreceptor reflex pathways regulating local vasoconstrictor and cardiac sympathetic premotor neurons, as well as the respiratory generating network and its regulation by central chemoreceptors.

A role for neurons in these same regions in regulating BAT thermogenesis has been recently described Cao et al. The VLM region from which inhibitions of BAT SNA could be evoked corresponds to the locations of the A1 and C1 cell groups in the region ventral to the nucleus ambiguous.

Similar inhibitions of BAT SNA were also produced by bilateral injections of bicuculline into the medial NTS Figure 7 B. However, application of leptin and TRH into the NTS elicits increases in BAT temperature Hermann et al. Whether the inhibitions of BAT thermogenesis evoked throughout this rostro-caudal extent of the VLM represent activation of a homogeneous inhibitory mechanism or stimulations of different mechanisms at different rosto-caudal levels remains to be determined, as do the mechanisms through which the VLM and the NTS inhibitions of BAT SNA is effected and the physiological circumstances under which such inhibitions of BAT thermogenesis would normally be elicited.

In this regard, both hypoxia and hypoglycemia are strong inhibitory signals for BAT thermogenesis see above and the commissural NTS contains second-order chemoreceptor sensory neurons mediating an inhibition of BAT SNA Madden and Morrison, , and the VLM contains neurons sensitive to glucopenia Ritter et al.

Figure 7. Activation of neurons in the ventrolateral medulla VLM or in the nucleus of the solitary tract NTS inhibits BAT sympathetic nerve activity SNA and BAT thermogenesis. A Cooling-evoked increases in BAT SNA, BAT temperature TBAT , and expired CO 2 Exp CO 2 were reversed following unilateral nanoinjection of either the glutamate receptor agonist, NMDA, or the GABAA receptor antagonist, bicuculline BIC , into the rostral VLM RVLM.

Core temperature TCORE was also reduced by activation of RVLM neurons. B Increases in BAT SNA, TBAT, and ExpCO 2 evoked by BIC nanoinjection into the rostral raphe pallidus rRPa were reversed by bilateral nanoinjections of BIC into the medial NTS.

Modified with permission from Cao et al. Brown adipose tissue thermogenesis is regulated primarily by a core thermoregulatory neural network which responds to the feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to alter the level of activation of the sympathetic outflow to BAT.

We have summarized the research leading to a model Figure 1 of the thermoregulatory reflex pathway through which environmental cold stimulates thermogenesis and includes the influence on this thermoregulatory network of the pyrogenic mediator, PGE 2 , to increase body temperature during fever.

The cold thermal afferent circuit from cutaneous thermal receptors, through second-order thermosensory neurons in the dorsal horn of the spinal cord ascends to activate neurons in the LPBel which drive GABAergic interneurons in the MnPO to inhibit warm-sensitive, inhibitory output neurons of the MPO.

Through the resulting disinhibition of thermogenesis-promoting neurons in the DMH, BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rRPa, are stimulated to increase the excitation to and responsiveness of the spinal circuits controlling BAT SPN discharge to drive BAT thermogenesis.

Hypoxia and hypoglycemia are strong metabolic regulators of BAT thermogenesis. The activity of neurons in several brain regions can influence the level of BAT thermogenesis and thus could modulate the thermoregulatory control of BAT, although their discharge does not appear to be required to mediate the skin cooling-evoked stimulation of BAT thermogenesis.

These include an orexinergic excitation of BAT thermogenesis from neurons in the PeF-LH and inhibitory regulation of BAT thermogenesis by neurons in the PVH, the pontine retrorubral field, the VLM and the NTS.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Support of the research that contributed to this review came from National Institutes of Health grants R01NS Shaun F.

Morrison , R01DK Shaun F. Morrison , F32DK Christopher J. Madden , R56DK Christopher J. Madden , and an American Heart Association Scientist Development Grant Christopher J. Almeida, M. Neural substrate of cold-seeking behavior in endotoxin shock.

PLoS ONE 1, e1. Pubmed Abstract Pubmed Full Text CrossRef Full Text. Amini-Sereshki, L. Brain stem tonic inhibition of thermoregulation in the rat. Pubmed Abstract Pubmed Full Text. Andrew, D. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Bacon, S.

Preganglionic sympathetic neurones innervating the rat adrenal medulla: immunocytochemical evidence of synaptic input from nerve terminals containing substance P, GABA or 5-hydroxytryptamine.

Balthasar, N. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell , — Bamshad, M. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Bartness, T.

Sympathetic and sensory innervation of brown adipose tissue. Bautista, D. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature , — Berthoud, H. Orexin inputs to caudal raphe neurons involved in thermal, cardiovascular, and gastrointestinal regulation.

Cell Biol. Blatteis, C. Autonomic thermoregulation after separation of the preoptic area from the hypothalamus in rats. Pflugers Arch. Boulant, J. Counterpoint: Heat-induced membrane depolarization of hypothalamic neurons: an unlikely mechanism of central thermosensitivity.

CrossRef Full Text. Temperature receptors in the central nervous system. The effect of spinal and skin temperatures on the firing rate and thermosensitivity of preoptic neurones. Bratincsak, A. Activation of brain areas in rat following warm and cold ambient exposure.

Neuroscience , — Evidence that peripheral rather than intracranial thermal signals induce thermoregulation. Buchanan, T. Hypothermia is critical for survival during prolonged insulin-induced hypoglycemia in rats.

Caldeira, J. Bilateral lesion of hypothalamic paraventricular nucleus abolishes fever induced by endotoxin and bradykinin in rats. Cammack, C. Excitation of rat sympathetic preganglionic neurones by selective activation of the NK1 receptor.

Cannon, B. Brown adipose tissue: function and physiological significance. Cano, G. Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure.

Cao, W. Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Inhibition of brown adipose tissue thermogenesis by neurons in the ventrolateral medulla and in the nucleus tractus solitarius. Brown adipose tissue thermogenesis contributes to fentanyl-evoked hyperthermia.

Glutamate receptors in the raphe pallidus mediate brown adipose tissue thermogenesis evoked by activation of dorsomedial hypothalamic neurons.

Neuropharmacology 51, — Caterina, M. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science , — Cerri, M. Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis.

Corticotropin releasing factor increases in brown adipose tissue thermogenesis and heart rate through dorsomedial hypothalamus and medullary raphe pallidus. Chen, X. Efferent projection from the preoptic area for the control of non-shivering thermogenesis in rats.

The caudal periaqueductal gray participates in the activation of brown adipose tissue in rats. Christensen, C. Reversal of hypermetabolic brown adipose tissue in F FDG PET imaging. Clapham, J. Central control of thermogenesis. Neuropharmacology doi: Colburn, R. Attenuated cold sensitivity in TRPM8 null mice.

Neuron 54, — Conte, D. Do serotonin immunoreactive terminals innervate GABAergic neurons in the central autonomic area of the mouse spinal cord. FASEB J. Coote, J. The response of individual sympathetic preganglionic neurones to microelectrophoretically applied endogenous monoamines.

Brain Res. Cowley, M. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24, — Craig, A. How do you feel? Interoception: the sense of the physiological condition of the body.

A thalamic nucleus specific for pain and temperature sensation. Quantitative response characteristics of thermoreceptive and nociceptive lamina I spinothalamic neurons in the cat.

Cypess, A. Identification and importance of brown adipose tissue in adult humans. de Lecea, L. II, Frankel, W. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.

de Menezes, R. Cardiovascular and thermal responses evoked from the periaqueductal grey require neuronal activity in the hypothalamus. Deuchars, S. GABAergic neurons in the central region of the spinal cord: a novel substrate for sympathetic inhibition.

Stimulation within the rostral ventrolateral medulla can evoke monosynaptic GABAergic IPSPs in sympathetic preganglionic neurons in vitro. Dhaka, A. TRPM8 is required for cold sensation in mice.

Dib, B. Thermoregulatory behaviour induced by intrathecal injection of substance P in the rat. Dimicco, J. The dorsomedial hypothalamus: a new player in thermoregulation. Egawa, M. Effects of 2-deoxy-D-glucose on sympathetic nerve activity to interscapular brown adipose tissue.

The low demands of thermogenesis mean that free fatty acids draw, for the most part, on lipolysis as the method of energy production. A comprehensive list of human and mouse genes regulating cold-induced thermogenesis CIT in living animals in vivo or tissue samples ex vivo has been assembled [15] and is available in CITGeneDB.

The biological processes which allow for thermogenesis in animals did not evolve from a singular, common ancestor.

However, while both clades are capable of performing thermogenesis, the biological processes involved are different. The reason that both avians and eutherians both developed the capacity to perform thermogenesis is a subject of ongoing study by evolutionary biologists , and two competing explanations have been proposed to explain why this character appears in both lineages.

This theory suggests that natural selection favored individuals with higher resting metabolic rates , and that as the metabolic capacity of birds and eutherians increased, they developed the capacity for endothermic thermogenesis. Rather than animals developing the capacity to maintain high and stable body temperatures only to be able to thermoregulate without the aid of the environment, this theory suggests that thermogenesis is actually a by-product of natural selection for higher aerobic and metabolic capacities.

This theory proposes that the convergent evolution of thermogenesis in birds and eutherians is based on shared behavioral traits. Specifically, birds and eutherians both provide high levels of parental care to young offspring.

This high level of care is theorized to give new born or hatched animals the opportunity to mature more rapidly because they have to expend less energy to satisfy their food, shelter, and temperature needs.

Despite both relying on similar explanations for the process by which organisms gained the capacity to perform non-shivering thermogenesis, neither of these explanations has secured a large enough consensus to be considered completely authoritative on convergent evolution of NST in birds and mammals, and scientists continue to conduct studies which support both positions.

Brown Adipose Tissue BAT thermogenesis is one of the two known forms of non-shivering thermogenesis NST. This type of heat-generation occurs only in eutherians, not in birds or other thermogenic organisms. Because eutherians are the only clade which store brown adipose tissue, scientists previously thought that UCP1 evolved in conjunction with brown adipose tissue.

However, recent studies have shown that UCP1 can also be found in non-eutherians like fish, birds, and reptiles. Since this evolutionary split, though, UCP1 has evolved independently in eutherians, through a process which scientists believe was not driven by natural selection, but rather by neutral processes like genetic drift.

The second form of NST occurs in skeletal muscle. While eutherians use both BAT and skeletal muscle NST for thermogenesis, birds only use the latter form. This process has also been shown to occur in rare instances in fish.

Skeletal muscle NST might also be used to maintain body temperature in heterothermic mammals during states of torpor or hibernation.

The fact that skeletal muscle NST is common among eutherians during periods of torpor and hibernation further supports the theory that this form of thermogenesis is older than BAT NST. This is because early eutherians would not have had the capacity for non-shivering thermogenesis as it currently exists, so they more frequently used torpor and hibernation as means of thermal regulation, relying on systems which, in theory, predate BAT NST.

However, there remains no consensus among evolutionary biologists on the order in which the two processes evolved, nor an exact timeframe for their evolution. Non-shivering thermogenesis is regulated mainly by thyroid hormone and the sympathetic nervous system.

Some hormones, such as norepinephrine and leptin , may stimulate thermogenesis by activating the sympathetic nervous system. Rising insulin levels after eating may be responsible for diet-induced thermogenesis thermic effect of food.

Progesterone also increases body temperature. Contents move to sidebar hide. Article Talk. When you are very cold your Hypothalamus or more accurately the primary motor centre that is found within the Hypothalamus can cause your muscles to shiver.

This can increase your metabolism five-fold and will raise your body temperature. This will lower your body temperature. Both of these are examples of thermoregulation. The purpose of thermoregulation is to keep your body temperature at the perfect balance, this is known as Homeostasis.

Thermoregulation is one control for Homeostasis but it is not the only one, the body also regulates blood glucose, calcium levels, the partial pressure of o2 and Co2, blood pressure etc The Thermic Effect of Food protein is best for weight loss.

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In other words you could probably manage 1. This form of activity is known as Non Exercise Activity Thermogenesis NEAT and it covers all forms of movement that are not exercise: walking, climbing stairs, doing the washing up, cooking, cleaning, even fidgeting whilst watching a movie.

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In these organs, the cognate metabolic processes are stimulated, and any such stimulation leads to thermogenesis. Thus, norepinephrine stimulation of the salivary gland leads to increased oxygen consumption Terzic and Stoji, , as does stimulation of the liver Binet and Claret, These reactions have never been discussed to represent thermoregulatory thermogenesis; the heat is simply a by-product of the increased metabolism related to increased secretion, etc.

Only because muscle is traditionally discussed as being a thermogenic organ are similar adrenergically induced responses in muscle discussed as representing a form of thermoregulatory thermogenesis.

Importantly, these brown-fat-independent types of adrenergic thermogenesis have never been shown to be adaptive. This means that they are not recruited during acclimation to cold or adaptation to diet, and they are therefore not part of a thermoregulatory process.

Particularly in humans, there are many results from studies using infusions of adrenergic agents and measurements of oxygen consumption Blaak et al. These studies are, for the reasons stated above, probably not relevant for the type of thermogenesis discussed here, i.

thermoregulatory nonshivering thermogenesis or diet-induced thermogenesis. To our knowledge, there are no indications that this thermogenesis is adaptive.

Additionally, there is the problem that the adrenergic concentrations achieved during infusion, particularly in humans, may be so low that only a hormonal action of adrenergic agonists is induced; i. the levels may not be high enough to reach the postsynaptic areas in a sufficiently high concentration.

In that case, brown adipose tissue may not be stimulated at all. The problem with the pharmacological response to norepinephrine can to some extent be overcome by using a specific β 3 -adrenergic agonist, notably CL, As β 3 -adrenergic receptors are only found in high density in adipose tissues, and as white adipose tissue is nearly inert with respect to oxygen consumption, the response seen would mainly emanate from brown adipose tissue, i.

However, the response may not represent the true capacity of brown adipose tissue because β 3 - and β 1 -adrenoreceptors may be needed to elicit the total β-adrenergic response, and there may be an α-adrenergic component Mohell et al.

Thus, only with norepinephrine is it certain that the entire thermogenic response is induced. Metabolic chambers measure the rate of oxygen consumption, and the outcome is thus in litres of oxygen per unit time.

This is an approximation of the total heat production but, because the thermal equivalent of an oxygen molecule is different when carbohydrate or fat is combusted, conversion factors depending on the respiratory quotient should be used to convert the oxygen consumption values to energy W.

This is particularly important if the food composition is changed from carbohydrate to fat or during day-and-night measurements when the animals change from burning a mixed diet active phase to burning stored fat inactive phase.

The problems occurring by expressing metabolism per kg body weight. The animals symbolized have similar amounts of normal tissue black but different amounts of white adipose tissue grey. Thus, to express metabolic rates per body weight or to any power of body weight leads to misleading conclusions.

In studies of all types of metabolism, there is one major difficulty in interpretation and representation of the results: the denominator or the divisor, i.

how the results should be expressed. If the animals are of the same size and body composition, there is no problem, but very often this is not the case. It may initially seem natural to express metabolism per gram body weight; however, in reality, animals are often studied that have become obese, e.

due to a diet intervention or a genetic alteration. Such animals may have identical amounts of active lean tissue but are carrying expanded amounts of lipid around in their white adipose tissue Fig.

Lipid as a chemical is totally metabolically inert, and in no way contributes to metabolism. However, if the metabolic rate is expressed per gram body weight, and one animal carries extra weight in the form of lipid, the metabolic rate expressed in this way will appear smaller in the obese animal.

This is evidently not an adequate description. By contrast, if a treatment leads to leanness, the lipid carried around is less, the divisor is smaller and thus we have an explanation for leanness: enhanced thermogenesis Fig.

Although these considerations would seem banal, the literature overflows with results calculated this way and conclusions based on these results. The problem has been repeatedly addressed, but still seems to persist Himms-Hagen, ; Butler and Kozak, In an apparently more advanced way, metabolic rates and thermogenic capacities can be expressed per gram body weight raised to some power.

Most often the conversion is to grams raised to the power 0. Firstly, evidently this in no way eliminates the problem discussed above; lipid is still inert even if raised to any power. Secondly, the power 0. mice and elephants. It turns out that the metabolism increases in proportion to the body weight to the power 0.

For mathematical reasons, the power raising makes nearly no difference if, for example, mice with only somewhat different body weights are compared, and it should therefore only be used for comparisons between species.

Occasionally, the power 0. This is the geometrical relationship between the surface area and the volume weight of a sphere or cube. The power relationship is of significance if thermal balance is discussed — but to use it to express rates of metabolism implies that all metabolism is due to heat loss to the surroundings, which is of course not the case.

The difference between the powers 0. What, then, is the solution to the dilemma of the divisor? The easiest — and in most circumstances most correct — solution is simply to give the results as per animal. A more sophisticated, and on occasion advantageous, solution is to express the rate per gram lean body mass.

Even to express the metabolic rates per gram lean mass assumes that all lean mass in the body has an equal metabolic rate. This is not the case; therefore, although lean mass is a better approximation, it is not without its own problems. After all, if the modification studied should be causative of the development of obesity or protection against obesity , the altered metabolic rate should be present before the new phenotype becomes evident.

Brown adipose tissue is an admirable defence mechanism against cold. It has an impressively high oxidative capacity and thermogenic activity per gram of tissue and provides chronically cold-exposed mammals with a comfortable means of defending body temperature.

As pointed out above, in its absence, shivering will function but shivering is notably less comfortable than nonshivering thermogenesis and will impose restrictions on the animal's freedom of movement. Some 30 years ago, it was observed that a nonshivering thermogenic capacity could also be recruited by exposing rodents to so-called cafeteria diets or, later, to high-fat diets Rothwell and Stock, The mechanism of recruitment of brown adipose tissue under these conditions has not been clarified but it presumably involves activation of the sympathetic nervous system either directly by components in the diet as has been the general view or secondarily to the developing obesity as such.

It was proposed that animals that could develop brown adipose tissue in this way could use its thermogenic capacity to combust excess energy in the diet and thus not become as obese as otherwise expected. Extensive studies by many groups have supported this view Cannon and Nedergaard, but see Maxwell et al.

The magnitude of the increase in metabolic rate induced by injected norepinephrine is enhanced following dietary treatment, in a manner similar to that following cold acclimation i. classical nonshivering thermogenesis Rothwell and Stock, ; Feldmann et al. The increases seen are smaller, but it would seem to be an adaptive process, as is classical nonshivering thermogenesis.

Also note that this metabolic increase is in addition to that caused by the direct metabolic costs of digesting the food. Whereas the purpose of classical nonshivering thermogenesis is clear, that of diet-induced thermogenesis is not equally evident.

There are indications that the magnitude of diet-induced thermogenesis is related to the protein content of the diet. An adequate explanation for the development of diet-induced thermogenesis was proposed by Stock: if diets with inadequate protein or another essential nutrient content — i.

unbalanced diets — were eaten to the extent that sufficient protein was ingested, a system had to exist to remove the excess of energy that this extra ingestion had incurred Stock, This system would thus be brown adipose tissue.

Good experimental evidence for this hypothesis is still lacking. If an animal does use brown fat thermogenesis to regulate its amount of stored body fat, it would be reasonable to assume that in the absence of active brown fat such as in an animal lacking UCP1 , the animal would become obese, provided it maintained the same energy intake.

It was therefore initially surprising perhaps even disappointing that the UCP1-ablated mice did not develop obesity Enerbäck et al. However, later studies performed in mice housed at their thermoneutral temperature showed a development of obesity even on a regular chow diet, and to a greater extent on a high-fat diet Feldmann et al.

This indicates that even the very small amount of UCP1 present in the wild-type mice at thermoneutrality is actually effective in modulating body fat content, its absence is not compensated by other means, and the absence is sufficient for obesity to occur. Animals living at their thermoneutral temperatures are not under any cold stress and, therefore, clearly do not have UCP1 and brown fat for this reason.

Brown fat is classically recruited in parallel with decreasing ambient temperatures. The presence of some active brown fat even at thermoneutrality can be taken to indicate that it indeed has a physiological function. Surprisingly, mice without UCP1 are protected against diet-obesity when studied under normal animal house conditions.

The reason for this is still not clarified but this is not a unique outcome for UCP1-ablated mice. Even mice with UCP1 i. wild-type mice are protected against obesity if they are placed in a cold environment; however, the degree of cold needed for this protection is higher for wild-type than for UCP1-ablated mice Cannon and Nedergaard, Perhaps the most important reason to acquire a thermal understanding when approaching studies of metabolism is to not be misled by false positive observations and thus to invest scientific time and effort in metabolic phenomena that are secondary to thermal regulation rather than to truly altered metabolism.

The risk of false positives. If, for example, a mutant mouse has fur with a decreased insulation, the slope of the thermal control curve becomes higher. If this mouse is only maintained and examined at normal temperature here 24°C , it will display a higher metabolism a than the control. The mutant thus appears to be hypermetabolic.

In reality, it feels much colder than the wild-type mouse, i. it feels like the wild-type mouse would feel if it were shifted to a lower temperature where the same metabolism would be needed b ; that is it feels as if it were at 14°C c.

It will therefore display all the features expected of mice at 14°C, e. All of these effects are, however, secondary to the animal feeling colder and will disappear if the mouse is kept and examined at thermoneutrality.

Such examinations are rarely performed. As seen, the mouse of interest for thermoregulatory reasons necessarily shows an increased metabolism a thermogenesis , which wrongly suggests that it has an enhanced metabolism due to some metabolic pathway being modified.

the appearance of UCP1-containing cells in white adipose tissue depots Xue et al. All of these observations would undoubtedly be formally correct, but when the thermoregulatory responses of the mouse are examined, these results become trivial in the sense that they are all consequences of decreased insulation.

Thus, as indicated in Fig. In this example, all differences would thus be ascribable to the expected effects of feeling colder. The fact that this is more than a theoretical situation has been demonstrated several times recently.

For example, a mouse without the fatty acid elongase Elovl3 demonstrated the above characteristics and was experimentally shown to have decreased insulation Westerberg et al. Similarly, the global absence of stearoyl CoA dehydrogenase 1 SCD1 leads to this type of apparently hypermetabolic phenotype Ntambi et al.

Thus, the metabolic changes can be explained by the altered skin phenotype, the resultant increased heat loss and the effects of this resultant increased metabolism. The risk of false negatives. If a mutant animal truly has a decreased intrinsic metabolic rate but unchanged body temperature and insulation, it will not display a metabolic rate different from the wild type if kept and examined at normal temperatures a.

Only if examined so as to establish the thermoneutral zone of the animal will the decreased metabolism become evident b. This is the case for thyroid receptor null mutants Golozoubova et al.

It is likely that many mutants or treatments with true effects on intrinsic metabolism have been overlooked because they have only been examined under conditions where their metabolic rate is controlled by the ambient temperature.

Other genetically modified mice have also been shown to exhibit changes in fur and skin properties together with resistance to diet-induced obesity; these include the global knock-out of acyl coenzyme A:diacylglycerol acyltransferase 1 DGAT1 Smith et al.

Again, it is unlikely that these modifications truly affect intrinsic metabolism; rather, the outcome is due to thermoregulatory thermogenesis. In addition, mice that lack the thyroid hormone receptor α show an increased metabolism, etc.

at 22°C but not at thermoneutrality Marrif et al. The most probable explanation for this is again an insulation problem although the authors propose another mechanism. It is likely that a number of recently published metabolic phenotypes where, for example, activation of brite adipose tissue has been demonstrated may in reality be due to alterations in insulation.

As these mice have not been examined after housing at thermoneutrality, it cannot be excluded that they demonstrate a thermoregulatory phenotype rather than the metaboloregulatory phenotype advocated.

Thus, we would suggest that concerning many of these genetically modified mice, the metabolic effects observed resistance to diet-induced obesity in combination with higher metabolism at normal animal house temperatures and activation of brown and brite adipose tissues are the same that would be observed by e.

simply shaving the mice. The phenotype is thus mainly or fully secondary to the loss of insulation. A scientifically equally disturbing problem — or perhaps an even larger problem — is that housing animals at normal temperatures may mask true metabolic phenotypes.

As seen in Fig. One clear example is the UCP1-ablated mouse that does not, as noted above, demonstrate an obesity-prone phenotype when kept at normal temperature Enerbäck et al.

However, when thermoregulatory metabolism is switched off when the mice are housed at thermoneutrality, the lack of metaboloregulatory thermogenesis becomes evident and the mice become obese Feldmann et al.

There are other examples of thermoregulatory thermogenesis resulting from keeping the mice at normal animal house temperatures obscuring alterations in intrinsic metabolism. Thus, mice that lack the mitochondrial glycerolphosphate dehydrogenase gene DosSantos et al.

In a broader sense, mice at thermoneutrality may be said to become more humanized in that, for example, their control of heart activity changes from being sympathetic to being vagal Swoap et al. Also, effects of pyrogens are only evident at thermoneutrality, not at normal room temperatures Rudaya et al.

In addition, the serum lipid pattern becomes closer to those of humans data not shown. As studies on mice are often performed to mimic a human situation, it is clearly most appropriate to house mice at thermoneutrality.

Few genetic modifications and few agents developed for metabolic control have been examined in animals living at thermoneutrality. Therefore, there is a great risk that several important candidate genes and several promising agents have been overlooked and dismissed as a result of the experiments being performed under conditions where metaboloregulatory processes are overshadowed by thermoregulatory processes.

Mainly for practical reasons and for the comfort of the animal house personnel, animal house temperatures are normally in the range of 18 to 20°C. However, this is not the case. This is most evident if the mouse is allowed to choose its thermal environment.

In experiments with temperature gradients, the mice always choose temperatures of approximately 30°C Gordon et al. Similarly, if a mouse is given the direct choice between an environment at 20°C or at 30°C, it chooses 30°C [see e.

wild-type mouse behaviour in supplementary video 1 in Bautista et al. Bautista et al. Thus, mice, just as humans, prefer to live under conditions of thermoneutrality.

The attempts to humanize mice to gain insights into human metabolism have acquired a much broader significance during the last few years.

For decades, it has been assumed that adult humans do not possess active brown adipose tissue, and studies of nonshivering thermogenesis have, therefore, been seen as being only of academic interest.

The insight that a significant fraction of adult humans possess brown adipose tissue Nedergaard et al. Our studies on metabolism and brown adipose tissue are supported by the Swedish Science Research Council.

We thank colleagues, particularly Valeria Golozoubova and Helena Feldmann, for discussions and experiments over the years. Learn more in our Editorial. Places are limited to 24 attendees, and applicants should apply through the SEB registration page by 30 April In their Review , Corinna Gebehart and Ansgar Büschges discuss how the motor systems of insects can provide insight into the mechanisms underlying the integration of multimodal information to allow flexible motor control.

Jason Dallas and colleagues show that the community of microbes inhabiting the guts of tadpoles contributes to their ability to withstand rising temperature and suggests that microbiome transplants could offer hope to species at risk as global temperatures rise.

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Skip Nav Destination Close navigation menu Article navigation. Volume , Issue 2. Previous Article Next Article. Article contents. The thermoneutral zone and cold-induced metabolism. Thermoneutrality is operationally defined.

Classical nonshivering thermogenesis. The mechanism of heat production in brown adipose tissue. Life without UCP1. Acute cold exposure does not test nonshivering thermogenic capacity. The significance of thermal prehistory for cold tolerance.

Norepinephrine injection as a test to determine nonshivering thermogenic capacity: certain limitations. Adrenergically induced thermogenesis is not necessarily nonshivering thermogenesis.

The difficult point of the divisor. Diet-induced thermogenesis. Influence of UCP1 ablation on obesity development. Thermoneutrality is the preferred temperature.

Article Navigation. ENERGY DEMAND 15 January The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University. cannon wgi. This site. Google Scholar. Jan Nedergaard Jan Nedergaard.

Author and article information. Jan Nedergaard. Accepted: 04 Nov