Brown Adipose Tissue Sympathetic Nerve Research Articles

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.

Neuropeptide Y suppresses thermogenic and cardiovascular sympathetic nerve activity via Y1 receptors in the paraventricular nucleus and dorsomedial hypothalamus.

In hungry animals, neuropeptide Y (NPY) neurones in the arcuate nucleus (ArcN) are activated to suppress energy expenditure, in part by decreasing brown adipose tissue sympathetic nerve activity (BAT SNA); however, the NPY receptor subtype and brain neurocircuitry are unclear. In the present study, we investigated the inhibition of BAT SNA by exogenous and endogenous NPY via binding to Y1 receptors (NPY1R) in the hypothalamic paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH), in anaesthetised male rats. Downstream projections of PVN/DMH NPY1R-expressing neurones were identified using male Npy1r-cre mice and localised unilateral DMH or PVN injections of an adeno-associated virus, which allows for the cre-dependent expression of a fluorescent protein (mCherry) in the cell bodies, axon fibres and nerve terminals of NPY1R-containing neurones. Nanoinjections of NPY into the DMH of cooled rats decreased BAT SNA, as well as mean arterial pressure (MAP) and heart rate (HR), and these responses were reversed by subsequent injection of the selective NPY1R antagonist, BIBO3304. In warmed rats, with little to no BAT SNA, bilateral nanoinjections of BIBO3304 into the DMH or PVN increased BAT SNA, MAP and HR. DMH NPY1R-expressing neurones projected heavily to the raphe pallidus (RPa), which houses BAT presympathetic neurones, as well as the PVN. In anaesthetised mice, DMH BIBO3304 increased splanchnic SNA, MAP and HR, all of which were reversed by nonselective blockade of the PVN with muscimol, suggesting that DMH-to-PVN connections are involved in this DMH BIBO3304 disinhibition. PVN Y1R expressing neurones also projected to the RPa, as well as to the nucleus tractus solitarius. We conclude that NPY tonically released in the DMH and PVN suppresses BAT SNA, MAP and HR via Y1R. Downstream neuropathways for BAT SNA may utilise direct projections to the RPa. Release of tonic NPY inhibition of BAT SNA may contribute to feeding- and diet-induced thermogenesis.

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.

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. Electrophysiological recordings, intravenous (iv) injections and nanoinjections in the brains of anaesthetized rats. 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. 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.

Systemic Administration of Serotonin Reduces the Excitability of the Raphé Pallidus‐Brown Adipose Tissue Sympathetic Nerve Pathway

Activation of 5‐HT1A receptors in the raphé pallidus (RPa) inhibits the skin cooling‐evoked increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA). Our aim was to determine whether intravenous (iv) 5‐HT would affect BAT SNA and if 5‐HT1A receptors in the RPa play a role in mediating any of the effects of iv 5‐HT. In urethane/α‐chloralose anesthetized, neuromuscularly blocked, ventilated rats, electrical stimulation (100–150 μA, single 1 ms pulses) of the RPa evoked compound potentials in BAT SNA. Iv infusion of 5‐HT (500 μg/h) reduced the amplitude of the RPa‐evoked compound potentials in BAT SNA. Skin cooling‐evoked increases in BAT SNA were also inhibited by the iv infusion of 5‐HT, and by an iv bolus of the 5‐HT1A/7 receptor agonist, 8‐OHDPAT (100 μg in 50 μl). Nanoinjection of the 5‐HT1A receptor antagonist, WAY100635 (10 mM, 100 nl), in the RPa completely prevented the iv 8‐OHDPAT‐induced inhibition of BAT SNA, but not that following iv 5‐HT. In conclusion, iv 5‐HT reduces the excitability of the sympathetic pathway from the RPa to BAT, but this effect is not mediated by activation of 5‐HT1A receptors in the RPa. In contrast, activation of 5‐HT1A receptors in the RPa plays a key role in the inhibition of cold‐evoked BAT SNA by iv administration of 8‐OHDPAT.Support or Funding InformationSupported by São Paulo Research Foundation (FAPESP) grant #2017/24232‐9 (C.M.D.M.) and by NIH R01‐NS091066 (S.F.M.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Tonic inhibition of brown adipose tissue sympathetic nerve activity via muscarinic acetylcholine receptors in the rostral raphe pallidus.

A tonically active, muscarinic cholinergic inhibition of rostral raphe pallidus (rRPa) neurons influences thermogenesis of brown adipose tissue (BAT) independent of ambient temperature conditions. The tonically active cholinergic input to rRPa originates caudal to the hypothalamus. Muscarinic acetylcholine receptor (mAChR) activation in rRPa contributes to the inhibition of BAT sympathetic nerve activity (SNA) evoked by activation of neurons in the rostral ventrolateral medulla (RVLM). The RVLM is not the sole source of the muscarinic cholinergic input to rRPa. Activation of GABA receptors in rRPa does not mediate the cholinergic inhibition of BAT SNA. We sought to determine if body temperature and energy expenditure are influenced by a cholinergic input to neurons in the rostral raphe pallidus (rRPa), the site of sympathetic premotor neurons controlling thermogenesis of brown adipose tissue (BAT). Nanoinjections of the muscarinic acetylcholine receptor (mAChR) agonist, oxotremorine, or the cholinesterase inhibitor, neostigmine (NEOS), in the rRPa of anaesthetized rats decreased cold-evoked BAT sympathetic nerve activity (SNA, nadirs: -72 and -95%), BAT temperature (Tbat, -0.5 and -0.6°C), expired CO2 (Exp. CO2 , -0.3 and -0.5%) and heart rate (HR, -22 and -41bpm). NEOS into rRPa reversed the increase in BAT SNA evoked by blockade of GABA receptors in rRPa. Nanoinjections of the mAChR antagonist, scopolamine (SCOP), in the rRPa of warm rats increased BAT SNA (peak: +1087%), Tbat (+1.8°C), Exp. CO2 (+0.7%), core temperature (Tcore, +0.5°C) and HR (+54bpm). SCOP nanoinjections in rRPa produced similar activations of BAT during cold exposure, following a brain transection caudal to the hypothalamus, and during the blockade of glutamate receptors in rRPa. We conclude that a tonically active cholinergic input to the rRPa inhibits BAT SNA via activation of local mAChR. The inhibition of BAT SNA mediated by mAChR in rRPa does not depend on activation of GABA receptors in rRPa. The increase in BAT SNA following mAChR blockade in rRPa does not depend on the activity of neurons in the hypothalamus or on glutamate receptor activation in rRPa.

Transient receptor potential vanilloid type 1 (TRPV1) activation in the Nucleus of the Solitary tract inhibits brown adipose tissue sympathetic nerve activity

Stimulation of vagal afferent fibers or activation of neurons in the NTS (the site of vagal afferent terminals) inhibits sympathetic outflow to BAT. TRPV1 which is densely expressed in visceral vagal afferents can be directly activated by endogenous lipids to increase visceral afferent activation of neurons in the NTS. The current study investigated whether activation of TRPV1 receptors in the NTS inhibits BAT SNA and compared the level of endogenous activation of TRPV1 in rats maintained on a control chow diet or a high fat diet. In urethane/chloralose anesthetized rats maintained on a control chow diet, nanoinjection of the highly potent and selective TRPV1 receptor agonist resiniferatoxin (RTX) completely inhibited cold‐evoked BAT SNA. In rats on a control chow diet blockade of TRPV‐1 receptors in the NTS by pretreatment with the TRPV1 antagonist capsazepine (CPZ) had no effect on basal or cold‐evoked BAT SNA but prevented the RTX evoked inhibition of BAT SNA. In contrast, in rats maintained on a high fat diet for at least 8 weeks BAT SNA failed to increase during cold exposure. Nanoinjection of CPZ in the NTS reversed the HFD‐induced impairment of cooling‐evoked BAT SNA. These data demonstrate that activation of TRPV1 receptors in the NTS inhibits cold‐evoked increases in BAT SNA and suggest that in rats maintained on a high fat diet there is an elevated endogenous activation of the TRPV1 receptors in the NTS that is necessary for the high fat diet‐induced impairment of BAT activation.Support or Funding InformationSupported by American Diabetes Association Basic Science grant #1‐13‐BS‐120.

Deletion of brain‐specific isoform of renin (renin‐b) increases resting metabolic rate by stimulating brown adipose tissue sympathetic nerve activity

Activation of the brain renin‐angiotensin system (RAS) stimulates energy expenditure through increasing sympathetic nerve activity (SNA). In the brain, the renin gene is transcribed from an alternative promoter‐first exon resulting in a product that lacks the signal peptide and a third of the prosegment. This product, termed renin‐b, is highly brain specific and likely remains intracellular. Deletion of renin‐b induces central RAS activation and hypertension, indicating that renin‐b is a negative regulator of the brain RAS. We hypothesize that genetic deletion of renin‐b interferes with the control of metabolism and energy expenditure by inducing brown adipose tissue (BAT) SNA and enhanced insulin sensitivity. We generated a mouse model carrying a selective loss of renin‐b (Renin‐bNull) while preserving the classical renin isoform expressed in the kidney (renin‐a). Resting metabolic rate was assessed by respirometry. Basal BAT SNA was evaluated using direct multifiber recording of SNA subserving BAT. Fasted mice were subjected to glucose tolerance test (GTT) and insulin tolerance test (ITT). Renin‐bNull mice exhibited increased resting metabolic rate in comparison to their control littermates (0.156 ± 0.005 kcal/h in Renin‐bNull vs. 0.145 ± 0.003 kcal/h in control littermates, p<0.015, mean ± SEM). Under basal conditions, Renin‐bNull mice do not show differences in body weight, food consumption, and physical activity. However, weight gain was attenuated in male but not female Renin‐bNull in response to high fat diet (36.8 ± 1.2 in male Renin‐bNull vs. 41.9 ± 1.4 in male control, p<0.03). The analysis of the area under the curve (AUC) in GTT revealed mild but significant glucose intolerance in Renin‐bNull in comparison to control (152.5 ± 20.9 in Renin‐bNull vs. 93.0 ± 14.3 in control, p<0.03). However, there were no significant differences in the AUC in the ITT between Renin‐bNull and the control (174.3 ± 12.8 in Renin‐bNull vs. 207.0 ± 12.8 in control, p=0.077). Deletion of renin‐b induced an increase in SNA in BAT (40.8 ± 3.1 in Renin‐bNull vs. 27.2 ± 3.1 in control, p<0.003) and this was associated with an increase in uncoupled protein 1 (UCP1) protein expression in BAT (2.1 ± 0.5 fold increase in Renin‐bNull vs. control, p<0.05). These data suggest that renin‐b is involved in maintaining energy homeostasis likely by preventing central RAS activation. The activation of BAT SNA and the subsequent UCP1 overexpression are likely to be mechanistically involved in the increased energy expenditure observed in Renin‐bNull mice. Downregulation of renin‐b and the consequent brain RAS activation may be an important pathophysiological mechanism involved not only in the development of neurogenic hypertension, but also in obesity and other metabolic diseases.Support or Funding InformationNIH and AHA

AT1A Receptors in AgRP Neurons Disinhibit αMSH Neurotransmission

The brain renin‐angiotensin system (RAS) and leptin contribute to the control of resting metabolic rate (RMR) and their receptors are co‐expressed in areas of the brain critical for metabolic control, supporting the concept that the central interaction between angiotensin and leptin may be critical to regulate RMR and thus obesity. We have previously demonstrated that angiotensin AT1A receptors co‐localize to leptin‐sensitive cells in the arcuate nucleus (ARC), which also express agouti‐related peptide (AgRP). Moreover, mice lacking angiotensin AT1A receptors in AgRP neurons (AT1AAgRP‐KO) exhibit attenuated brown adipose tissue sympathetic nerve activity in response to leptin (4 hrs post‐leptin, control n=4, 221±18 vs AT1AAgRP‐KO n=5, 150±10 % baseline, p<0.05). AT1AAgRP‐KO mice also exhibit suppressed stimulation of RMR in response to exogenous alpha‐melanocyte stimulating hormone (αMSH; control n=13, +0.032±0.005 vs AT1AAgRP‐KO n=9, +0.012±0.005 kcal/hr, p<0.05), leading us to hypothesize that the activation of AT1A receptors in leptin‐sensitive AgRP neurons disinhibits αMSH neurotransmission and subsequent stimulation of RMR via suppression of inhibitory signaling within the ARC. We examined brain punches from the ARC of AT1AAgRP‐KO mice for the expression of AgRP, neuropeptide Y (NPY), and genes involved in gamma‐aminobutyric acid (GABA) signaling, including the glutamate decarboxylase enzymes, GAD1 and GAD2, and the vesicular GABA transporter VGAT, in response to selective ablation of the AT1A receptor. AT1AAgRP‐KO mice (n=5) exhibited significant (p<0.05) inductions in AgRP (10.3‐fold), NPY (4.8‐fold), GAD1 (1.9‐fold), GAD2 (1.5‐fold) and VGAT (6.9‐fold) in the ARC compared to control littermates (n=10). Taken together, these data support a role for AT1A receptors within AgRP neurons of the ARC in the control of BAT SNA and RMR through suppression of inhibitory AgRP/NPY/GABA signaling and thus disinhibition of stimulatory αMSH neurotransmission.

Vagal afferent activation decreases brown adipose tissue (BAT) sympathetic nerve activity and BAT thermogenesis

ABSTRACTIn urethane/α-chloralose anesthetized rats, electrical stimulation of cervical vagal afferent fibers inhibited the increases in brown adipose tissue sympathetic nerve activity and brown adipose tissue thermogenesis evoked by cold exposure, by nanoinjection of the GABAA receptor antagonist, bicuculline, in the dorsomedial hypothalamus, and by nanoinjection of N-methyl-D-aspartate in the rostral raphe pallidus. Vagus nerve stimulation-evoked inhibition of brown adipose tissue sympathetic nerve activity was prevented by blockade of ionotropic glutamate receptors in the termination site of vagal afferents in the nucleus of the solitary tract, and by nanoinjection of GABAA receptor antagonists in the rostral raphe pallidus. In conclusion, the brown adipose tissue sympathoinhibitory effect of cervical afferent vagal nerve stimulation is mediated by glutamatergic activation of second-order sensory neurons in the nucleus of the solitary tract and by a GABAergic inhibition of brown adipose tissue sympathetic premotor neurons in the rostral raphe pallidus, but does not require GABAergic inhibition of the brown adipose tissue sympathoexcitatory neurons in the dorsomedial hypothalamus.

Effects of intracerebroventricular injection of nesfatin‐1 on autonomic nerve activities in rats and mice

Nesfatin‐1, one of neuropeptides, reduces appetite and enhances energy expenditure in animals. Previous our experiment showed that intracerebroventricular (ICV) administration of nesfatin‐1 suppressed food intake and stimulated sympathetic nerve outflows to the kidney and the white adipose tissue through the hypothalamic ERK signals (Tanida M., et al., Diabetes 2015). However, it has not been examined whether central nesfatin‐1 affects efferent sympathetic nerve activities to the adrenal gland or the brown adipose tissue regulating cardiovascular function or thermogenesis, respectively, and efferent vagal nerve outflow. Here, we investigated effects of ICV injection of nesfatin‐1 on efferent adrenal sympathetic nerve activity (ASNA) and brown adipose tissue sympathetic nerve activity (BAT‐SNA), and efferent gastric vagal nerve activity (GVNA) in anesthetized rats. In addition, to check species difference in nesfatin‐1 action on autonomic nerves, sympathetic response to ICV injection of nesfatin‐1 was determined in anesthetized mice.Electrophysiological recordings of autonomic nerve activities in anesthetized rats and mice were performed within the scope of our previous studies (Tanida M., et al., Diabetes 2015, Tanida M., Neuroscience 2013). All animal care and handling procedures were approved by the Animal Research Committees of Kanazawa Medical University. 7–10days after ICV surgery, rats and mice were anesthetized with intraperitoneal injections of a urethane (750 mg/kg) and a‐chloralose (75 mg/kg) mixture. ASNA, BAT‐SNA and GVNA in rats, and sympathetic nerve to the kidney in mice were measured by electrophysiological system.In the present study, we found that ICV injection of nesfatin‐1 (20, 200 pmol) activated ASNA and BAT‐SNA in dose‐dependent manner while the GVNA was suppressed by nesfatin‐1. In addition, pretreatment with the melanocortin‐3/4 receptor antagonist, SHU9119, attenuated the increase in ASNA induced by nesfatin‐1. These data suggest that hypothalamic nesfatin‐1 stimulates not only renal sympathetic nerve but also sympathetic nerve activities to the adrenal gland and the brown adipose tissue via the hypothalamic melanocortin system to regulate cardiovascular and thermogenic actions. Similar with sympathetic responses of rats to nesfatin‐1, nesfatin‐1 injection to the mice also activated renal sympathetic outflow, indicating that sympathoexcitation of the kidney was also induced in mice.

Central Control of Neurogenic Fever Following Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is a devastating form of stroke that is associated with autonomic dysfunction including neurogenic fever (NF) that contributes to an increase in mortality and worse outcomes. Drugs that inhibit cyclooxygenase (COX) are generally ineffective in treating NF which suggesting a different central mediator for the generation of NF than prostaglandins. The aim of this work was to determine in a rat model of SAH if (1) the generation of NF requires the same central thermogenic control and (2) the same thermogenic organs, as that required for the generation of PGE2 mediated fever.In urethane chloralose‐anesthetized Wistar rats direct injection of blood into the subarachnoid space evoked an increase of brown adipose tissue sympathetic nerve activity (BAT SNA) and thermogenesis leading to a rapid increase in core temperature. Inhibition of central regions important for cold‐evoked and PGE2‐mediated thermogenesis, such as the dorsal medial hypothalamus and medullary raphe pallidus, promptly blocked the NF response. However the use of a COX inhibitor to prevent the production of PGE2, failed to completely inhibit NF.We demonstrate for the first time that NF following SAH requires the same central neuronal thermoregulatory circuit and thermogenic organs involved in the generation of PGE2 mediated fever. A significant component of NF appears to be dependent on a different trigger than PGE2.Merit Award Department of Veterans Affairs

Effects of inhaled citronella oil and related compounds on rat body weight and brown adipose tissue sympathetic nerve.

Citronella oil is one of the most famous Indonesian essential oils, having a distinctive aroma. As with other essential oils, it is crucial to explore the effects of inhalation of this oil. Therefore, the aim of this research was to elucidate the effects of inhalation of citronella oil and its components isolated from Cymbopogon nardus L. (Poaceae), Indonesian local name: “Sereh Wangi” on the body weight, blood lipid profile, and liver function of rats, as well as on the sympathetic nerve activity and temperature of brown adipose tissue. Sprague-Dawley male adult rats fed with high fat diet (HFD) were made to inhale citronella oil, R-(+)-citronellal, and β-citronellol for five weeks, and the observations were compared to those of HFD rats that were not subjected to inhalation treatment. The results showed that inhalation of β-citronellol decreased feed consumption. As a consequence, the percentage of weight gain decreased compared with that in control group and the blood cholesterol level in the β-citronellol group was significantly lowered. Concentration of liver function enzymes were not significantly different among the groups. In conclusion, inhalation of citronella oil, specifically β-citronellol, decreased body weight by decreasing appetite, without any marked changes in liver enzyme concentrations.

Vagal nerve stimulation can elicit both activation and inhibition of brown adipose tissue sympathetic nerve activity (1131.6)

The dependence of BAT thermogenesis on the availability of metabolic substrates suggests that metabolic signals from the viscera could influence the sympathetic outflow driving BAT thermogenesis. Viscerosensory afferents in the proximal end of the sectioned left cervical vagus nerve were activated with electrical stimulation in anesthetized, ventilated rats while recording the SNA to the contralateral interscapular BAT pad. Paired‐pulse VNS delivered once every 5 sec evoked excitatory evoked potentials in BAT SNA with a peak latency of ~ 180 ms, followed by a ~2 s period of quiescent BAT SNA. Within a few seconds of stimulus onset, continuous, single‐pulse VNS at 2 Hz produced a complete inhibition of cold‐evoked BAT SNA that was sustained for at least 2 hrs of maintained VNS. Similarly, activation of neurons in the intermediate nucleus of the solitary tract (iNTS), at the level of the area postrema, with nanoinjections (60 pmol) of bicuculline also inhibits the VNS‐evoked excitation of BAT SNA. Inhibition of neurons in the rostral ventromedial medullary raphe pallidus region also eliminates the VNS‐evoked excitation of BAT SNA. These data support the existence of populations of vagal afferents whose stimulation can (1) increase BAT SNA via activation of BAT sympathetic premotor neurons or (2) inhibit BAT SNA via activation of BAT sympathoinhibitory neurons in the iNTS (see Am. J. Physiol. Regul. Integr. Comp. Physiol., 299:R277‐R290, 2010. PMC2904145).Grant Funding Source: Supported by NIH NS40987

Capsaicin as an anti-obesity drug.

Laboratory studies support a role of capsaicin as an anti-obesity agent. Intestinal mucosal afferent nerves appear to play a role in controlling adipose tissue distribution between visceral and subcutaneous sites. Activation of the transient receptor potential vanilloid-1 channels by capsaicin prevents adipogenesis. A neurogenic mechanism modulates the regulation of fat metabolism by transient receptor potential vanilloid-1-sensitive sensory nerves. A neural pathway enables the selective activation of the central network that regulates brown adipose tissue sympathetic nerve activity in response to a specific stimulation of gastrointestinal transient receptor potential channels. Dietary capsaicin reduces metabolic dysregulation in obese/diabetic mice by enhancing expression of adiponectin and its receptor. The effects of capsaicin in adipose tissue and liver are related to its dual action on peroxisome proliferator-activated receptor alpha and transient receptor potential vanilloid-1 expression/activation. Local desensitization of the abdominal capsaicin-sensitive fibers attenuates the hypometabolic adaptation to food deprivation. Truncal vagotomy leads to significant reductions in both diet-induced weight gain and visceral abdominal fat deposition. Vagal de-afferentation leads to a more modest, but clinically and statistically significant, reduction in visceral abdominal fat. Thermogenesis and lipid metabolism-related proteins are altered upon capsaicin treatment in white adipose tissue. Capsaicin induces apoptosis and inhibits adipogenesis in preadipocytes and adipocytes. Epidemiologic data show that consumption of foods containing capsaicin is associated with a lower prevalence of obesity. Clinical evidence supports a role of capsaicin as an anti-obesity agent. Both oral and gastrointestinal exposure to capsaicin increase satiety and reduce energy and fat intake; the stronger reduction with oral exposure suggests a sensory effect of capsaicin. Bioactive components containing capsaicin may support weight maintenance after a hypocaloric diet. Capsaicin consumption 1 h before low intensity exercise is a valuable supplement for the treatment of individuals with hyperlipidemia and/or obesity because it improves lipolysis. Capsinoid ingestion increases energy expenditure through the activation of brown adipose tissue in humans. Capsinoid ingestion is associated with an increase in fat oxidation that is nearly significant; and two common genetic variants may be predictors of response. Further clinical research to develop convenient approaches for obese individuals to take advantage of this common dietary ingredient to prevent the onset or curtail the progression of obesity will be instructive and clinically relevant.

Systemic CCK increases brown adipose tissue sympathetic nerve activity

The neural circuits responsible for governing sympathetic outflow to brown adipose tissue in response to thermoregulatory and febrile stimuli are very well characterized. In contrast we are only beginning to understand the organization of the metabolic regulation of the sympathetic outflow to brown adipose. The current study determines whether cholecystokine (CCK), a gut hormone released postprandially, activates brown adipose tissue sympathetic nerve activity via the vagus nerve. In urethane/chloralose anesthetized rats (n=3), intravenous administration of cholecystokinin (CCK, 0.5μg/kg) increased brown adipose tissue sympathetic nerve activity (BAT SNA: +141 ± 39% control), brown adipose tissue temperature (+0.5 ± 0.1 oC) and expired CO2 (+0.5 ± 0.1%). The CCK‐evoked increases in BAT SNA, BAT temperature and expired CO2 were sustained for at least 40 minutes. Bilateral cervical vagotomy prevented the CCK‐evoked increases in BAT SNA, BAT temperature and expired CO2 (n=2). These results indicate that peripheral CCK acts via vagal afferents to increase metabolism, energy expenditure and thermogenesis in BAT. The neural circuitry mediating this effect and the physiological significance of this system are under investigation.

Optogenetic stimulation of preoptic neurons inhibits brown adipose tissue sympathetic nerve activity

The preoptic area (POA) is known as the center for body temperature regulation. Based on previous experimental results, we hypothesize that GABAergic projection neurons in the POA provide descending tonic inhibition to sympathoexcitatory neurons in the dorsomedial hypothalamus and in the medullary raphe and thereby, regulate the tone of sympathetic outflows to thermoregulatory effectors, such as brown adipose tissue (BAT) and cutaneous vasoconstrictors. If this is the case, stimulation of POA neurons should inhibit thermoregulatory sympathetic outflows. In this study, we examined the effect of optogenetic stimulation of POA neurons on metabolic thermogenesis in BAT in anesthetized rats. Expression of the light‐activated cation channel channelrhodopsin‐2 (ChR2) was introduced into many neurons in the POA by injection of adeno‐associated virus and an optical fiber was inserted into the brain to illuminate the POA. Skin cooling‐evoked sympathetic nerve activity in BAT and increase in heart rate were consistently inhibited only during illumination of the POA. This result supports the hypothesis that tonic descending inhibition from the POA determines the tone of sympathoexcitatory outflows to thermoregulatory effectors.

The Brain Subfornical Organ Mediates Leptin-induced Increases in Renal Sympathetic Activity but not its Metabolic Effects

The adipocyte-derived hormone leptin acts within the central nervous system to decrease food intake and body weight and to increase renal and thermogenic brown adipose tissue sympathetic nerve activity (SNA). Previous studies have focused on hypothalamic brain regions, although recent findings have identified leptin receptors (ObR) in a distributed brain network, including the circumventricular subfornical organ (SFO), a forebrain region devoid of a blood-brain barrier. We tested the hypothesis that ObR in the SFO are functionally linked to leptin-induced decreases in food intake and body weight and increases in SNA. SFO-targeted microinjections of an adenovirus encoding Cre-recombinase in ObR(flox/flox) mice resulted in selective ablation of ObR in the SFO. Interestingly, deletion of ObR in the SFO did not influence the decreases in either food intake or body weight in response to daily systemic or cerebroventricular administration of leptin. In line with these findings, reduction in SFO ObR did not attenuate leptin-mediated increases in thermogenic brown adipose tissue SNA. In contrast, increases in renal SNA induced by systemic or cerebroventricular administration of leptin were abolished in mice with SFO-targeted deletion of ObR. These results demonstrate that ObR in the SFO play an important role in leptin-induced renal sympathoexcitation, but not in the body weight, food intake, or brown adipose tissue SNA thermogenic effects of leptin. These findings highlight the concept of a distributed brain network of leptin action and illustrate that brain regions, including the SFO, can mediate distinct cardiovascular and metabolic responses to leptin.

Identificaton of 2,3-Dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one Isolated from Lactobacillus pentosus Strain S-PT84 Culture Supernatants as a Compound That Stimulates Autonomic Nerve Activities in Rats

Intestinal administration of various lactobacilli has been reported to affect autonomic neurotransmission, blood pressure, and body weight in rats. In this study, three molecules (peaks A, B, and C) were isolated from Lactobacillus pentosus strain S-PT84 (S-PT 84) culture supernatants. Intraduodenal (ID) injection of these molecules increased or inhibited renal sympathetic nerve activity (RSNA) in rats as follows: peak A, 134%; peak B, 40.1%; peak C, 408%. Furthermore, we identified peak C as 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP). ID injection of DDMP increased brown adipose tissue sympathetic nerve activity (BAT-SNA; 118 ± 15.3%), whereas intraoral injection of DDMP increased the body temperature above the interscapular brown adipose tissue (BAT-T; 0.72 ± 0.13 °C) in rats. These data suggest that S-PT84 produces molecules that modulate autonomic nerve activity. In addition, DDMP increased BAT-SNA and BAT-T, and these changes in BAT-T may be caused by changes in BAT-SNA.

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.

Glucoprivation in the ventrolateral medulla decreases brown adipose tissue sympathetic nerve activity by decreasing the activity of neurons in raphé pallidus

In urethane/α-chloralose anesthetized rats, cold exposure increased brown adipose tissue sympathetic nerve activity (BAT SNA: +699 ± 104% control). Intravenous administration of 2-deoxy-D-glucose (2-DG; 200 mg·ml(-1)·kg(-1)) reversed the cold-evoked activation of BAT SNA (nadir: 139 ± 36% of control) and decreased BAT temperature (-1.1 ± 0.2°C), expired CO(2) (-0.4 ± 0.1%), and core temperature (-0.5 ± 0.0). Similarly, unilateral nanoinjection of the glucoprivic agent 5-thioglucose (5-TG; 12 μg/100 nl) in the ventrolateral medulla (VLM) completely reversed the cold-evoked increase in BAT SNA (nadir: 104 ± 7% of control), and decreased T(BAT) (-1.4 ± 0.3°C), expired CO(2) (-0.2 ± 0.0%), and heart rate (-35 ± 10 beats/min). The percentage of rostral raphé pallidus (RPa)-projecting neurons in the dorsal hypothalamic area/dorsomedial hypothalamus that expressed Fos in response to cold exposure (ambient temperature: 4-10°C) did not differ between saline (28 ± 6%) and 2-DG (30 ± 5%) pretreated rats, whereas the percentage of spinally projecting neurons in the RPa/raphé magnus that expressed Fos in response to cold exposure was lower in 2-DG- compared with saline-pretreated rats (22 ± 6% vs. 42 ± 5%, respectively). The increases in BAT SNA evoked by nanoinjection of bicuculline in the RPa or by transection of the neuraxis at the pontomedullary border were resistant to inhibition by glucoprivation. These results suggest that neurons within the VLM play a role in the glucoprivic inhibition of BAT SNA and metabolism, that this inhibition requires neural structures rostral to the pontomedullary border, and that this inhibition is mediated by a GABAergic input to the RPa.