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Central Nervous System Regulation of Brown Adipose Tissue

Shaun F. Morrison, Christopher J. Madden

10.1002/cphy.c140013

Source: Volume 4, Issue 4, October 2014

Published online: September 2014

Full Article on Wiley Online Library



Abstract

Thermogenesis, the production of heat energy, in brown adipose tissue is a significant component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature in many species from mouse to man and plays a key role in elevating body temperature during the febrile response to infection. The sympathetic neural outflow determining brown adipose tissue (BAT) thermogenesis is regulated by neural networks in the CNS which increase BAT sympathetic nerve activity in response to cutaneous and deep body thermoreceptor signals. Many behavioral states, including wakefulness, immunologic responses, and stress, are characterized by elevations in core body temperature to which central command‐driven BAT activation makes a significant contribution. Since energy consumption during BAT thermogenesis involves oxidation of lipid and glucose fuel molecules, the CNS network driving cold‐defensive and behavioral state‐related BAT activation is strongly influenced by signals reflecting the short‐ and long‐term availability of the fuel molecules essential for BAT metabolism and, in turn, the regulation of BAT thermogenesis in response to metabolic signals can contribute to energy balance, regulation of body adipose stores and glucose utilization. This review summarizes our understanding of the functional organization and neurochemical influences within the CNS networks that modulate the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolic alterations in BAT thermogenesis and BAT energy expenditure that contribute to overall energy homeostasis and the autonomic support of behavior. © 2014 American Physiological Society. Compr Physiol 4:1677‐1713, 2014.

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Figure 1. Figure 1. Model for the neuroanatomical and neurotransmitter/hormonal organization of the core thermoregulatory network and other CNS sites controlling and modulating brown adipose tissue (BAT) thermogenesis. Cool and warm cutaneous thermal sensory receptors transmit signals to respective primary sensory neurons in the dorsal root ganglia which relay this thermal information to second‐order thermal sensory neurons in the dorsal horn (DH). Cool sensory DH neurons glutamatergically activate third‐order sensory neurons in the external lateral subnucleus of the lateral parabrachial nucleus (LPBel), while warm sensory DH neurons project to third‐order sensory neurons in the dorsal subnucleus of the lateral parabrachial nucleus (LPBd). Thermosensory signals for thermoregulatory responses are transmitted from the LPB to the preoptic area (POA) where GABAergic interneurons in the median preoptic (MnPO) subnucleus are activated by glutamatergic inputs from cool‐activated neurons in LPBel and inhibit a BAT‐regulating population of warm‐sensitive (W‐S) neurons in the medial preoptic area (MPA). In contrast, glutamatergic interneurons in the MnPO, postulated to be excited by glutamatergic inputs from warm‐activated neurons in LPBd, excite W‐S neurons in MPA. Prostaglandin (PG) E2 binds to EP3 receptors to inhibit the activity of W‐S neurons in the POA. Preoptic W‐S neurons providing thermoregulatory control of BAT thermogenesis inhibit BAT sympathoexcitatory neurons in the dorsomedial hypothalamus and dorsal hypothalamic area (DMH/DA) which, when disinhibited during skin cooling, excite BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus (rRPa) and parapyramidal area (PaPy), that project to BAT sympathetic preganglionic neurons (SPN) in the spinal intermediolateral nucleus (IML). Some BAT premotor neurons can release glutamate (GLU) to excite BAT sympathetic preganglionic neurons and increase BAT sympathetic nerve activity, while others can release serotonin (5‐HT) to interact with 5‐HT1A receptors, potentially on inhibitory interneurons in the IML, to increase the BAT sympathetic outflow. Modulatory regions represent areas of the CNS that are not within the core thermoregulatory pathway, but from which chemical manipulation of the activity of local neurons produced effects (see text) on BAT activity. Dotted lines to question marks indicate that the pathway mediating the effect on BAT activity is unknown. Neurochemicals/hormones in yellow boxes activated and those in blue boxes reduced BAT activity. Neurons in the anterior piriform cortex (APC) sense the absence of indispensible amino acids (IAA) from the diet and stimulate an elevated level of BAT activity. Orexinergic neurons in the perifornical lateral hypothalamus (PeF‐LH) project to the rRPa to increase the excitability of BAT sympathetic premotor neurons. Histaminergic neurons in the tuberomammillary nucleus (TMN) project to the POA to increase BAT activity by influencing the discharge of neurons in the core thermoregulatory pathway. Activation of neurons in the ventrolateral medulla (VLM) produces an inhibition of BAT thermogenesis, at least in part by noradrenergic (NE) activation of α2 receptors on rRPa neurons. Neurons in the nucleus of the solitary tract (NTS) mediate the effects of afferents in the vagus and carotid sinus (CSN) and aortic depressor nerves. 2‐DG, 2‐deoxyglucose; 5‐HT, 5‐hydroxytryptamine; 5‐TG, 5‐thioglucose; αMSH, alpha melanocyte‐stimulating hormone; AngII, angiotensin II; BDNF, brain‐derived neurotrophic factor; CRF, corticotrophin releasing factor; NPY, neuropeptide Y; PGE2, prostaglandin E2; T3, triiodothyronine; TIP39, tuberoinfundibular peptide of 39 residues; TRH, thyrotropin‐releasing hormone; VGLUT3, vesicular glutamate transporter 3. Copyright 2014 by Oregon Health and Science University.
Figure 2. Figure 2. Lateral parabrachial neurons mediate cutaneous thermoreceptor afferent signaling regulating BAT thermogenesis. [(A) and (B) Bilateral nanoinjections into the lateral parabrachial nucleus (LPB) of the glutamate receptor antagonists, (2R)‐amino‐5‐phosphonovaleric acid (AP5), and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dionesaline (CNQX), but not the saline (SAL) vehicle, reverse the skin cooling‐evoked increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (Tbat), expired CO2, and heart rate (HR).TSKIN, skin temperature. Modified, with permission, from (243). [(C) and (D)] Injection into the median preoptic area (MnPO) of the retrograde tracer, cholera toxin B (orange injectate top panels), labels neurons in the dorsal subnucleus of the LPB (LPBd, middle panel in C), or in the external lateral subnucleus of the LPB (LPBel, middle panel in D) that also express c‐fos immunoreactivity (arrows in lower panels) following exposure to a warm ambient temperature (C) or a cool ambient temperature (D). Modified, with permission, from (243,244). (E) The discharge of a neuron (Unit) in LPBd is increased during episodes of skin warming that inhibit BAT SNA. Filled circles in inset indicate recording sites of warming‐activated units in LPBd. Modified, with permission, from (244). (F) The discharge of a neuron in LPBel is increased during episodes of skin cooling that activate BAT SNA. Filled circles in inset indicate recording sites of cooling‐activated units in LPBel. Modified, with permission, from (243).
Figure 3. Figure 3. POA microcircuitry integrates cutaneous and central thermal sensation and mediates febrile activations of BAT thermogenesis. (A) Action potentials (left panel) of a GABAergic (lower middle panel), warm‐sensitive neuron recorded in a brain slice (upper middle panel) through the preoptic area of a GAD65‐GFP mouse. Bath application of the histamine 3 receptor (H3R) agonist, R‐α‐methylhistamine, reduced the firing rate and eliminated the temperature sensitivity (right panel) of such GABAergic neurons in POA. Modified from (189). (B) The median preoptic area (MnPO) contains neurons (yellow) that express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) inoculations of BAT in LepRbEGFP mice. POA microcircuitry integrates cutaneous and central thermal sensation and mediates febrile activations of BAT thermogenesis. (A) Action potentials (left panel) of a GABAergic (lower middle panel), warm‐sensitive neuron recorded in a brain slice (upper middle panel) through the preoptic area of a GAD65‐GFP mouse. Bath application of the histamine 3 receptor (H3R) agonist, R‐α‐methylhistamine, reduced the firing rate and eliminated the temperature sensitivity (right panel) of such GABAergic neurons in POA. Modified from (189). (B) The median preoptic area (MnPO) contains neurons (yellow) that express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) inoculations of BAT in LepRbEGFP mice. Modified, with permission, from (418). Ca: blockade of GABAA receptors with bicuculline (BIC) nanoinjections in the medial preoptic area (MPA) reverses the skin cooling‐evoked increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (Tbat), expired CO2 (Exp CO2), and heart rate (HR). TSKIN, skin temperature; SAL, saline vehicle, modified, with permission, from (241). Cb: nanoinjection into the MnPO of the glutamate receptor antagonists, (2R)‐amino‐5‐phosphonovaleric acid (AP5) and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dionesaline (CNQX), but not the saline (SAL) vehicle, reversed the increases in BAT SNA, Tbat, Exp CO2, and HR evoked by activation of neurons in the lateral parabrachial nucleus (LPB) with nanoinjection of the glutamate receptor agonist, N‐methyl‐D‐aspartate (NMDA). Modified, with permission, from (243). Cc: bilateral nanoinjections of BIC, but not the SAL vehicle, into the MPA reversed the increases in BAT SNA, Tbat, Exp CO2, and HR evoked by disinhibition of neurons in the MnPO with a nanoinjection of BIC. Modified from (242). Cd: schematic drawings and histological section indicating representative nanoinjection sites in MnPO (left panel) and in MPA (middle and right panels). Modified, with permission, from (242). Da: immunohistochemical localization of the EP3 receptor in the rat MnPO and MPA (left panel). Modified, with permission, from (237). Selective genetic deletion of the EP3 receptor in the MnPO of Ptger 3ΔCNS/NesCre mice prevents the rise in body temperature observed in wild‐type mice following icv PGE2 (right panel). Modified, with permission, from (172). Db: prostaglandin (PG)E2 reduced the firing rate of a POA warm‐responsive neuron recorded in a rat brain slice, whose discharge frequency was increased during increases in bath temperature. Modified, with permission, from (286). Dc: nanoinjection of PGE2 into the MPA dramatically increased BAT SNA, Tbat, Tcore, Exp CO2, and HR and these fever‐mimicking thermogenic responses were completely reversed by inhibition of neuronal activity in the DMH with bilateral injections of muscimol (MUSC). Modified, with permission, from (246).
Figure 4. Figure 4. Neurons in the dorsomedial hypothalamus (DMH) and dorsal hypothalamic area (DA) mediate BAT sympathoexcitation. (A) Histological sections and drawings through the DMH/DA (upper panels) indicating (a) CTb retrogradely labeled neurons in the DMH/DA following iontophoretic CTb deposit (lower panel) in the rostral raphe pallidus (rRPa), modified, with permission, from (322); [(b) and (c)] the locations of CTb retrogradely labeled neurons (green circles) following nanoinjections of CTb (lower panel) in the rostral raphe pallidus (rRPa, b) or in the parapyramidal area (PaPy, c); red circles depict orexin immunoreactive neurons; filled black circles represent double‐labeled, orexinergic neurons that project to the rRPa; modified, with permission, from (386); and (D) the DMH/DA contains neurons (yellow) that both express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) injections into BAT in LepRbEGFP mice, modified, with permission, from (418). mt, mamillothalamic tract; f, fornix; py, pyramidal tract; B: the increases in BAT sympathetic nerve activity (SNA), BAT temperature (Tbat), expired CO2 (ExpCO2) and heart rate (HR) elicited by skin cooling are unaffected (Ba) by nanoinjections of saline vehicle (SAL) into the DMH/DA (Bc, right panel), but are reversed (Bb) by inhibition of local DMH/DA neurons with nanoinjections of muscimol (MUSC) into the DMH/DA (Bc). Modified, with permission, from (241). (C) Disinhibition of neurons in the DMH/DA (white arrowhead in inset histological section through the rat DMH/DA) by nanoinjection of the GABAA antagonist, bicuculline (BIC), resulted in an increase in BAT SNA, Tbat, and Exp CO2. Modified, with permission, from (226). D: nanoinjection of prostaglandin E2 (PGE2) into the medial preoptic area (MPA) increased BAT SNA, Tbat, Exp CO2, and heart rate (HR). Subsequent bilateral nanoinjections of the glutamate receptor antagonist, kynurenate (KYN), into the DMH completely reversed these PGE2‐evoked responses. Modified, with permission, from (193).
Figure 5. Figure 5. Rostral raphe pallidus (rRPa) contains BAT sympathetic premotor neurons whose activity determines the level of BAT thermogenesis. (A) Histological section through the rostral medulla at the level of the facial nucleus and the rostral raphe pallidus (rRPa) illustrating the transsynaptic, pseudorabies virus (PRV) labeling of BAT sympathetic premotor neurons (red) following PRV inoculations in interscapular BAT, and serotonergic neurons (green) immunohistochemically labeled for tryptophan hydroxylase, and rRPa‐BAT neurons that contain both markers (yellow). py, pyramidal tract. Modified, with permission, from (44). (B) Nanoinjection of bicuculline (BIC) in rRPa disinhibits BAT sympathetic premotor neurons and elicits a dramatic increase in BAT sympathetic nerve activity (SNA), BAT temperature (Tbat), and metabolic oxygen consumption, indirectly indicated by the elevation in expired CO2 (EXP CO2). Subsequent activation of the inhibitory 5‐HT1A receptors in rRPa with a local injection of 8OH‐DPAT completely reverses the activation of BAT SNA, likely by inhibiting BAT sympathetic premotor neurons. (C) Inhibition of local neurons in the rRPa with a nanoinjection of glycine produces a rapid and complete reversal of the skin cooling‐evoked increases in BAT SNA and Tbat, despite the sustained reduction in skin temperature (TSKIN). Modified, with permission, from (241). (D) Decreases in core body temperature after microinjection (dotted line) of 10, 20, and 80 pmol/100 nL of muscimol (MUSC) or saline vehicle into the RPa in four conscious rats. Bars with asterisk denote intervals during which temperature was significantly less than after saline treatment: solid bar, MUSC 80 pmol; dotted bar, MUSC 20 pmol. Modified, with permission, from (416).
Figure 6. Figure 6. Paraventricular hypothalamic nucleus (PVH) mechanisms influencing BAT thermogenesis. (A) Unilateral nanoinjection of bicuculline (BIC) into the PVH completely reversed the cooling‐evoked increases in BAT sympathetic nerve activity (SNA), BAT temperature (Tbat), and expired CO2 (Exp CO2). Modified, with permission, from (197). (Ba) The increases in BAT SNA and Tbat evoked by activation of rRPa neurons with nanoinjection of NMDA are unaffected by unilateral saline injection into the PVH (upper panel), but are markedly reduced by increasing the activity of PVH neurons with a unilateral nanoinjection of bicuculline (BIC) in the PVH (lower panel). Modified from (197). (Bb) Nanoinjection of BIC into the rostral raphe pallidus (rRPa) increases BAT SNA, Tbat, and Exp CO2, and prevents the inhibition of BAT SNA evoked by unilateral nanoinjection of BIC into the PVH. Modified from (197). (Ca) Channelrhodopsin2 (CHR2)‐tranfected, RIP‐Cre neurons (left panel) and their terminals in PVH (right panel) following adeno‐associated virus (AAV) injection in the arcuate nucleus (ARC) of a RIP‐Cre mouse; 3V, third ventricle; opt, optic chiasm; fx, fornix. Laser light (blue dashes) pulses depolarizing the CHR2‐expressing terminals of ARC RIP‐Cre neurons in PVH elicits inhibitory postsynaptic currents (IPSCs, lower panel) in a PVH neuron in a brain slice. (Cb) Leptin increases interscapular BAT (iBAT) temperature in vesicular GABA transporter (Vgat)‐floxxed mice, but not in RIP‐Cre, Vgatflox/flox mice. (Cc) Following injection into ARC of a cre‐dependent AAV producing expression of the designer receptor (hM3Dq) exclusively activated by designer drug (DREADD), selective activation of ARC RIP‐Cre neurons with clozapine‐N‐oxide (CNO) elicits a significant increase in oxygen consumption (VO2) and in iBAT temperature (Temp). Panels Ca‐Cc were modified, with permission, from (166). (D) Histological section through the PVH illustrating the overlap of transsynaptically infected, pseudorabies virus (PRV)‐labeled neurons (brown) following PRV injections into interscapular BAT and in situ hybridization for melanocortin 4‐receptor (MC4‐R) mRNA expression (black granules). Inset: High magnification of the outlined portion of the PVH. Note the presence of PRV in neurons surrounded by MC4‐R (curved black arrows) and PRV in neurons without associated MC4‐R (curved open arrows). Modified, with permission, from (349); 3V, third ventricle; ZI, zona inserta; oc, optic chiasm; SCH, suprachiasmatic nucleus. E: immunohistochemical labeling of PVH neurons for oxytocin (OXY, red) and for transsynaptic infection with PRV (green) after PRV injections into interscapular BAT. Arrows indicate neurons containing both PRV and OXY (yellow). Modified, with permission, from (259). (E) Schematic, based in part on (71), of the local PVH neurocircuitry proposed to mediate the GABAergic, neuropeptide Y (NPY) and α‐melanocyte‐stimulating hormone (αMSH) influences on BAT thermogenesis mediated by PVH neurons.
Figure 7. Figure 7. Orexinergic and other PeF/LH neurons influence BAT thermogenesis. (A) Coronal brain section through the PeF/LH shows many double‐labeled (white arrowheads, yellow fluorescence in the cytoplasm) orexinergic (red) neurons that were pseudorabies virus (PRV)‐infected (green), indicating their synaptic connection to BAT. Modified, with permission, from (386). (B) Orexinergic fibers (red) surround putative BAT sympathetic premotor neurons in rRPa (and in PaPy) transsynaptically infected following PRV inoculations of interscapular BAT. Modified, with permission, from (386). (C) Under cool conditions (Tcore < 37°C) with a low level of basal BAT SNA, nanoinjection of orexin‐A (Orx‐A, dashed line) in the rRPa elicited prolonged increases in BAT SNA, Tbat, Exp CO2, and heart rate (HR). Modified, with permission, from (386). (D) Under cool conditions (Tcore < 37°C) with a low level of basal BAT SNA, nanoinjection of NMDA (dashed line) in the PeF/LH elicited prolonged increases in BAT SNA, Tbat, Exp CO2, and HR. Modified, with permission, from (386). (E) icv PGE2 (filled symbols), but not ACSF (open symbols), elicited a marked increase in BAT temperature in orexin‐KO mice (triangles) and in the wild‐type littermates for either the orexin‐KO (circles) and for the orexin neuron‐ablated (squares) mice, but had no effect on Tbat in orexin neuron‐ablated mice (diamonds). Modified, with permission, from (372). (F) The activation of BAT SNA and BAT thermogenesis produced by disinhibitory activation of PeF/LH neurons with bicuculline (BIC) nanoinjection is dependent on the activation of glutamate receptors on DMH/DA neurons. Modified, with permission, from (55).
Figure 8. Figure 8. NTS neurons mediate both inhibition and excitation of BAT thermogenesis. (A) The disinhibitory activation of neurons in the intermediate NTS (iNTS), with injections of bicuculline (BIC), completely reversed the increases in BAT SNA, BAT temperature (Tbat), and expired CO2 that follow blockade of GABAA receptors in the rostral raphe pallidus (rRPa). Modified, with permission, from (47). (B) Activation of adenosine 1A receptors in iNTS at the level of the area postrema (inset), with bilateral injections of the agonist, N6‐cyclohexyladenosine (CHA), reverses the cooling‐evoked increases in BAT SNA and Tbat. Inhibition of iNTS neurons with bilateral injections of muscimol (MUSC) reverses the CHA‐evoked inhibition of BAT SNA, consistent with adenosine producing an increase in the activity of BAT sympathoinhibitory neurons in iNTS. Modified, with permission, from (387). (C) Ventilation with an hypoxic (8% O2) gas mixture that produces increases in integrated phrenic nerve amplitude (int PHR), heart rate (HR) and arterial pressure (AP), also elicits a complete inhibition of the increase in BAT SNA evoked by nanoinjection of BIC in rRPa. Inhibition of neuronal activity in the commissural subnucleus of the NTS (commNTS), with a nanoinjection of MUSC, eliminates the hypoxic inhibition of BAT SNA. Modified, with permission, from (194). (D) Changes in Tbat elicited by agents applied to the fourth ventricle. When preceded by leptin in the fourth ventricle, thyrotropin releasing hormone (TRH) markedly increases Tbat, indicating BAT thermogenesis. This effect is prevented by prior blockade of signal transduction pathways via fourth ventricle administration of wortmannin to block leptin‐evoked PIP3 generation or by the Src‐SH2 antagonist, PP2. Modified, with permission, from (291). (E) The iNTS contains neurons (yellow) that both express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) injections into BAT in LepRbEGFP mice. Modified, with permission, from (418).
Figure 9. Figure 9. Neurons in the ventrolateral medulla (VLM), including catecholaminergic neurons, provide an inhibitory regulation of BAT SNA and BAT thermogenesis. (A) The A1/C1 area of the VLM (bregma −13 mm) contains transsynaptically infected neurons (green) following pseudorabies virus (PRV) injections into interscapular BAT, tyrosine hydroxylase (TH)‐immunoreactive neurons (red), and double‐labeled (yellow, arrowhead) neurons indicative of catecholaminergic VLM neurons synaptically‐connected to BAT. (B) Distribution relative to the distance from bregma of catecholaminergic (red squares) and total (filled circles) neurons in the VLM retrogradely labeled following CTb injections into the rRPa. (C) Following PRSx8‐channel rhodopsin 2‐mCherry (ChR2) lentivirus, which preferentially transfects catecholaminergic neurons, nanoinjections into VLM, the rostral raphe pallidus (rRPa, white dotted outline) contains highly varicose fibers (red) expressing ChR2. (D) Laser photostimulation of VLM neurons containing the ChR2 (largely catecholaminergic neurons) inhibited BAT SNA and reduced BAT temperature (Tbat), an effect on BAT thermogenesis that was attenuated by blockade of α2‐adrenergic receptors in the rRPa. Panels A‐D, consistent with an activation of catecholaminergic neurons in the VLM inhibiting BAT SNA via a direct catecholaminergic input to the rRPa, are modified, with permission, from (199). (E) Glucoprivation with systemic 2‐deoxyglucose (2‐DG) activates [increases c‐fos (black nuclei)] many catecholaminergic neurons (gray) in the A1/C1 area of the VLM. Modified, with permission, from (290). (F) Local glucoprivation in the VLM by nanoinjection of 5‐thioglucose (5‐TG, dashed line) completely inhibits BAT SNA and reduces (Tbat) and metabolic oxygen consumption, indirectly indicated by the level of expired CO2 (Exp CO2). Modified, with permission, from (191).


Figure 1. Model for the neuroanatomical and neurotransmitter/hormonal organization of the core thermoregulatory network and other CNS sites controlling and modulating brown adipose tissue (BAT) thermogenesis. Cool and warm cutaneous thermal sensory receptors transmit signals to respective primary sensory neurons in the dorsal root ganglia which relay this thermal information to second‐order thermal sensory neurons in the dorsal horn (DH). Cool sensory DH neurons glutamatergically activate third‐order sensory neurons in the external lateral subnucleus of the lateral parabrachial nucleus (LPBel), while warm sensory DH neurons project to third‐order sensory neurons in the dorsal subnucleus of the lateral parabrachial nucleus (LPBd). Thermosensory signals for thermoregulatory responses are transmitted from the LPB to the preoptic area (POA) where GABAergic interneurons in the median preoptic (MnPO) subnucleus are activated by glutamatergic inputs from cool‐activated neurons in LPBel and inhibit a BAT‐regulating population of warm‐sensitive (W‐S) neurons in the medial preoptic area (MPA). In contrast, glutamatergic interneurons in the MnPO, postulated to be excited by glutamatergic inputs from warm‐activated neurons in LPBd, excite W‐S neurons in MPA. Prostaglandin (PG) E2 binds to EP3 receptors to inhibit the activity of W‐S neurons in the POA. Preoptic W‐S neurons providing thermoregulatory control of BAT thermogenesis inhibit BAT sympathoexcitatory neurons in the dorsomedial hypothalamus and dorsal hypothalamic area (DMH/DA) which, when disinhibited during skin cooling, excite BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus (rRPa) and parapyramidal area (PaPy), that project to BAT sympathetic preganglionic neurons (SPN) in the spinal intermediolateral nucleus (IML). Some BAT premotor neurons can release glutamate (GLU) to excite BAT sympathetic preganglionic neurons and increase BAT sympathetic nerve activity, while others can release serotonin (5‐HT) to interact with 5‐HT1A receptors, potentially on inhibitory interneurons in the IML, to increase the BAT sympathetic outflow. Modulatory regions represent areas of the CNS that are not within the core thermoregulatory pathway, but from which chemical manipulation of the activity of local neurons produced effects (see text) on BAT activity. Dotted lines to question marks indicate that the pathway mediating the effect on BAT activity is unknown. Neurochemicals/hormones in yellow boxes activated and those in blue boxes reduced BAT activity. Neurons in the anterior piriform cortex (APC) sense the absence of indispensible amino acids (IAA) from the diet and stimulate an elevated level of BAT activity. Orexinergic neurons in the perifornical lateral hypothalamus (PeF‐LH) project to the rRPa to increase the excitability of BAT sympathetic premotor neurons. Histaminergic neurons in the tuberomammillary nucleus (TMN) project to the POA to increase BAT activity by influencing the discharge of neurons in the core thermoregulatory pathway. Activation of neurons in the ventrolateral medulla (VLM) produces an inhibition of BAT thermogenesis, at least in part by noradrenergic (NE) activation of α2 receptors on rRPa neurons. Neurons in the nucleus of the solitary tract (NTS) mediate the effects of afferents in the vagus and carotid sinus (CSN) and aortic depressor nerves. 2‐DG, 2‐deoxyglucose; 5‐HT, 5‐hydroxytryptamine; 5‐TG, 5‐thioglucose; αMSH, alpha melanocyte‐stimulating hormone; AngII, angiotensin II; BDNF, brain‐derived neurotrophic factor; CRF, corticotrophin releasing factor; NPY, neuropeptide Y; PGE2, prostaglandin E2; T3, triiodothyronine; TIP39, tuberoinfundibular peptide of 39 residues; TRH, thyrotropin‐releasing hormone; VGLUT3, vesicular glutamate transporter 3. Copyright 2014 by Oregon Health and Science University.


Figure 2. Lateral parabrachial neurons mediate cutaneous thermoreceptor afferent signaling regulating BAT thermogenesis. [(A) and (B) Bilateral nanoinjections into the lateral parabrachial nucleus (LPB) of the glutamate receptor antagonists, (2R)‐amino‐5‐phosphonovaleric acid (AP5), and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dionesaline (CNQX), but not the saline (SAL) vehicle, reverse the skin cooling‐evoked increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (Tbat), expired CO2, and heart rate (HR).TSKIN, skin temperature. Modified, with permission, from (243). [(C) and (D)] Injection into the median preoptic area (MnPO) of the retrograde tracer, cholera toxin B (orange injectate top panels), labels neurons in the dorsal subnucleus of the LPB (LPBd, middle panel in C), or in the external lateral subnucleus of the LPB (LPBel, middle panel in D) that also express c‐fos immunoreactivity (arrows in lower panels) following exposure to a warm ambient temperature (C) or a cool ambient temperature (D). Modified, with permission, from (243,244). (E) The discharge of a neuron (Unit) in LPBd is increased during episodes of skin warming that inhibit BAT SNA. Filled circles in inset indicate recording sites of warming‐activated units in LPBd. Modified, with permission, from (244). (F) The discharge of a neuron in LPBel is increased during episodes of skin cooling that activate BAT SNA. Filled circles in inset indicate recording sites of cooling‐activated units in LPBel. Modified, with permission, from (243).


Figure 3. POA microcircuitry integrates cutaneous and central thermal sensation and mediates febrile activations of BAT thermogenesis. (A) Action potentials (left panel) of a GABAergic (lower middle panel), warm‐sensitive neuron recorded in a brain slice (upper middle panel) through the preoptic area of a GAD65‐GFP mouse. Bath application of the histamine 3 receptor (H3R) agonist, R‐α‐methylhistamine, reduced the firing rate and eliminated the temperature sensitivity (right panel) of such GABAergic neurons in POA. Modified from (189). (B) The median preoptic area (MnPO) contains neurons (yellow) that express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) inoculations of BAT in LepRbEGFP mice. POA microcircuitry integrates cutaneous and central thermal sensation and mediates febrile activations of BAT thermogenesis. (A) Action potentials (left panel) of a GABAergic (lower middle panel), warm‐sensitive neuron recorded in a brain slice (upper middle panel) through the preoptic area of a GAD65‐GFP mouse. Bath application of the histamine 3 receptor (H3R) agonist, R‐α‐methylhistamine, reduced the firing rate and eliminated the temperature sensitivity (right panel) of such GABAergic neurons in POA. Modified from (189). (B) The median preoptic area (MnPO) contains neurons (yellow) that express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) inoculations of BAT in LepRbEGFP mice. Modified, with permission, from (418). Ca: blockade of GABAA receptors with bicuculline (BIC) nanoinjections in the medial preoptic area (MPA) reverses the skin cooling‐evoked increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (Tbat), expired CO2 (Exp CO2), and heart rate (HR). TSKIN, skin temperature; SAL, saline vehicle, modified, with permission, from (241). Cb: nanoinjection into the MnPO of the glutamate receptor antagonists, (2R)‐amino‐5‐phosphonovaleric acid (AP5) and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dionesaline (CNQX), but not the saline (SAL) vehicle, reversed the increases in BAT SNA, Tbat, Exp CO2, and HR evoked by activation of neurons in the lateral parabrachial nucleus (LPB) with nanoinjection of the glutamate receptor agonist, N‐methyl‐D‐aspartate (NMDA). Modified, with permission, from (243). Cc: bilateral nanoinjections of BIC, but not the SAL vehicle, into the MPA reversed the increases in BAT SNA, Tbat, Exp CO2, and HR evoked by disinhibition of neurons in the MnPO with a nanoinjection of BIC. Modified from (242). Cd: schematic drawings and histological section indicating representative nanoinjection sites in MnPO (left panel) and in MPA (middle and right panels). Modified, with permission, from (242). Da: immunohistochemical localization of the EP3 receptor in the rat MnPO and MPA (left panel). Modified, with permission, from (237). Selective genetic deletion of the EP3 receptor in the MnPO of Ptger 3ΔCNS/NesCre mice prevents the rise in body temperature observed in wild‐type mice following icv PGE2 (right panel). Modified, with permission, from (172). Db: prostaglandin (PG)E2 reduced the firing rate of a POA warm‐responsive neuron recorded in a rat brain slice, whose discharge frequency was increased during increases in bath temperature. Modified, with permission, from (286). Dc: nanoinjection of PGE2 into the MPA dramatically increased BAT SNA, Tbat, Tcore, Exp CO2, and HR and these fever‐mimicking thermogenic responses were completely reversed by inhibition of neuronal activity in the DMH with bilateral injections of muscimol (MUSC). Modified, with permission, from (246).


Figure 4. Neurons in the dorsomedial hypothalamus (DMH) and dorsal hypothalamic area (DA) mediate BAT sympathoexcitation. (A) Histological sections and drawings through the DMH/DA (upper panels) indicating (a) CTb retrogradely labeled neurons in the DMH/DA following iontophoretic CTb deposit (lower panel) in the rostral raphe pallidus (rRPa), modified, with permission, from (322); [(b) and (c)] the locations of CTb retrogradely labeled neurons (green circles) following nanoinjections of CTb (lower panel) in the rostral raphe pallidus (rRPa, b) or in the parapyramidal area (PaPy, c); red circles depict orexin immunoreactive neurons; filled black circles represent double‐labeled, orexinergic neurons that project to the rRPa; modified, with permission, from (386); and (D) the DMH/DA contains neurons (yellow) that both express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) injections into BAT in LepRbEGFP mice, modified, with permission, from (418). mt, mamillothalamic tract; f, fornix; py, pyramidal tract; B: the increases in BAT sympathetic nerve activity (SNA), BAT temperature (Tbat), expired CO2 (ExpCO2) and heart rate (HR) elicited by skin cooling are unaffected (Ba) by nanoinjections of saline vehicle (SAL) into the DMH/DA (Bc, right panel), but are reversed (Bb) by inhibition of local DMH/DA neurons with nanoinjections of muscimol (MUSC) into the DMH/DA (Bc). Modified, with permission, from (241). (C) Disinhibition of neurons in the DMH/DA (white arrowhead in inset histological section through the rat DMH/DA) by nanoinjection of the GABAA antagonist, bicuculline (BIC), resulted in an increase in BAT SNA, Tbat, and Exp CO2. Modified, with permission, from (226). D: nanoinjection of prostaglandin E2 (PGE2) into the medial preoptic area (MPA) increased BAT SNA, Tbat, Exp CO2, and heart rate (HR). Subsequent bilateral nanoinjections of the glutamate receptor antagonist, kynurenate (KYN), into the DMH completely reversed these PGE2‐evoked responses. Modified, with permission, from (193).


Figure 5. Rostral raphe pallidus (rRPa) contains BAT sympathetic premotor neurons whose activity determines the level of BAT thermogenesis. (A) Histological section through the rostral medulla at the level of the facial nucleus and the rostral raphe pallidus (rRPa) illustrating the transsynaptic, pseudorabies virus (PRV) labeling of BAT sympathetic premotor neurons (red) following PRV inoculations in interscapular BAT, and serotonergic neurons (green) immunohistochemically labeled for tryptophan hydroxylase, and rRPa‐BAT neurons that contain both markers (yellow). py, pyramidal tract. Modified, with permission, from (44). (B) Nanoinjection of bicuculline (BIC) in rRPa disinhibits BAT sympathetic premotor neurons and elicits a dramatic increase in BAT sympathetic nerve activity (SNA), BAT temperature (Tbat), and metabolic oxygen consumption, indirectly indicated by the elevation in expired CO2 (EXP CO2). Subsequent activation of the inhibitory 5‐HT1A receptors in rRPa with a local injection of 8OH‐DPAT completely reverses the activation of BAT SNA, likely by inhibiting BAT sympathetic premotor neurons. (C) Inhibition of local neurons in the rRPa with a nanoinjection of glycine produces a rapid and complete reversal of the skin cooling‐evoked increases in BAT SNA and Tbat, despite the sustained reduction in skin temperature (TSKIN). Modified, with permission, from (241). (D) Decreases in core body temperature after microinjection (dotted line) of 10, 20, and 80 pmol/100 nL of muscimol (MUSC) or saline vehicle into the RPa in four conscious rats. Bars with asterisk denote intervals during which temperature was significantly less than after saline treatment: solid bar, MUSC 80 pmol; dotted bar, MUSC 20 pmol. Modified, with permission, from (416).


Figure 6. Paraventricular hypothalamic nucleus (PVH) mechanisms influencing BAT thermogenesis. (A) Unilateral nanoinjection of bicuculline (BIC) into the PVH completely reversed the cooling‐evoked increases in BAT sympathetic nerve activity (SNA), BAT temperature (Tbat), and expired CO2 (Exp CO2). Modified, with permission, from (197). (Ba) The increases in BAT SNA and Tbat evoked by activation of rRPa neurons with nanoinjection of NMDA are unaffected by unilateral saline injection into the PVH (upper panel), but are markedly reduced by increasing the activity of PVH neurons with a unilateral nanoinjection of bicuculline (BIC) in the PVH (lower panel). Modified from (197). (Bb) Nanoinjection of BIC into the rostral raphe pallidus (rRPa) increases BAT SNA, Tbat, and Exp CO2, and prevents the inhibition of BAT SNA evoked by unilateral nanoinjection of BIC into the PVH. Modified from (197). (Ca) Channelrhodopsin2 (CHR2)‐tranfected, RIP‐Cre neurons (left panel) and their terminals in PVH (right panel) following adeno‐associated virus (AAV) injection in the arcuate nucleus (ARC) of a RIP‐Cre mouse; 3V, third ventricle; opt, optic chiasm; fx, fornix. Laser light (blue dashes) pulses depolarizing the CHR2‐expressing terminals of ARC RIP‐Cre neurons in PVH elicits inhibitory postsynaptic currents (IPSCs, lower panel) in a PVH neuron in a brain slice. (Cb) Leptin increases interscapular BAT (iBAT) temperature in vesicular GABA transporter (Vgat)‐floxxed mice, but not in RIP‐Cre, Vgatflox/flox mice. (Cc) Following injection into ARC of a cre‐dependent AAV producing expression of the designer receptor (hM3Dq) exclusively activated by designer drug (DREADD), selective activation of ARC RIP‐Cre neurons with clozapine‐N‐oxide (CNO) elicits a significant increase in oxygen consumption (VO2) and in iBAT temperature (Temp). Panels Ca‐Cc were modified, with permission, from (166). (D) Histological section through the PVH illustrating the overlap of transsynaptically infected, pseudorabies virus (PRV)‐labeled neurons (brown) following PRV injections into interscapular BAT and in situ hybridization for melanocortin 4‐receptor (MC4‐R) mRNA expression (black granules). Inset: High magnification of the outlined portion of the PVH. Note the presence of PRV in neurons surrounded by MC4‐R (curved black arrows) and PRV in neurons without associated MC4‐R (curved open arrows). Modified, with permission, from (349); 3V, third ventricle; ZI, zona inserta; oc, optic chiasm; SCH, suprachiasmatic nucleus. E: immunohistochemical labeling of PVH neurons for oxytocin (OXY, red) and for transsynaptic infection with PRV (green) after PRV injections into interscapular BAT. Arrows indicate neurons containing both PRV and OXY (yellow). Modified, with permission, from (259). (E) Schematic, based in part on (71), of the local PVH neurocircuitry proposed to mediate the GABAergic, neuropeptide Y (NPY) and α‐melanocyte‐stimulating hormone (αMSH) influences on BAT thermogenesis mediated by PVH neurons.


Figure 7. Orexinergic and other PeF/LH neurons influence BAT thermogenesis. (A) Coronal brain section through the PeF/LH shows many double‐labeled (white arrowheads, yellow fluorescence in the cytoplasm) orexinergic (red) neurons that were pseudorabies virus (PRV)‐infected (green), indicating their synaptic connection to BAT. Modified, with permission, from (386). (B) Orexinergic fibers (red) surround putative BAT sympathetic premotor neurons in rRPa (and in PaPy) transsynaptically infected following PRV inoculations of interscapular BAT. Modified, with permission, from (386). (C) Under cool conditions (Tcore < 37°C) with a low level of basal BAT SNA, nanoinjection of orexin‐A (Orx‐A, dashed line) in the rRPa elicited prolonged increases in BAT SNA, Tbat, Exp CO2, and heart rate (HR). Modified, with permission, from (386). (D) Under cool conditions (Tcore < 37°C) with a low level of basal BAT SNA, nanoinjection of NMDA (dashed line) in the PeF/LH elicited prolonged increases in BAT SNA, Tbat, Exp CO2, and HR. Modified, with permission, from (386). (E) icv PGE2 (filled symbols), but not ACSF (open symbols), elicited a marked increase in BAT temperature in orexin‐KO mice (triangles) and in the wild‐type littermates for either the orexin‐KO (circles) and for the orexin neuron‐ablated (squares) mice, but had no effect on Tbat in orexin neuron‐ablated mice (diamonds). Modified, with permission, from (372). (F) The activation of BAT SNA and BAT thermogenesis produced by disinhibitory activation of PeF/LH neurons with bicuculline (BIC) nanoinjection is dependent on the activation of glutamate receptors on DMH/DA neurons. Modified, with permission, from (55).


Figure 8. NTS neurons mediate both inhibition and excitation of BAT thermogenesis. (A) The disinhibitory activation of neurons in the intermediate NTS (iNTS), with injections of bicuculline (BIC), completely reversed the increases in BAT SNA, BAT temperature (Tbat), and expired CO2 that follow blockade of GABAA receptors in the rostral raphe pallidus (rRPa). Modified, with permission, from (47). (B) Activation of adenosine 1A receptors in iNTS at the level of the area postrema (inset), with bilateral injections of the agonist, N6‐cyclohexyladenosine (CHA), reverses the cooling‐evoked increases in BAT SNA and Tbat. Inhibition of iNTS neurons with bilateral injections of muscimol (MUSC) reverses the CHA‐evoked inhibition of BAT SNA, consistent with adenosine producing an increase in the activity of BAT sympathoinhibitory neurons in iNTS. Modified, with permission, from (387). (C) Ventilation with an hypoxic (8% O2) gas mixture that produces increases in integrated phrenic nerve amplitude (int PHR), heart rate (HR) and arterial pressure (AP), also elicits a complete inhibition of the increase in BAT SNA evoked by nanoinjection of BIC in rRPa. Inhibition of neuronal activity in the commissural subnucleus of the NTS (commNTS), with a nanoinjection of MUSC, eliminates the hypoxic inhibition of BAT SNA. Modified, with permission, from (194). (D) Changes in Tbat elicited by agents applied to the fourth ventricle. When preceded by leptin in the fourth ventricle, thyrotropin releasing hormone (TRH) markedly increases Tbat, indicating BAT thermogenesis. This effect is prevented by prior blockade of signal transduction pathways via fourth ventricle administration of wortmannin to block leptin‐evoked PIP3 generation or by the Src‐SH2 antagonist, PP2. Modified, with permission, from (291). (E) The iNTS contains neurons (yellow) that both express the leptin receptor (LepRb) (green) and are synaptically connected to BAT, as indicated by their transsynaptic retrograde infection (red) following pseudorabies virus (PRV) injections into BAT in LepRbEGFP mice. Modified, with permission, from (418).


Figure 9. Neurons in the ventrolateral medulla (VLM), including catecholaminergic neurons, provide an inhibitory regulation of BAT SNA and BAT thermogenesis. (A) The A1/C1 area of the VLM (bregma −13 mm) contains transsynaptically infected neurons (green) following pseudorabies virus (PRV) injections into interscapular BAT, tyrosine hydroxylase (TH)‐immunoreactive neurons (red), and double‐labeled (yellow, arrowhead) neurons indicative of catecholaminergic VLM neurons synaptically‐connected to BAT. (B) Distribution relative to the distance from bregma of catecholaminergic (red squares) and total (filled circles) neurons in the VLM retrogradely labeled following CTb injections into the rRPa. (C) Following PRSx8‐channel rhodopsin 2‐mCherry (ChR2) lentivirus, which preferentially transfects catecholaminergic neurons, nanoinjections into VLM, the rostral raphe pallidus (rRPa, white dotted outline) contains highly varicose fibers (red) expressing ChR2. (D) Laser photostimulation of VLM neurons containing the ChR2 (largely catecholaminergic neurons) inhibited BAT SNA and reduced BAT temperature (Tbat), an effect on BAT thermogenesis that was attenuated by blockade of α2‐adrenergic receptors in the rRPa. Panels A‐D, consistent with an activation of catecholaminergic neurons in the VLM inhibiting BAT SNA via a direct catecholaminergic input to the rRPa, are modified, with permission, from (199). (E) Glucoprivation with systemic 2‐deoxyglucose (2‐DG) activates [increases c‐fos (black nuclei)] many catecholaminergic neurons (gray) in the A1/C1 area of the VLM. Modified, with permission, from (290). (F) Local glucoprivation in the VLM by nanoinjection of 5‐thioglucose (5‐TG, dashed line) completely inhibits BAT SNA and reduces (Tbat) and metabolic oxygen consumption, indirectly indicated by the level of expired CO2 (Exp CO2). Modified, with permission, from (191).
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Article Title: Central Nervous System Regulation of Brown Adipose Tissue
 

How to Cite

Shaun F. Morrison, Christopher J. Madden. Central Nervous System Regulation of Brown Adipose Tissue. Compr Physiol 2014, 4: 1677-1713. doi: 10.1002/cphy.c140013