Raphe pallidus neurons mediate prostaglandin E2-evoked increases in brown adipose tissue thermogenesis

To elucidate central neural pathways contributing to the febrile component of the acute phase response to pyrogenic insult, I sought to determine whether activation of neurons in the rostral raphe pallidus (RPa) is required for the increase in brown adipose tissue (BAT) thermogenesis evoked by i.c.v. prostaglandin E(2) (PGE(2)) in urethane-chloralose-anesthetized, ventilated rats. BAT sympathetic nerve activity (SNA; +224% of control), BAT temperature (+1.8 degrees C), expired CO(2) (+1.3%), mean arterial pressure (+23 mm Hg), and heart rate (+73 beats per minute) were significantly increased after i.c.v. PGE(2) (2 microg). Microinjection of either the GABA(A) receptor agonist, muscimol (2 mM, 60 nl), or glycine (0.5M, 60 nl) into RPa resulted in a prompt reversal of the PGE(2)-evoked stimulation of BAT SNA, BAT thermogenesis and heart rate, with these variables returning to control levels prior to i.c.v. PGE(2) following the long-lasting, muscimol-induced inhibition of RPa neurons. In conclusion, activation of neurons in RPa, possibly BAT sympathetic premotor neurons, is essential for the increases in BAT SNA and BAT thermogenesis stimulated by i.c.v. administration of PGE(2). The increased heart rate likely contributing to an augmented cardiac output supporting the increased BAT thermogenesis in response to PGE(2) is also dependent on neurons in RPa. These results contribute to our understanding of central neural substrates for the augmented thermogenesis during fever.     

Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus

We sought to determine which medullary sympathetic premotor neurons mediate the cardiovascular and thermogenic effects resulting from activation of neurons in the dorsomedial hypothalamus (DMH) in urethane/chloralose-anesthetized, artificially ventilated rats. Unilateral disinhibition of neurons in the DMH with microinjection of bicuculline (2 mM, 30 nl) caused significant increases in brown adipose tissue sympathetic nerve activity (BAT SNA, +828+/-169% of control, n=16), cardiac SNA (+516+/-82% of control, n=16), renal SNA (RSNA, +203+/-25% of control, n=28) and, accompanied by increases in BAT temperature (+1.6+/-0.3 degrees C, n=11), end-tidal CO(2) (+0.7+/-0.1%, n=15), heart rate (+113+/-7 beats/min, n=32), arterial pressure (+19+/-2 mm Hg, n=32) and plasma epinephrine and norepinephrine concentrations. Inhibition of neurons in the rostral raphe pallidus (RPa) with microinjection of muscimol (6 mM, 60 nl) abolished the increases in BAT SNA and BAT temperature and reduced the tachycardia induced by disinhibition of DMH neurons. Inhibition of neurons in the RVLM with microinjection of muscimol (6 mM, 60 nl) markedly reduced the increase in RSNA, but did not affect the evoked tachycardia or the increase in arterial pressure. Combined glutamic acid decarboxylase (GAD-67) immunocytochemistry and pseudorabies viral retrograde tracing from BAT indicated close appositions between GABAergic terminals and DMH neurons in sympathetic pathways to BAT. In conclusion, these results demonstrate the existence of a tonically active, GABAergic inhibitory input to neurons in the DMH and that blockade of this inhibition increases sympathetic outflow to thermogenic and cardiovascular targets by activating functionally specific populations of sympathetic premotor neurons: the excitation of BAT SNA and BAT thermogenesis is mediated through putative sympathetic premotor neurons in the RPa, while the activation in RSNA is dependent on those in RVLM. These data increase our understanding of the central pathways mediating changes in sympathetically mediated thermogenesis that is activated in thermoregulation, stress responses and energy balance.     

Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis

The lateral hypothalamic area, containing orexin neurons, is involved in several aspects of autonomic regulation, including thermoregulation and energy expenditure. To determine if activation of lateral hypothalamic area neurons influences sympathetically-regulated thermogenesis in brown adipose tissue, we microinjected bicuculline (120 pmol, 60 nl, unilateral) into the lateral hypothalamic area in urethane/chloralose-anesthetized, artificially-ventilated rats. Disinhibition of neurons in lateral hypothalamic area evoked a significant increase (+1309%) in brown adipose tissue sympathetic nerve activity accompanied by parallel increases in brown adipose tissue temperature (+2.0 degrees C), in expired CO2 (+0.6%), in heart rate (+88 bpm) and in mean arterial pressure (+11 mm Hg). Subsequent microinjections of glycine (30 nmol, 60 nl) to inhibit local neurons in raphe pallidus or in dorsomedial hypothalamus or of glutamate receptor antagonists into dorsomedial hypothalamus promptly reversed the increases in brown adipose tissue sympathetic nerve activity, brown adipose tissue temperature and heart rate evoked by disinhibition of neurons in lateral hypothalamic area. We conclude that neurons in the lateral hypothalamic area can influence brown adipose tissue sympathetic nerve activity, brown adipose tissue thermogenesis and heart rate through pathways that are dependent on the activation of neurons in dorsomedial hypothalamus and raphe pallidus.     

Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigs

In urethane–chloralose anaesthetized, neuromuscularly blocked, artificially ventilated rats, we demonstrated that activation of carotid chemoreceptors inhibits the elevated levels of brown adipose tissue (BAT) sympathetic nerve activity (SNA) evoked by hypothermia, by microinjection of prostaglandin E₂ into the medial preoptic area or by disinhibition of neurones in the raphe pallidus area (RPa). Peripheral chemoreceptor stimulation with systemic administration of NaCN (50 μg in 0.1 ml) or with hypoxic ventilation (8% O₂–92% N₂, 30 s) completely inhibited BAT SNA. Arterial chemoreceptor-evoked inhibition of BAT SNA was eliminated by prior bilateral transections of the carotid sinus nerves or by prior inhibition of neurones within the commissural nucleus tractus solitarii (commNTS) with glycine (40 nmol/80 nl) or with the GABA_A receptor agonist muscimol (160 pmol/80 nl; 77 ± 10% attenuation), or by prior blockade of ionotropic excitatory amino acid receptors in the commNTS with kynurenate (8 nmol/80 nl; 82 ± 10% attenuation). Furthermore, activation of commNTS neurones following local microinjection of bicuculline (30 pmol/60 nl) completely inhibited the elevated level of BAT SNA resulting from disinhibition of neurones in the RPa. These results demonstrate that hypoxic stimulation of arterial chemoreceptor afferents leads to an inhibition of BAT SNA and BAT thermogenesis through an EAA-mediated activation of second-order, arterial chemoreceptor neurones in the commNTS. Peripheral chemoreceptor-evoked inhibition of BAT SNA could directly contribute to (or be permissive for) the hypoxia-evoked reductions in body temperature and oxygen consumption that serve as an adaptive response to decreased oxygen availability.     

Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis

To investigate the role of excitatory amino acid neurotransmission within the rostral raphe pallidus area (RPa) in thermogenic and cardiovascular responses, changes in sympathetic nerve activity to brown adipose tissue (BAT), BAT temperature, expired CO(2), arterial pressure, and heart rate were recorded after microinjection of excitatory amino acid (EAA) receptor agonists into the RPa in urethan-chloralose-anesthetized, ventilated rats. To determine whether EAA neurotransmission within the RPa is necessary for the responses evoked by disinhibition of the RPa or by prostaglandin E(2) acting within the medial preoptic area, BAT sympathetic nerve activity, BAT temperature, expired CO(2), arterial pressure, and heart rate were measured during these treatments both before and after blockade of EAA receptors within the RPa. Microinjection of EAA receptor agonists into the RPa resulted in significant increases in all measured variables; these increases were attenuated by prior microinjection of the respective EAA receptor antagonists into the RPa. Microinjection of prostaglandin E(2) into the medial preoptic area or microinjection of bicuculline into the RPa resulted in respective significant increases in BAT sympathetic nerve activity (+approximately 190% and +approximately 235% of resting levels), in BAT temperature (approximately 1.8 degrees C and approximately 2 degrees C), in expired CO(2) (approximately 1.1% and approximately 1.1%), and in heart rate (approximately 97 beats per minute (bpm) and approximately 100 bpm). Blockade of ionotropic EAA receptors within the RPa by microinjection of kynurenate completely reversed the prostaglandin E(2) or bicuculline-evoked increases in all of the measured variables. Blockade of either N-methyl-D-aspartate (NMDA) receptors or non-NMDA receptors alone resulted in marked attenuations of the prostaglandin E(2)-evoked effects on all of the measured variables. These data demonstrate that activation of an EAA input to the RPa is necessary for the BAT thermogenic and the cardiovascular effects resulting from the actions of prostaglandin E(2) within the medial preoptic area or from the disinhibition of local neurons in the RPa.     

Orexin receptor type 2 agonism inhibits thermogenesis in brown adipose tissue by attenuating afferent innervation

Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.     

Role of sympathetic nervous system in immobilization- and cold-induced brown adipose tissue thermogenesis in rats

The role of the sympathetic nervous system in 10-min cold (5 degrees C)- or 2-min immobilization-induced thermogenesis in brown adipose tissue (BAT) was studied in warm (25 degrees C)-acclimated rats. Both cold- and immobilization-stresses increased heat production (M), interscapular brown adipose tissue temperature ( Tbat ), and colonic temperature ( Tcol ). Resulting from both stresses, the increase in Tbat was greater than that in Tcol , the differences (delta Tbat ) becoming approximately 0.48 and 0.46 degrees C by the cold exposure and the immobilization, respectively. After sympathectomy, Tbat and delta Tbat did not change on immobilization but increased significantly on the cold exposure. Delta Tbat was 0.31 degrees C in the sympathectomized rats at the end of the cold exposure period. Immobilization-induced BAT thermogenesis may be mainly controlled by the sympathetic nervous system. On the other hand cold-induced BAT thermogenesis seems to be controlled by certain hormonal factors as well as the sympathetic nervous system.     

Thermogenesis in brown adipose tissue: increase by 5-HT2A receptor activation and decrease by 5-HT1A receptor activation in conscious rats

Body temperature is decreased by 5-hydroxytryptamine 1A (5-HT1A) agonists and increased by 5-HT2A agonists. The present study determined whether changes in interscapular brown adipose tissue (iBAT) thermogenesis contribute to these effects in conscious unrestrained animals. Male Sprague-Dawley rats were pre-instrumented for measurement of iBAT and core temperature and tail artery blood flow one week before experiments. In the first series of experiments, rats were transferred from warm (25-28 degrees C) to cold (5-10 degrees C) environments. This increased iBAT temperature (+1.3 +/- 0.2 degrees C, P<0.01, n = 7) and reduced tail artery flow. Injection of the 5-HT1A agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin, 0.5 mg/kg, s.c.) reversed the increase in iBAT thermogenesis (-1.5 +/- 0.4 degrees C, P<0.01, n = 6), and decreased core temperature (-1.5 +/- 0.4 degrees C, P<0.01, n = 6). Pre-treatment with WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride), a 5-HT1A antagonist, prevented effects of 8-OH-DPAT. In the second series of experiments, injection of a 5-HT2A agonist, DOI (R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride, 0.1 mg/kg, s.c.) increased both iBAT (+1.9 +/- 0.1 degrees C, P<0.01, n = 7) and core temperatures (+1.4+/-0.2 degrees C, P<0.01, n=7), and decreased tail artery blood flow. Subsequent injection of SR 46349B (trans-4-((3Z)3-[(2-dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl) propen-1-yl)-phenol, hemifumarate, 0.5 mg/kg, s.c.), a 5-HT2A antagonist, reduced all these changes. Results indicate that activation of 5-HT1A receptors reduces sympathetic outflow to BAT and that activation of 5-HT2A receptors increases this outflow. Changes in core temperature mediated by brain/spinal pathways regulated by 5-HT1A and 5-HT2A receptors reflect coordinated changes in BAT-mediated heat production as well as changes in heat dissipation via the thermoregulatory cutaneous vascular beds.     

Bradycardia elicited by microinjections of nociceptin/orphanin FQ into the intermediolateral cell column at T1-T2 in the rat

Microinjections (30 nl) of nociceptin/orphanin FQ (N/OFQ) into the intermediolateral cell column (IML) at T1 and T2 levels of the spinal cord elicited bradycardia. The decreases in HR were 12.3+/-2.9, 17.3+/-2.7, 26.7+/-3.1, and 18.6+/-3.4 beats/min in response to 0.075, 0.15, 0.62, and 1.25 mM concentrations, respectively. Maximally effective concentration of N/OFQ was 0.62 mM. No changes in BP were elicited by microinjections of N/OFQ into the IML at T1-T2. The bradycardic responses were completely blocked by prior microinjections of a N/OFQ receptor (NOP receptor) antagonist ([N-phe(1)]-nociceptin-(1-13)-NH(2), 9 mM) into the IML at T1-T2. Blockade of myocardial beta-1 adrenergic receptors also abolished the bradycardic responses elicited by microinjections of N/OFQ into the IML. It was concluded that activation of NOP receptors in right IML at T1-T2 by N/OFQ elicited bradycardic responses which were mediated via the sympathetic nervous system.     

Hypothalamic neuronal histamine regulates sympathetic nerve activity and expression of uncoupling protein 1 mRNA in brown adipose tissue in rats

To clarify how hypothalamic neuronal histamine regulates peripheral energy expenditure, we investigated the effect of infusion of histamine into the third cerebral ventricle or discrete hypothalamic regions on sympathetic nerve activity and expression of uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT). Infusion of histamine (200 nmol) into the third cerebral ventricle of anesthetized rats significantly increased the electrophysiological activity of sympathetic nerves (P<0.01) and UCP1 mRNA expression in the BAT (P<0.05). Microinjection of histamine (10 nmol) into the paraventricular nucleus (PVN) and preoptic area (POA) produced similar significant increases in BAT sympathetic nerve activity (P<0.01 for each). By contrast, injection of histamine into the ventromedial hypothalamic nucleus or lateral hypothalamic area had no effect. We conclude that hypothalamic neuronal histamine may regulate energy expenditure in BAT through the activation of sympathetic nerves. The PVN and/or POA appear to be the principal hypothalamic sites that mediate the stimulatory effect of histamine on this efferent pathway.     

Activation of brown adipose tissue thermogenesis increases slow wave sleep in rat

Considering the thermoregulatory role of slow wave sleep (SWS), we wondered whether the sole increase of brown adipose tissue (BAT) thermogenesis could enhance this sleep state. We tested this hypothesis by administering to rats an agonist (BRL 37,344) of the beta-3 adrenoceptor subtype that is massively localized in BAT cell membrane and that is known to activate BAT thermogenesis. Sleep was electrographically characterized. The temperature of interscapular BAT (Tibat) and cortex (Tco) were also assessed. Tibat significantly increased 2-3 h after BRL injection (but not Tco), concomitantly with SWS (+56-57%). At the maximum of Tibat, a significant positive correlation was found between their changes and those of SWS. We demonstrated for the first time that sleep (and especially SWS) can be affected by the specific activation of BAT.     

Pituitary and autonomic responses to cold exposures in man

This review presents hormonal responses to various cold exposures and their calorigenic effects in man and some animals. Previous studies in rats have shown that cold exposures activate the hypothalamic-pituitary-thyroid axis. Increased thyroid hormone concentrations lead to heat production via general stimulation of metabolism (obligatory thermogenesis) and possibly via activation of thyroid hormone receptors and uncoupling protein 1 (UCP 1) and deiodinase enzyme genes in the brown adipose tissue (BAT). In human subjects long-term cold exposures do not seem to activate the pituitary-thyroid axis, but rather accelerate the elimination of triiodothyronine (T3), leading to low serum concentrations of free T3 hormone. In corollary to this a hypothyreotic condition with increased serum thyroid-stimulating hormone and impaired mood and cognitive performance can be observed after long-term cold exposures such as wintering. During cold exposures the sympathetic nerve system is activated and noradrenaline is released to blood circulation and to BAT, where it leads to production of cAMP, lipolysis and free fatty acids. Free fatty acids open the mitochondrial proton channel protein in BAT. Protons enter the mitochondria and inhibit ATP synthesis (uncoupling). By this way energy is transformed into heat (facultatory or adaptive thermogenesis). In adult human subjects the amount of BAT is small and adaptive thermogenesis (non-shivering thermogenesis) has a smaller role. UCP 1 with other uncoupling proteins may have other functions in the control of body weight, sugar balance and formation of reactive oxygen species.     

Independence of ultrasonic vocalization and thermogenic responses in infant rats

Ultrasonic vocalizations (USV) normally accompany brown adipose tissue (BAT) thermogenesis in infant rats exposed to cold. BAT activation (measured by implanted thermistors) was pharmacologically blocked with hexamethonium (20 mg/kg ip) in 12-13-day-old pups, but they nevertheless showed normal USV responses to cold. Activation of BAT in warm pups by norepinephrine (800 micrograms/kg sc) failed to elicit USV. It is concluded that BAT activation is neither necessary nor sufficient for USV production. To evaluate how tightly the two responses may be coupled centrally, rat pups deprived of nutrients for 24 hr, in which sympathetic activation is known to be inhibited centrally (Bignall, Heggeness, & Palmer, 1975), were studied. These pups vocalized with the same latency in response to cold as normals but failed to show evidence of concurrent BAT activation. It is concluded that USV and BAT thermogenesis are normally elicited together by cold but are not tightly linked physiologically.     

The effect of forced running on heat production in brown adipose tissue in rats

The effect of running on heat production in brown adipose tissue (BAT) was compared between trained and untrained rats. Rats were forced to run a treadmill while temperatures of colon (T col) and interscapular BAT (T bat) were measured. The daily running for 5 weeks neither changed the size of interscapular BAT nor the norepinephrine-induced thermogenesis (8 micrograms/kg X min). During running, both T bat and T col increased. In rats trained for 2 weeks, the increases in T bat were similar to those in T col. In untrained rats, however, the increases in T bat were larger than those in T col. It is suggested that exercise increases heat production in BAT in untrained rats, but such heat production in BAT is abolished by daily exercise. Exercise suppresses cold-induced heat production in BAT of trained rats.     

Effect of acute cold-exposure on norepinephrine turnover and thermogenesis in brown adipose tissue and metabolic rate in MSG-induced obese mice

Mice treated neonatally with monosodium-L-glutamate (MSG) are known to develop into obese adults without hyperphagia, which are characterized by the reduced levels in the resting metabolic rate (RMR) and the thermogenesis of brown adipose tissue (BAT) in the thermoneutral environment. The present study revealed that an acute cold-exposure (5 degrees C, 1 h) of these animals resulted in the increase in norepinephrine turnover and mitochondrial-5'-diphosphate (GDP) binding in the interscapular BAT as well as the guanosine RMR, suggesting a normal thermogenic responsiveness of BAT to cold.     

Microinjection of methysergide into the raphe nucleus attenuated phrenic long-term facilitation in rats

Exposure to acute intermittent hypoxia (AIH) evokes persistent increase in respiratory activity that lasts up to 60 min after hypoxic episodes have ceased. This persistent increase in phrenic nerve activity (PNA) is known as phrenic long-term facilitation (LTF). AIH-induced phrenic LTF in anesthetized rats is serotonin dependant. The present study was performed to determine whether microinjection of methysergide (4 mM, 20 ± 5 nl), a broad spectrum 5-HT receptor antagonist, into the caudal raphe nuclei influences phrenic LTF. Peak integrated PNA and respiratory frequency were recorded at 15, 30, and 60 min after five 3-min episodes of normocapnic hypoxia in urethane-anesthetized, vagotomized, paralyzed and ventilated male Sprague–Dawley rats. In control animals, phrenic nerve amplitude was elevated 66.7 ± 8.6% from baseline 1 h after episodic hypoxia, indicating phrenic LTF. Experimental microinjections of methysergide prior to AIH exposure attenuated phrenic LTF (amplitude increase 2.62 ± 2.9% over baseline). We conclude that methysergide microinjections into the caudal raphe region attenuated phrenic LTF induced by AIH, indicating involvement of 5-HT receptor activation at a supraspinal level.     

Effects of cold and immobilization stress on noradrenaline turnover in brown adipose tissue of rat

Noradrenaline (NA) turnover of the interscapular brown adipose tissue (BAT) was determined in order to evaluate a role of sympathetic NA of this tissue in an enhanced nonshivering thermogenesis which had been previously evidenced in the repetitively stressed rats by immobilization (daily 3-h immobilization for 4 weeks) and the cold-acclimated ones (5 degrees C, 4 weeks). The disappearance rate of NA from the BAT following blockade of NA synthesis with alpha-methyl-p-tyrosine was adopted for estimation of NA turnover of the tissue. Cold acclimation increased both fractional turnover rate (%/h) (k) and turnover rate (ng/(g BAT.h)). Repetitive immobilization stress also elevated turnover rate, but not k. In the warm non-stressed controls acute cold exposure to -5 degrees C and acute immobilization stress elevated the turnover rate. The effect of cold exposure was significantly greater than that of immobilization stress for both indices of NA turnover. In the cold-acclimated rats acute cold exposure increased k as well as turnover rate, but not acute immobilization stress. In the repetitively immobilized rats both acute cold exposure and acute immobilization stress elevated k and turnover rate. These results indicate that immobilization enhances sympathetic activity of thermogenic tissue, BAT. The results also suggest that the extent of sympathetic participation is not necessarily the same between the cold-acclimated and the stressed rats.     

Reduced norepinephrine turnover in brown adipose tissue of ob/ob mice

Obese (ob/ob) mice have a lower thermogenic capacity than lean mice. The possible role of brown adipose tissue (BAT) in this defect was investigated. Lean and obese mice were exposed to 33 (thermoneutral), 25, or 14 degrees C for up to 3 wk. BAT cytochrome oxidase activity and numbers of Na+-K+-ATPase enzyme units, enzymes involved in thermogenesis, were similar at 33 or 25 degrees C. Chronic exposure to 14 degrees C increased these enzymes 34 and 62%, respectively, in lean mice and nearly 150% in obese mice. Sympathetic nervous system activity, which stimulates thermogenesis in BAT, was evaluated by measuring norepinephrine (NE) turnover. At 25 degrees C, NE turnover rate in BAT of obese mice was only 40% as rapid as in BAT of lean mice. Chronic exposure to 33 degrees C depressed NE turnover in BAT of lean mice, but not in obese mice, whereas exposure to 14 degrees C accelerated NE turnover in both lean and obese mice. Lower sympathetic nervous system activity in BAT of obese mice at 25 degrees C is likely a major factor in their reduced nonshivering thermogenesis and resultant high efficiency of energy storage.     

Involvement of thermosensitive TRP channels in energy metabolism

To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.     

The effect of non-esterified long-chain fatty acids on blood flow and thermogenesis in brown adipose tissue in the young dog

In vitro experiments have demonstrated that increasing the molar ratio of extracellular non-esterified fatty acids (NEFA) to albumin stimulates thermogenesis in brown adipocytes. To test these results, in vivo blood flow and local temperature were measured in perirenal brown adipose tissue (BAT) in puppies during thermogenesis induced by increasing the plasma NEFA: albumin ratio by injection of intralipid and heparin. Plasma NEFA concentration increased to 1.5 mmol X 1-I and plasma NEFA:albumin ratio to 4. Concomitantly, the whole body oxygen consumption rose on average about 100% above baseline level. Plasma noradrenaline concentration increased about three-fold and plasma adrenaline concentration about six-fold. The BAT temperature increased by an average of 0.9 degrees C. However, since BAT blood flow was simultaneously reduced by about 50%, it can be calculated that the local heat production was also reduced. Consequently, the increase in whole body oxygen consumption was not due to stimulation of BAT thermogenesis. It is concluded that in vivo assessment of BAT thermogenesis requires concomitant measurements of both local BAT temperature and blood flow.