Neural circuits of long-term thermoregulatory adaptations to cold temperatures and metabolic demands.

The mammalian brain controls heat generation and heat loss mechanisms that regulate body temperature and energy metabolism. Thermoeffectors include brown adipose tissue, cutaneous blood flow and skeletal muscle, and metabolic energy sources include white adipose tissue. Neural and metabolic pathways modulating the activity and functional plasticity of these mechanisms contribute not only to the optimization of function during acute challenges, such as ambient temperature changes, infection and stress, but also to longitudinal adaptations to environmental and internal changes. Exposure of humans to repeated and seasonal cold ambient conditions leads to adaptations in thermoeffectors such as habituation of cutaneous vasoconstriction and shivering. In animals that undergo hibernation and torpor, neurally regulated metabolic and thermoregulatory adaptations enable survival during periods of significant reduction in metabolic rate. In addition, changes in diet can activate accessory neural pathways that alter thermoeffector activity. This knowledge may be harnessed for therapeutic purposes, including treatments for obesity and improved means of therapeutic hypothermia.

Mediobasal hypothalamic neurons contribute to the control of brown adipose tissue sympathetic nerve activity and cutaneous vasoconstriction.

The mediobasal hypothalamus (MBH) contains heterogeneous neuronal populations that regulate food intake and energy expenditure. However, the role of MBH neurons in the neural control of thermoeffector activity for thermoregulation is not known. This study sought to determine the effects of modulating the activity of MBH neurons on the sympathetic outflow to brown adipose tissue (BAT), BAT thermogenesis, and cutaneous vasomotion. Pharmacological inhibition of MBH neurons by local administration of muscimol, a GABAA receptor agonist, reduced skin cooling-evoked BAT thermogenesis, expired CO2, body temperature, heart rate, and mean arterial pressure, while blockade of GABAA receptors by nanoinjection of bicuculline in the MBH induced large increases in BAT sympathetic nerve activity (SNA), BAT temperature, body temperature, expired CO2, heart rate, and cutaneous vasoconstriction. Neurons in the MBH send projections to neurons in the dorsal hypothalamic area and dorsomedial hypothalamus (DMH), which excite sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) that control sympathetic outflow to BAT. The increases in BAT SNA, BAT temperature, and expired CO2 elicited by blockade of GABAA receptors in the MBH were reversed by blocking excitatory amino acid receptors in the DMH or in the rRPa. Together, our data show that MBH neurons provide a modest contribution to BAT thermogenesis for cold defense, while GABAergic disinhibition of these neurons produces large increases in the sympathetic outflow to BAT, and cutaneous vasoconstriction. Activation of glutamate receptors on BAT thermogenesis-promoting neurons of the DMH and rRPa is necessary for the increased sympathetic outflow to BAT evoked by disinhibition of MBH neurons. These data demonstrate neural mechanisms that contribute to the control of thermoeffector activity, and may have important implications for regulating body temperature and energy expenditure.

High Fat Diet Suppresses Energy Expenditure Via Neurons in the Brainstem.

Oxidation of fat by brown adipose tissue (BAT) contributes to energy balance and heat production. During cold exposure, BAT thermogenesis produces heat to warm the body. Obese subjects and rodents, however, show impaired BAT thermogenesis to the cold. Our previous studies suggest that vagal afferents synapsing in the nucleus tractus solitarius (NTS), tonically inhibit BAT thermogenesis to the cold in obese rats. NTS neurons send projections to the dorsal aspect of the lateral parabrachial nucleus (LPBd), which is a major integrative center that receives warm afferent inputs from the periphery and promotes inhibition of BAT thermogenesis. This study investigated the contribution of LPBd neurons in the impairment of BAT thermogenesis in rats fed a high-fat diet (HFD). By using a targeted dual viral vector approach, we found that chemogenetic activation of an NTS-LPB pathway inhibited BAT thermogenesis to the cold. We also found that the number of Fos-labelled neurons in the LPBd was higher in rats fed a HFD than in chow diet-fed rats after exposure to a cold ambient temperature. Nanoinjections of a GABAA receptor agonist into the LPBd area rescued BAT thermogenesis to the cold in HFD rats. These data reveal the LPBd as a critical brain area that tonically suppresses energy expenditure in obesity during skin cooling. These findings reveal novel effects of high-fat diets in the brain and in the control of metabolism and can contribute to the development of therapeutic approaches to regulate fat metabolism.

Acute deep brain stimulation of the paraventricular nucleus of the hypothalamus increases brown adipose tissue thermogenesis in rats.

Brown adipose tissue (BAT) activity is controlled by the sympathetic nervous system. Activation of BAT has shown significant promise in preclinical studies to elicit weight loss. Since the hypothalamic paraventricular nucleus (PVN) contributes to the regulation of BAT thermogenic activity, we sought to determine the effects of electrical stimulation of the PVN as a model of deep brain stimulation (DBS) for increasing BAT sympathetic nerve activity (SNA). The rostral raphe pallidus area (rRPa) was also chosen as a target for DBS since it contains the sympathetic premotor neurons for BAT. Electrical stimulation (100 µA, 100 µs, 100 Hz, for 5 min at a 50 % duty cycle) of the PVN increased BAT SNA and BAT thermogenesis. These effects were prevented by a local nanoinjection of bicuculline, a GABAA receptor antagonist. We suggest that electrical stimulation of the PVN elicited local release of GABA, which inhibited BAT sympathoinhibitory neurons in PVN, thereby releasing a restraint on BAT SNA. Electrical stimulation of the rRPa inhibited BAT thermogenesis and this was prevented by a local nanoinjection of bicuculline, suggesting that local release of GABA suppressed BAT SNA. Electrical stimulation of the PVN activates BAT metabolism via a mechanism that may include activation of local GABAA receptors. These findings contribute to our understanding of the mechanisms underlying the effects of DBS in the regulation of fat metabolism and provide a foundation for further DBS studies targeting hypothalamic circuits regulating BAT thermogenesis as a therapy for obesity.

Neural control of the spleen as an effector of immune responses to inflammation: mechanisms and treatments.

Immune system responses are a vital defense mechanism against pathogens. Inflammatory mediators finely regulate complex inflammatory responses from initiation to resolution. However, in certain conditions, the inflammation is initiated and amplified, but not resolved. Understanding the biological mechanisms underlying the regulation of the immune response is critical for developing therapeutic alternatives, including pharmaceuticals and bioelectronic tools. The spleen is an important immune effector organ since it orchestrates innate and adaptive immune responses such as pathogen clearance, cytokine production, and differentiation of cells, therefore playing a modulatory role that balances pro- and anti-inflammatory responses. However, modulation of splenic immune activity is a largely unexplored potential therapeutic tool that could be used for the treatment of inflammatory and life-threatening conditions. This review discusses some of the mechanisms controlling neuroimmune communication and the brain-spleen axis.

Neural circuits mediating circulating interleukin-1ß-evoked fever in the absence of prostaglandin E2 production.

Infectious diseases and inflammatory conditions recruit the immune system to mount an appropriate acute response that includes the production of cytokines. Cytokines evoke neurally-mediated responses to fight pathogens, such as the recruitment of thermoeffectors, thereby increasing body temperature and leading to fever. Studies suggest that the cytokine interleukin-1ß (IL-1ß) depends upon cyclooxygenase (COX)-mediated prostaglandin E2 production for the induction of neural mechanisms to elicit fever. However, COX inhibitors do not eliminate IL-1ß-induced fever, thus suggesting that COX-dependent and COX-independent mechanisms are recruited for increasing body temperature after peripheral administration of IL-1ß. In the present study, we aimed to build a foundation for the neural circuit(s) controlling COX-independent, inflammatory fever by determining the involvement of brain areas that are critical for controlling the sympathetic outflow to brown adipose tissue (BAT) and the cutaneous vasculature. In anesthetized rats, pretreatment with indomethacin, a non-selective COX inhibitor, did not prevent BAT thermogenesis or cutaneous vasoconstriction (CVC) induced by intravenous IL-1ß (2 µg/kg). BAT and cutaneous vasculature sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) are required for IL-1ß-evoked BAT thermogenesis and CVC, with or without pretreatment with indomethacin. Additionally, activation of glutamate receptors in the dorsomedial hypothalamus (DMH) is required for COX-independent, IL-1ß-induced BAT thermogenesis. Therefore, our data suggests that COX-independent mechanisms elicit activation of neurons within the DMH and rRPa, which is sufficient to trigger and mount inflammatory fever. These data provide a foundation for elucidating the brain circuits responsible for COX-independent, IL-1ß-elicited fevers.

A general pattern of trade-offs between ecosystem resistance and resilience to tropical cyclones.

Tropical cyclones drive coastal ecosystem dynamics, and their frequency, intensity, and spatial distribution are predicted to shift with climate change. Patterns of resistance and resilience were synthesized for 4138 ecosystem time series from n = 26 storms occurring between 1985 and 2018 in the Northern Hemisphere to predict how coastal ecosystems will respond to future disturbance regimes. Data were grouped by ecosystems (fresh water, salt water, terrestrial, and wetland) and response categories (biogeochemistry, hydrography, mobile biota, sedentary fauna, and vascular plants). We observed a repeated pattern of trade-offs between resistance and resilience across analyses. These patterns are likely the outcomes of evolutionary adaptation, they conform to disturbance theories, and they indicate that consistent rules may govern ecosystem susceptibility to tropical cyclones.

Dynamic 13 C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

PURPOSE: This study is to investigate time-resolved 13 C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-13 C]pyruvate in the human brain. METHODS: Time-resolved 13 C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-13 C]pyruvate. 13 C MRS with low flip-angle excitations and a multichannel 13 C/1 H dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of 13 C-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO3- . Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise 13 C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval. RESULTS: [1-13 C]Lactate relative to the total 13 C signal (tC) was 0.21-0.24 in all slices. [13 C] HCO3- /tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO3- were calculated as 0.014-0.018 s-1 and 0.0043-0.0056 s-1 , respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1-13 C]pyruvate. CONCLUSIONS: Dynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1-13 C]pyruvate.

Dopaminergic input from the posterior hypothalamus to the raphe pallidus area inhibits brown adipose tissue thermogenesis.

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA's hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of N-methyl-d-aspartate (NMDA) receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2Rs are expressed in cold-activated and serotonergic neurons in the rRPa, and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pretreatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically active, dopaminergic input from the PH that suppresses BAT thermogenesis.

Activation of Transient Receptor Potential Vanilloid 1 Channels in the Nucleus of the Solitary Tract and Activation of Dynorphin Input to the Median Preoptic Nucleus Contribute to Impaired BAT Thermogenesis in Diet-Induced Obesity.

The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high-fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid (LA) metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared with chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine (CPZ) in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of CPZ into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neurons that project to the MnPO. Many of the neurons in the LPBd that expressed c-fos during cold challenge were dynorphinergic. In HFD rats, nanoinjections of the κ opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), in the MnPO rescued the impaired BAT SNA and thermogenic responses to cold. These data suggest that HFD increases the content of endogenous ligands of TRPV1 in the NTS, which increases the drive to LPBd neurons that in turn release dynorphin in the MnPO to impair activation of BAT.

Imaging Acute Metabolic Changes in Patients with Mild Traumatic Brain Injury Using Hyperpolarized [1-13C]Pyruvate.

Traumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of 13C-labeled substrates provides a unique opportunity to map the metabolic changes in the brain after traumatic injury in real-time without invasive procedures. In this report, we investigated two patients with acute mild TBI (Glasgow coma scale 15) but no anatomical brain injury or hemorrhage. Patients were imaged with hyperpolarized [1-13C]pyruvate MRSI 1 or 6 days after head trauma. Both patients showed significantly reduced bicarbonate (HCO3 -) production, and one showed hyperintense lactate production at the injured sites. This study reports the feasibility of imaging altered metabolism using hyperpolarized pyruvate in patients with TBI, demonstrating the translatability and sensitivity of the technology to cerebral metabolic changes after mild TBI.

Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus.

Whether leptin acts in the paraventricular nucleus (PVN) to increase sympathetic nerve activity (SNA) is unclear, since PVN leptin receptors (LepR) are sparse. We show in rats that PVN leptin slowly increases SNA to muscle and brown adipose tissue, because it induces the expression of its own receptor and synergizes with local glutamatergic neurons. PVN LepR are not expressed in astroglia and rarely in microglia; instead, glutamatergic neurons express LepR, some of which project to a key presympathetic hub, the rostral ventrolateral medulla (RVLM). In PVN slices from mice expressing GCaMP6, leptin excites glutamatergic neurons. LepR are expressed mainly in thyrotropin-releasing hormone (TRH) neurons, some of which project to the RVLM. Injections of TRH into the RVLM and dorsomedial hypothalamus increase SNA, highlighting these nuclei as likely targets. We suggest that this neuropathway becomes important in obesity, in which elevated leptin maintains the hypothalamic pituitary thyroid axis, despite leptin resistance.

Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness.

BACKGROUND: High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness. METHODS: We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival. RESULTS: Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC. CONCLUSIONS: The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome. KEY POINTS: 1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.

Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT1A receptor activation in raphe pallidus.

AIM: Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter and hormone, modulates many physiological functions including body temperature. We investigated neural mechanisms involved in the inhibition of brown adipose tissue (BAT) sympathetic nerve activity (SNA) and BAT thermogenesis evoked by 5-HT. METHODS: Electrophysiological recordings, intravenous (iv) injections and nanoinjections in the brains of anaesthetized rats. RESULTS: Cooling-evoked increases in BAT SNA were inhibited by the intra-rostral raphé pallidus (rRPa) and the iv administration of the 5-HT1A receptor agonist, 8-OH-DPAT or 5-HT. The intra-rRPa 5-HT, the intra-rRPa and the iv 8-OH-DPAT, but not the iv 5-HT-induced inhibition of BAT SNA were prevented by nanoinjection of a 5-HT1A receptor antagonist in the rRPa. The increase in BAT SNA evoked by nanoinjection of NMDA in the rRPa was not inhibited by iv 5-HT, indicating that iv 5-HT does not inhibit BAT SNA by acting in the rRPa or in the sympathetic pathway distal to the rRPa. In contrast, under a warm condition, blockade of 5HT1A receptors in the rRPa increased BAT SNA and BAT thermogenesis, suggesting that endogenous 5-HT in the rRPa contributes to the suppression of BAT SNA and BAT thermogenesis. The increases in BAT SNA and BAT thermogenesis evoked by nanoinjection of NMDA in the dorsomedial hypothalamus (DMH) were inhibited by iv 5-HT, but those following bicuculline nanoinjection in the DMH were not inhibited. CONCLUSIONS: The systemic 5-HT-induced inhibition of BAT SNA requires a GABAergic inhibition of BAT sympathoexcitatory neurones in the DMH. In addition, during warming, 5-HT released endogenously in rRPa inhibits BAT SNA.

TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons.

The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca2+-activated chloride (Cl-) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current. Its expression is reduced, as is CCK current activity in obese mice on a high-fat diet (HFD). Reduced expression of TMEM16B in the heterozygote KO of the channel in sensory neurons results in an obese phenotype with a loss of CCK sensitivity in intestinal nodose neurons, a loss of CCK-induced satiety, and metabolic changes, including decreased energy expenditure. The effect on energy expenditure is further supported by evidence in rats showing that CCK enhances sympathetic nerve activity and thermogenesis in brown adipose tissue, and these effects are abrogated by a HFD and vagotomy. Our findings reveal that Ano2/TMEM16B is a Ca2+-activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity.

Central nervous system circuits that control body temperature.

Maintenance of mammalian core body temperature within a narrow range is a fundamental homeostatic process to optimize cellular and tissue function, and to improve survival in adverse thermal environments. Body temperature is maintained during a broad range of environmental and physiological challenges by central nervous system circuits that process thermal afferent inputs from the skin and the body core to control the activity of thermoeffectors. These include thermoregulatory behaviors, cutaneous vasomotion (vasoconstriction and, in humans, active vasodilation), thermogenesis (shivering and brown adipose tissue), evaporative heat loss (salivary spreading in rodents, and human sweating). This review provides an overview of the central nervous system circuits for thermoregulatory reflex regulation of thermoeffectors.

Neurons in the rat ventral lateral preoptic area are essential for the warm-evoked inhibition of brown adipose tissue and shivering thermogenesis.

AIM: To determine the role of neurons in the ventral part of the lateral preoptic area (vLPO) in CNS thermoregulation. METHODS: In vivo electrophysiological and neuropharmacological were used to evaluate the contribution of neurons in the vLPO to the regulation of brown adipose tissue (BAT) thermogenesis and muscle shivering in urethane/chloralose-anaesthetized rats. RESULTS: Nanoinjections of NMDA targeting the medial preoptic area (MPA) and the vLPO suppressed the cold-evoked BAT sympathetic activity (SNA), reduced the BAT temperature (TBAT ), expired CO2 , mean arterial pressure (MAP), and heart rate. Inhibition of vLPO neurons with muscimol or AP5/CNQX elicited increases in BAT SNA, TBAT , tachycardia, and small elevations in MAP. The BAT thermogenesis evoked by AP5/CNQX in vLPO was inhibited by the activation of MPA neurons. The inhibition of BAT SNA by vLPO neurons does not require a GABAergic input to dorsomedial hypothalamus (DMH), but MPA provides a GABAergic input to DMH. The activation of vLPO neurons inhibits the BAT thermogenesis evoked by NMDA in the rostral raphe pallidus (rRPa), but not that after bicuculline in rRPa. The BAT thermogenesis elicited by vLPO inhibition is dependent on glutamatergic inputs to DMH and rRPa, but these excitatory inputs do not arise from MnPO neurons. The activation of neurons in the vLPO also inhibits cold- and prostaglandin-evoked muscle shivering, and vLPO inhibition is sufficient to evoke shivering. CONCLUSION: The vLPO contains neurons that are required for the warm ambient-evoked inhibition of muscle shivering and of BAT thermogenesis, mediated through a direct or indirect GABAergic input to rRPa from vLPO.

Preoptic area cooling increases the sympathetic outflow to brown adipose tissue and brown adipose tissue thermogenesis.

Modest cold exposures are likely to activate autonomic thermogenic mechanisms due to activation of cutaneous thermal afferents, whereas central thermosensitive neurons set the background tone on which this afferent input is effective. In addition, more prolonged or severe cold exposures that overwhelm cold defense mechanisms would directly activate thermosensitive neurons within the central nervous system. Here, we examined the involvement of the canonical brown adipose tissue (BAT) sympathoexcitatory efferent pathway in the response to direct local cooling of the preoptic area (POA) in urethane-chloralose-anesthetized rats. With skin temperature and core body temperature maintained between 36 and 39°C, cooling POA temperature by ~1-4°C evoked increases in BAT sympathetic nerve activity (SNA), BAT temperature, expired CO2, and heart rate. POA cooling-evoked responses were inhibited by nanoinjections of ionotropic glutamate receptor antagonists or the GABAA receptor agonist muscimol into the median POA or by nanoinjections of ionotropic glutamate receptor antagonists into the dorsomedial hypothalamic nucleus (bilaterally) or into the raphe pallidus nucleus. These results demonstrate that direct cooling of the POA can increase BAT SNA and thermogenesis via the canonical BAT sympathoexcitatory efferent pathway, even in the face of warm thermal input from the skin and body core.

Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.

Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist exendin-4 (Ex4, 0.3 µg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glp1r knockdown (kd) in VANs. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with HFD-fed controls. Anterograde transsynaptic viral tracing of VANs infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VANs expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis and imply that through this gut-brain-BAT connection, intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.