Olfactory stimulatory with grapefruit and lavender oils change autonomic nerve activity and physiological function.

This review summarizes the effects of olfactory stimulation with grapefruit and lavender oils on autonomic nerve activity and physiological function. Olfactory stimulation with the scent of grapefruit oil (GFO) increases the activity of sympathetic nerves that innervate white and brown adipose tissues, the adrenal glands, and the kidneys, decreases the activity of the gastric vagal nerve in rats and mice. This results in an increase in lipolysis, thermogenesis, and blood pressure, and a decrease in food intake. Olfactory stimulation with the scent of lavender oil (LVO) elicits the opposite changes in nerve activity and physiological variables. Olfactory stimulation with scent of limonene, a component of GFO, and linalool, a component of LVO, has similar effects to stimulation with GFO and LVO, respectively. The histamine H1-receptor antagonist, diphenhydramine, abolishes all GFO-induced changes in nerve activity and physiological variables, and the hitstamine H3-receptor antagonist, thioperamide, eliminates all LVO-induced changes. Lesions to the hypothalamic suprachiasmatic nucleus and anosmic treatment with ZnSO4 also abolish all GFO- and LVO-induced changes. These findings indicate that limonene and linalool might be the active substances in GFO and LVO, and suggest that the suprachiasmatic nucleus and histamine are involved in mediating the GFO- and LVO-induced changes in nerve activity and physiological variables.

Neurohormones, rikkunshito and hypothalamic neurons interactively control appetite and anorexia.

Ghrelin is the orexigenic peptide produced in the periphery, and its plasma level shows remarkable pre/postprandial changes. Ghrelin is considered a pivotal signal to the brain to stimulate feeding. Hence, characterizing the target neurons for ghrelin in the hypothalamic feeding center and the signaling cascade in the target neurons are essential for understanding the mechanisms regulating appetite. Anorexia and cachexia associated with gastric surgery, stress-related diseases, and use of anti-cancer drugs cause the health problems, markedly deteriorating the quality of life. The anorexia involves several neurotransmitters and neuropeptides in the hypothalamic feeding center, in which corticotropin-releasing hormone (CRH), urocortine, serotonin (5HT) and brain-derived neurotrophic factor (BDNF) play a pivotal role. A Japanese herbal medicine, rikkunshito, has been reported to ameliorate the anorexia by promoting the appetite. This review describes 1) the interaction of ghrelin with the orexigenic neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) and underlying signaling cascade in NPY neurons, 2) the anorectic pathway driven by BDNF-CRH/urocortine and 5HTCRH/ urocortine pathways, 3) the effect of rikkunshito on the interaction of ghrelin and NPY neurons in ARC, and 4) the effect of rikkunshito on the interaction of 5HT on CRH neurons in paraventricular nucleus (PVN).

Parathyroid hormone-related protein has an anorexigenic activity via activation of hypothalamic urocortins 2 and 3.

Cancer cachexia is reported to be a major cause of cancer-related death. Since the pathogenesis is not entirely understood, only few effective therapies have been established. Since myriad tumors produce parathyroid hormone-related protein (PTHrP), plasma concentrations of PTHrP are increased in cancer cachexia. We measured the food intake, gastric emptying, conditioned taste aversion (CTA), and gene expression of hypothalamic neuropeptides in mice after administering PTHrP intraperitoneally. We administered PTHrP intravenously in rats and examined the gastroduodenal motility and vagal nerve activities. We also examined whether chronic administration of PTHrP influenced the food intake and body weight. Peripherally administered PTHrP induced negative energy balance by decreasing the food intake and gastric emptying; however, it did not induce CTA. The mechanism involved the activation of hypothalamic urocortins 2 and 3 through vagal afferent pathways and the suppression of gastroduodenal motor activity. The continuous infusion of PTHrP reduced the food intake and body weight gain with a concomitant decrease in the fat and skeletal muscle. Our findings suggest that PTHrP influences the food intake and body weight; therefore, PTHrP can be considered as a therapeutic target for cancer cachexia.

Effect of auditory stimulation on parasympathetic nerve activity in urethane-anesthetized rats.

Previously, it has been demonstrated that auditory stimulation with music (Traeumerei [TM] by Schumann) decreased renal sympathetic nerve activity (RSNA) and blood pressure (BP) with a central mechanism, while it is unknown whether TM affects parasympathetic nerve activity. Here, the effects of auditory stimulation with TM on gastric vagal nerve activity (GVNA) in urethane-anesthetized rats were investigated. Auditory stimulation with TM, but not with white noise (WN) caused a significant elevation of GVNA. In addition, exposure to TM increased the number of c-Fos-immunoreactive cells in the auditory cortex (AuC). These findings suggest that exposure to music can increase GVNA through the auditory pathway.

Day-night difference in thermoregulatory responses to olfactory stimulation.

Previously, we observed that olfactory stimulation with scent of grapefruit oil (SGFO) or scent of lavender oil (SLVO) affected, elevated or lowered brown adipose tissue temperature (BAT-T) in conscious mice, respectively. In the present study, to test the day-night difference in the actions of olfactory stimulations, we examined the responses of BAT-T and body temperature (BT) measured as the abdominal temperature to SGFO or SLVO during day-time at 14:00 and night-time at 2:00 in conscious rats. In the light period, BAT-T and BT were suppressed after SLVO and elevated after SGFO whereas in the dark period, these parameters remained unchanged with olfactory stimulations. Bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) eliminated the effects of olfactory stimulations with SGFO and SVLO on BAT-T and BT. Moreover, sympathetic nerve activity innervating brown adipose tissue (BAT-SNA) changes after SGFO or SLVO were abolished in SCN-lesioned rats. Thus, we concluded that there is day-night difference in the effects of SGFO or SLVO on BAT-T and BT, and that the SCN might be involved in these effects.

Effects of olfactory stimulations with scents of grapefruit and lavender oils on renal sympathetic nerve and blood pressure in Clock mutant mice.

Previously, we observed that in mice, olfactory stimulation with scent of grapefruit oil elevates renal sympathetic nerve activity and blood pressure. In contrast, olfactory stimulation with scent of lavender oil has opposite effects in mice. Moreover, electrolytic lesions of the mouse hypothalamic suprachiasmatic nucleus eliminated changes in renal sympathetic nerve activity and blood pressure induced by either scent of grapefruit oil or scent of lavender oil. Here, we show that grapefruit oil-induced elevations in renal sympathetic nerve activity and blood pressure were not observed in Clock mutant mice, which harbor mutations in Clock and lack normal circadian rhythms, whereas lavender oil-suppressions were preserved in Clock mutant mice. In addition, responses of c-Fos inductions in the suprachiasmatic nucleus and paraventricular nucleus of the hypothalamus to scent of grapefruit oil observed in wild-type mice were not observed in Clock mutant mice. These findings suggest that the Clock gene might be implicated in elevating responses of autonomic and cardiovascular functions to olfactory stimulation with scent of grapefruit oil.

Characterization of weight loss and weight regain mechanisms after Roux-en-Y gastric bypass in rats.

Roux-en-Y gastric bypass (RYGB) is the most effective therapy for morbid obesity, but it has a approximately 20% failure rate. To test our hypothesis that outcome depends on differential modifications of several energy-related systems, we used our established RYGB model in Sprague-Dawley diet-induced obese (DIO) rats to determine mechanisms contributing to successful (RGYB-S) or failed (RYGB-F) RYGB. DIO rats were randomized to RYGB, sham-operated Obese, and sham-operated obese pair-fed linked to RYGB (PF) groups. Body weight (BW), caloric intake (CI), and fecal output (FO) were recorded daily for 90 days, food efficiency (FE) was calculated, and morphological changes were determined. d-Xylose and fat absorption were studied. Glucose-stimulated vagal efferent nerve firing rates of stomach were recorded. Gut, adipose, and thyroid hormones were measured in plasma. Mitochondrial respiratory complexes in skeletal muscle and expression of energy-related hypothalamic and fat peptides, receptors, and enzymes were quantified. A 25% failure rate occurred. RYGB-S, RYGB-F, and PF rats showed rapid BW decrease vs. Obese rats, followed by sustained BW loss in RYGB-S rats. RYGB-F and PF rats gradually increased BW. BW loss in RYGB-S rats is achieved not only by RYGB-induced decreased CI and increased FO, but also via sympathetic nervous system activation, driven by increased peptide YY, CRF, and orexin signaling, decreasing FE and energy storage, demonstrated by reduced fat mass associated with the upregulation of mitochondrial uncoupling protein-2 in fat. These events override the compensatory response to the drop in leptin levels aimed at conserving energy.

Auditory stimulation affects renal sympathetic nerve activity and blood pressure in rats.

Here, we examined the effects of auditory stimulation at 50 dB with white noise (WN) or music (Traeumerei [TM] by Schumann or Etude by Chopin) on renal sympathetic nerve activity (RSNA) and BP in urethane-anesthetized rats. Auditory stimulation with TM, but not with WN or the Etude, significantly decreased RSNA and BP. Complete bilateral destruction of the cochleae and bilateral lesions of the auditory cortex (AuC) eliminated the effects of TM stimulation on RSNA and BP, but bilateral lesions of primary somatosensory cortex (S1C) had no effect. Bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) or intracerebral administration of thioperamide, a histaminergic H3 receptor antagonist, also abolished TM-induced decreases in RSNA and BP. These findings suggest that exposure to music can decrease RSNA and BP through the auditory pathway, histaminergic neurons, and the SCN.

Mechanism of changes induced in plasma glycerol by scent stimulation with grapefruit and lavender essential oils.

In a previous study, we found that stimulation with scent of grapefruit oil (SGFO) elevated plasma glycerol levels in rats. However, stimulation with scent of lavender oil (SLVO) triggered a negative effect. To identify the mechanism of these changes during lipolysis, we examined the role of autonomic blockers and bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) in the modification of plasma glycerol in rats exposed to SGFO and SLVO. We found that intraperitoneal injection of propranolol hydrochloride and atropine sulfate eliminated the changes in plasma glycerol levels induced by SGFO and SLVO, respectively. Bilateral lesions of the SCN completely abolished the effects of SGFO and SLVO on lipolysis. In addition, we investigated tyrosine phosphorylation of the transmembrane glycoprotein BIT (a brain immunoglobulin-like molecule with tyrosine-based activation motifs, a member of the signal-regulator protein family), which was found to be involved in the activation of renal sympathetic nerves and increase in body temperature on cold exposure. SGFO was found to enhance the immunoreactivity of BIT to the 4G10 anti-phosphotyrosine antibody in the SCN, whereas SLVO decreased the immunoreactivity. The changes in BIT phosphorylation resulting from the exposure to SGFO and SLVO were eliminated by the corresponding histamine receptor antagonists, which eliminated the changes in plasma glycerol concentration. The results suggest that SGFO and SLVO affect the autonomic neurotransmission and lipolysis. The SCN and histamine neurons are involved in the lipolytic responses to SGFO and SLVO, and tyrosine phosphorylation of BIT is implicated in the relevant signaling pathways.

Dose-different effects of orexin-A on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats.

Previous studies have demonstrated that central injection of orexin-A affects renal sympathetic nerve activity (RSNA) and blood pressure (BP) in both anesthetized and unanesthetized rats. In the present study, we examined, using urethane-anesthetized rats, the dose-dependent effects of intravenous (iv) or intralateral cerebral ventricular (LCV) injection of various doses of orexin-A on RSNA and BP. We found that injection of a low dose of orexin-A (10 ng iv or 0.01 ng LCV) suppressed RSNA and BP significantly. Conversely, a high dose (1000 ng iv or 10 ng LCV) of orexin-A elevated both RSNA and BP significantly. Pretreatment with either iv or LCV injection of thioperamide, a histaminergic H(3)-receptor antagonist, eliminated the effects of a low dose of orexin-A on both RSNA and BP. Both iv and LCV injection of diphenhydramine, a histaminergic H(1)-receptor antagonist, abolished the effects of a high dose of orexin-A on RSNA and BP. Furthermore, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of both low and high doses of orexin-A on RSNA and BP. These findings suggest that orexin-A affects RSNA and BP in a dose-dependent manner and that the SCN and histaminergic nerve may be involved in the dose-different effects of orexin-A in rats.

Olfactory stimulation with scent of lavender oil affects autonomic neurotransmission and blood pressure in rats.

Previously, we observed that olfactory stimulation with scent of lavender oil (SLVO) suppressed sympathetic nerve activities and elevated gastric vagal (parasympathetic) nerve activity (GVNA), decreased plasma glycerol concentration and body temperature, and enhanced appetite in rats. Here, we further showed that olfactory stimulation with SLVO lowered renal sympathetic nerve activity (RSNA) and blood pressure (BP) and elevated GVNA in urethane-anesthetized rats. Olfactory stimulation with linalool, a component of lavender oil, also elicited decreases in RSNA and BP and an increase in GVNA in urethane-anesthetized rats. Anosmia induced by pretreatment of the nasal cavity by application of ZnSO4 eliminated the effects of both SLVO and scent of linalool on RSNA, GVNA and BP. Furthermore, intracerebroventricular administration of thioperamide, a histaminergic H3-antagonist, abolished the suppression of RSNA and BP as well as the elevation of GVNA mediated by both SLVO and scent of linalool. Finally, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) eliminated RSNA and BP suppression and the elevation of GVNA due to SLVO or linalool. Thus, it was concluded that scent of lavender oil and its active component, linalool, affects autonomic neurotransmission and reduces blood pressure through the central histaminergic nervous system and the SCN.

Olfactory stimulation with scent of essential oil of grapefruit affects autonomic neurotransmission and blood pressure.

Previously, we observed that olfactory stimulation with scent of grapefruit oil (SGFO) enhances sympathetic nerve activities and suppresses gastric vagal (parasympathetic) nerve activity (GVNA), increases plasma glycerol concentration and body temperature, and decreases appetite in rats. Here, we show that olfactory stimulation with SGFO for 10 min elevates renal sympathetic nerve activity (RSNA) and blood pressure (BP) and lowers GVNA in urethane-anesthetized rats. Olfactory stimulation with limonene, a major component of grapefruit oil, also elicited increases in RSNA and BP in urethane-anesthetized rats. Anosmic treatment with ZnSO(4) eliminated both the effects of SGFO and scent of limonene on RSNA and BP. Intracerebral administration of diphenhydramine, a histaminergic H1-antagonist, abolished SGFO- or scent of limonene-mediated increases in RSNA and BP as well as the decrease in GVNA. Moreover, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) eliminated the SGFO- and limonene-mediated increases in RSNA and BP and decrease in GVNA, but bilateral lesions of the cerebral cortex did not have any affect on these parameters. These findings suggest that scent of grapefruit oil and its active component, limonene, affect autonomic neurotransmission and blood pressure through central histaminergic nerves and the suprachiasmatic nucleus.

Olfactory stimulation with scent of grapefruit oil affects autonomic nerves, lipolysis and appetite in rats.

In a previous study, we found that olfactory stimulation with scent of grapefruit oil (SGFO) excites the sympathetic nerve innervating the white adipose tissue in rats. Here we further examined the effects of SGFO in rats and observed that olfactory stimulation with SGFO excited the sympathetic nerves innervating the brown adipose tissue and adrenal gland and inhibited the parasympathetic gastric nerve. Local anesthesia of the nasal mucosa with xylocaine or anosmic treatment using ZnSO4 eliminated the autonomic changes caused by SGFO. Moreover, stimulation with SGFO elevated the plasma glycerol level, and treatment with either ZnSO4 or an intraperitoneal injection of diphenhydramine, a histamine H1 receptor-antagonist, abolished the glycerol elevation by SGFO. Furthermore, a 15-min exposure to SGFO three times a week reduced food intake and body weight. Finally, limonene, a component of grapefruit oil, induced responses similar to those caused by SGFO, and diphenhydramine eliminated the glycerol response to limonene. Thus, the scent of grapefruit oil, and particularly its primary component limonene, affects autonomic nerves, enhances lipolysis through a histaminergic response, and reduces appetite and body weight.

Olfactory stimulation with scent of lavender oil affects autonomic nerves, lipolysis and appetite in rats.

In a previous study, we presented evidence that scent of grapefruit oil excites sympathetic nerves innervating white and brown adipose tissues and the adrenal gland, inhibits the vagal nerve innervating the stomach, increases lipolysis and heat production (energy consumption), and reduces appetite and body weight. Here, we examined the effects of olfactory stimulation with scent of lavender oil (SLVO) in rats and observed that in contrast to grapefruit oil, it inhibits the sympathetic nerves innervating the white and brown adipose tissues and adrenal gland and excites the parasympathetic gastric nerve. Local anesthesia of the nasal mucosa with xylocaine or anosmic treatment using ZnSO(4) eliminated the autonomic changes caused by SLVO. Moreover, stimulation with SLVO lowered the plasma glycerol level, and treatment with either ZnSO(4) or an intracranial injection of thioperamide, a histamine H3 receptor-antagonist, abolished SLVO-mediated glycerol decline. Furthermore, a 15-min daily exposure to SLVO increased food intake and body weight. Finally, linalool, a component of lavender oil, induced responses similar to those caused by SLVO, and the glycerol response to linalool was eliminated by thioperamide. Thus, scent of lavender oil and its active component, linalool, affect autonomic nerves, suppress lipolysis through a histaminergic response, and enhance appetite and body weight.

Effect of olfactory stimulation with flavor of grapefruit oil and lemon oil on the activity of sympathetic branch in the white adipose tissue of the epididymis.

It has been mentioned in the field of aromatherapy that the fragrance of grapefruit has a refreshing and exciting effect, which suggests an activation of sympathetic nerve activity. It also can be assumed that the activation of sympathetic nerve innervating the white adipose tissue (WAT) facilitates lipolysis, then results in a suppression of body weight gain. This study addressed the effect of olfactory stimulation with the scent of grapefruit oil and lemon oil on the efferent nerve activity in the sympathetic branch of the WAT of the epididymis in the anesthetized rat. The results of the experiments demonstrated that the flavor of the citron group increased sympathetic nerve activity to WAT in anaesthetized rat, which suggests an increase in lipolysis and a suppression in body weight gain.

Characterization of the effects of pancreatic polypeptide in the regulation of energy balance.

BACKGROUND & AIMS: Pancreatic polypeptide (PP) belongs to a family of peptides including neuropeptide Y and peptide YY. We examined the role of PP in the regulation of body weight as well as the therapeutic potential of PP. METHODS: We measured food intake, gastric emptying, oxygen consumption, and gene expression of hypothalamic neuropeptides, gastric ghrelin, and adipocytokines in mice after administering PP intraperitoneally. Peptide gene expression was also examined in PP-overexpressing mice. Vagal and sympathetic nerve activities were recorded after intravenous administration in rats. Effects of repeated administrations of PP on energy balance and on glucose and lipid metabolism were examined in both ob/ob obese mice and fatty liver Shionogi (FLS)-ob/ob obese mice. RESULTS: Peripherally administered PP induced negative energy balance by decreasing food intake and gastric emptying while increasing energy expenditure. The mechanism involved modification of expression of feeding-regulatory peptides (decrease in orexigenic neuropeptide Y, orexin, and ghrelin along with an increase in anorexigenic urocortin) and activity of the vagovagal or vagosympathetic reflex arc. PP reduced leptin in white adipose tissue and corticotropin-releasing factor gene expression. The expression of gastric ghrelin and hypothalamic orexin was decreased in PP-overexpressing mice. Repeated administrations of PP decreased body weight gain and ameliorated insulin resistance and hyperlipidemia in both ob/ob obese mice and FLS-ob/ob obese mice. Liver enzyme abnormalities in FLS-ob/ob obese mice were also ameliorated by PP. CONCLUSIONS: These observations indicate that PP may influence food intake, energy metabolism, and the expression of hypothalamic peptides and gastric ghrelin.

The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats.

BACKGROUND & AIMS: Visceral sensory information is transmitted to the brain through the afferent vagus nerve. Ghrelin, a peptide primarily produced in the stomach, stimulates both feeding and growth hormone (GH) secretion. How stomach-derived ghrelin exerts these central actions is still unknown. Here we determined the role of the gastric afferent vagal nerve in ghrelin's functions. METHODS: Food intake and GH secretion were examined after an administration of ghrelin intravenously (IV) to rats with vagotomy or perivagal application of capsaicin, a specific afferent neurotoxin. We investigated Fos expression in neuropeptide Y (NPY)-producing and growth hormone-releasing hormone (GHRH)-producing neurons by immunohistochemistry after administration IV of ghrelin to these rats. The presence of the ghrelin receptor in vagal afferent neurons was assessed by using reverse-transcription polymerase chain reaction and in situ hybridization histochemistry. A binding study on the vagus nerve by (125)I-ghrelin was performed to determine the transport of the ghrelin receptor from vagus afferent neurons to the periphery. We recorded the electric discharge of gastric vagal afferent induced by ghrelin and compared it with that by cholecystokinin (CCK), an anorectic gut peptide. RESULTS: Blockade of the gastric vagal afferent abolished ghrelin-induced feeding, GH secretion, and activation of NPY-producing and GHRH-producing neurons. Ghrelin receptors were synthesized in vagal afferent neurons and transported to the afferent terminals. Ghrelin suppressed firing of the vagal afferent, whereas CCK stimulated it. CONCLUSIONS: This study indicated that the gastric vagal afferent is the major pathway conveying ghrelin's signals for starvation and GH secretion to the brain.

Hypothalamic histamine neurons activate lipolysis in rat adipose tissue.

The contribution of hypothalamic histamine neurons to the central regulation of peripheral lipid metabolism was investigated in rats using in vivo microdialysis system. A bolus infusion of L-histamine at doses of 10--10(3) nmol/rat into the third cerebral ventricle (i3vt) dose-dependently increased glycerol concentration in the perfusate from the epididymal adipose tissue. I3vt infusion of 10(2) nmol/rat thioperamide, an autoinhibitory H(3) receptor antagonist that activates histamine neurons to increase synthesis and release of neuronal histamine, convincingly mimicked histamine action in the augmented lipolysis. Intraperitoneal pretreatment with propranolol, a beta-adrenoceptor antagonist, abolished the thioperamide-induced lipolytic action. An electrophysiological study demonstrated that efferent sympathetic nerves innervating the epididymal fat were activated after the i3vt infusion of thioperamide. Hypothalamic histamine neurons thus regulate peripheral lipid metabolism through the accelerating lipolytic action by activation of sympathetic beta-adrenoceptor.