Effects of ethyl hexanoate on activities of sympathetic nerves innervating the brown and white adipose tissues, body temperature, and plasma fatty acids.

The autonomic nervous system (ANS) is implicated in maintaining homeostasis of the internal environment in mammals. Therefore, changes occurring in the ANS can cause alterations of physiological phenomena. Ethyl hexanoate (EH) is known as the aroma component of apples. To study the action of ethyl hexanoate on physiological phenomena, we examined the effect of an intragastric (IG) injection of 1 mL/kg body weight of 0.1 ppm EH solution on sympathetic nerve activity innervating the brown adipose tissue (BAT) and white adipose tissue (WAT) in anesthetized rats. Consequently, IG administration of EH increased activity of the sympathetic nerves innervating both the BAT and WAT. In addition, the effects of the IG injection on body temperature above the interscapular BAT and plasma free fatty acid (FFA) concentration were also examined in conscious rats. In this attempt IG injection of EH elevated both the body temperature and plasma FFA levels. Furthermore, subdiaphragmatic vagotomy eliminated the effects of EH on sympathetic nerves innervating BAT and WAT. These findings suggest that EH causes excitations of sympathetic nerves innervating BAT and WAT, and enhances thermogenesis and lipolysis via the afferent vagus nerve. Thus, these present findings also suggest the possibility that EH might have anti-obesity effects.

Topical application of L-carnosine to skeletal muscle excites the sympathetic nerve innervating the contralateral skeletal muscle in rats.

We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats. Topical application of 10 pg (44.2 fmol) of CAR increased either skeletal muscle sympathetic nerve activity (skeletal muscle-SNA) or skeletal muscle blood flow (skeletal muscle-BF) of the contralateral skeletal muscle. Furthermore, thioperamide, a histamine H3-antagonist, inhibited the increase in skeletal muscle-SNA, and butoxamine, a ß2-antagonist, abolished the increase in skeletal muscle-BF caused by topical application of CAR. The present results suggest that CAR released from muscles during physical exercise might affect skeletal muscle-SNA and skeletal muscle-BF on the opposite side of the body via a CAR evoked effect in muscles.

L-Carnosine's dose-dependent effects on muscle sympathetic nerves and blood flow.

L-Carnosine is synthesized in mammalian muscles and brain and affects autonomic neurotransmission and physiological phenomena. To clarify the role of l-carnosine, the effects of intraduodenal administration of l-carnosine on muscle sympathetic nerve activity (muscle-SNA) and blood flow (BF) were examined. The changes in muscle-SNA and BF were examined using electrophysiological and Doppler flowmeter in urethane-anesthetized rats. The effect of propranolol, a ß-adrenergic antagonist, on the increase in muscle BF due to l-carnosine was also examined. Low dose (1µg/300g body weight [bw]) of l-carnosine increased both muscle-SNA and muscle BF, while high dese (100mg/300g bw) of l-carnosine decreased both muscle-SNA and muscle BF. Furthermore, propranolol eliminated the increase in muscle BF caused by a low dose of l-carnosine. These results suggest that l-carnosine has dose-dependent effects on muscle BF via changes in muscle-SNA, and the ß-adrenergic receptor is implicated in the increase in muscle BF due to l-carnosine.

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.

The effect of the sympathetic nervous system on splenic natural killer cell activity in mice administered the Lactobacillus pentosus strain S-PT84.

Splenic sympathetic nerve activity (SNA) modulates cellular immune functions such as splenic natural killer cell activity. Lactobacillus pentosus strain S-PT84 enhances splenic natural killer cell activity. Here, we examined whether S-PT84 affects splenic natural killer activity through splenic SNA in BALB/c mice. Splenic SNA was significantly decreased following the administration of S-PT84. This phenomenon was inhibited by pretreatment with thioperamide (histamine H3 receptor antagonist), suggesting that S-PT84 directly affected splenic SNA. Thioperamide also inhibited the increase in splenic natural killer activity by S-PT84. Thus, the change in splenic natural killer activity by S-PT84 may be partially modulated through SNA.

Effects of intraduodenal injection of Lactobacillus brevis SBC8803 on autonomic neurotransmission and appetite in rodents.

Lactobacilli provide several health benefits to mammals, including humans. We previously observed that in rats, intraduodenal injection of Lactobacillus johnsonii La1 elevated efferent gastric vagal nerve activity (efferent-GVNA), while Lactobacillus paracasei ST11 suppressed efferent-GVNA, and thereby increased or decreased food intake. To determine the function of Lactobacillus brevis (SBC8803), its effect on food intake was examined by providing food containing heat-killed SBC8803 to mice. We observed that administration of SBC8803 elevated food intake. Because the afferent intestinal vagal nerve (IVN) is hypothesized to be involved in efferent-GVNA changes, we examined the effect of intraduodenal administration of heat-killed SBC8803 on efferent-GVNA and afferent-IVN activity (IVNA) in rats. In this study, we found that intraduodenal administration of heat-killed SBC8803 increased both efferent-GVNA and afferent-IVNA in rats. Moreover, IV administration of the serotonin 3 receptor antagonist granisetron eliminated the effects of SBC8803 on efferent-GVNA and afferent-IVNA. These findings suggest that heat-killed SBC8803 enhances appetite by elevating digestion and absorption abilities via changes in autonomic neurotransmission that might be mediated by the serotonin 3 receptor.

Order of exposure to pleasant and unpleasant odors affects autonomic nervous system response.

When mammals are exposed to an odor, that odor is expected to elicit a physiological response in the autonomic nervous system. An unpleasant aversive odor causes non-invasive stress, while a pleasant odor promotes healing and relaxation in mammals. We hypothesized that pleasant odors might reduce a stress response previously induced by an aversive predator odor. Rats were thus exposed to pleasant and unpleasant odors in different orders to determine whether the order of odor exposure had an effect on the physiological response in the autonomic nervous system. The first trial examined autonomic nerve activity via sympathetic and parasympathetic nerve response while the second trial examined body temperature response. Initial exposure to a pleasant odor elicited a positive response and secondary exposure to an unpleasant odor elicited a negative response, as expected. However, we found that while initial exposure to an unpleasant odor elicited a negative stress response, subsequent secondary exposure to a pleasant odor not only did not alleviate that negative response, but actually amplified it. These findings were consistent for both the autonomic nerve activity response trial and the body temperature response trial. The trial results suggest that exposure to specific odors does not necessarily result in the expected physiological response and that the specific order of exposure plays an important role. Our study should provide new insights into our understanding of the physiological response in the autonomic nervous system related to odor memory and discrimination and point to areas that require further research.

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.

Effects of culture supernatant from Lactobacillus pentosus strain S-PT84 on autonomic nerve activity in rats.

Intestinal administration of various lactobacilli has been reported to affect autonomic neurotransmission, blood pressure, blood glucose, and body weight in rats, however, the mechanisms of action of the lactobacilli remain to be clarified. Therefore, the effect of the culture supernatant of Lactobacillus pentosus strain S-PT84 on the autonomic nerve activity in urethane-anesthetized rats was investigated. Intraduodenal injection of the low-molecular-weight (LMW) fraction (molecules less than 10,000 Da) of the S-PT84 culture supernatant elevated the brown adipose tissue sympathetic nerve activity and reduced the gastric vagal nerve activity. Moreover, intraoral administration of this LMW fraction increased the body temperature of rats above the interscapular brown adipose tissue. These results suggest that the LMW fraction of the S-PT84 culture supernatant affects the autonomic nerve activity and thermogenesis, and that the change in thermogenesis may be caused by the change in the sympathetic nerve activity of brown adipose tissue.

Role of L-carnosine in the control of blood glucose, blood pressure, thermogenesis, and lipolysis by autonomic nerves in rats: involvement of the circadian clock and histamine.

L-carnosine (ß-alanyl-L-histidine; CAR) is synthesized in mammalian skeletal muscle. Although the physiological roles of CAR have not yet been clarified, there is evidence that the release of CAR from skeletal muscle during physical exercise affects autonomic neurotransmission and physiological functions. In particular, CAR affects the activity of sympathetic and parasympathetic nerves innervating the adrenal glands, liver, kidney, pancreas, stomach, and white and brown adipose tissues, thereby causing changes in blood pressure, blood glucose, appetite, lipolysis, and thermogenesis. CAR-mediated changes in neurotransmission and physiological functions were eliminated by histamine H1 or H3 receptor antagonists (diphenhydramine or thioperamide) and bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN), a master circadian clock. Moreover, a carnosine-degrading enzyme (carnosinase 2) was shown to be localized to histamine neurons in the hypothalamic tuberomammillary nucleus (TMN). Thus, CAR released from skeletal muscle during exercise may be transported into TMN-histamine neurons and hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of CAR on neurotransmission and physiological function. Thus, CAR appears to influence hypoglycemic, hypotensive, and lipolytic activity through regulation of autonomic nerves and with the involvement of the SCN and histamine. These findings are reviewed and discussed in the context of other recent reports, including those on carnosine synthetases, carnosinases, and carnosine transport.

Effects of L-carnosine on splenic sympathetic nerve activity and tumor proliferation.

l-Carnosine (ß-alanyl-l-histidine), a dipeptide of the amino acids ß-alanine and histidine, is found in mammalian tissues including those in the central nervous system and in skeletal muscles. In the present study, we examined the effects of intraduodenal (ID) injection of l-carnosine on splenic sympathetic nerve activity (splenic-SNA) in urethane-anesthetized rats and found that ID injection of 3.3mg/kg of body weight of l-carnosine significantly suppressed splenic-SNA. Since it has been suggested that splenic-SNA reduction increases natural killer (NK) activity of splenic cells, which in turn elevates tumor immunity, we then investigated the effect of l-carnosine on the proliferation of human colon cancer cells transplanted into athymic nude mice. The findings of this study revealed that 1mg/mL of l-carnosine solution given as the only drinking water inhibited tumor proliferation. These results suggest that l-carnosine suppresses splenic-SNA and inhibits cancer cell proliferation, probably by elevating NK activity.

Skin application of urea-containing cream affected cutaneous arterial sympathetic nerve activity, blood flow, and water evaporation.

BACKGROUND/PURPOSE: We observed that olfactory stimulation with scent of grapefruit oil elevated the activities of sympathetic nerves, and increased the plasma glycerol concentration and blood pressure. In contrast, olfactory stimulation with scent of lavender oil had opposite effects in rats. These suggest that changes in autonomic activities cause physiological functions via histaminergic H1 and H3 receptor. Moreover, it has been reported that somatic sensory stimulation affected autonomic neurotransmission. To examine effects of skin application of urea-containing cream on cutaneous arterial sympathetic nerve activity (CASNA), blood flow, and transepidermal water loss (TEWL). METHOD: The activity of CASNA was determined by electrophysiological method, and cutaneous blood flow was determined using laser flowmeter in urethane-anesthetized rats, TEWL was measured using VapoMeter in the back skin of HWY hairless rats. RESULTS: CASNA was markedly and significantly inhibited by skin application of 10% urea-containing cream, whereas cutaneous blood flow was significantly elevated via histaminergic H3-receptor. In conscious hairless rats, TEWL was significantly decreased 24 h after application of 10% urea-containing cream to the back skin. CONCLUSION: These findings suggest that skin application of 10% urea-containing cream increases the cutaneous blood flow and water retaining ability, and that histaminergic H3-receptors may mediate these effects.

Exposure to TMT odor affects adrenal sympathetic nerve activity and behavioral consequences in rats.

The odor of 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a synthetic compound isolated from fox feces, induces various emotional behavioral and stress responses. Here we examined the effect of TMT on behavioral responses and adrenal sympathetic nerve activity (ASNA) in rats. TMT increased freezing behavior, defensive-burying and defensive-attack, and decreased exploration, grooming and approach behaviors. On the other hand, butyric acid (BA), a pungent but non-predatory odor, increased defensive-burying only. TMT increased ASNA strongly, whereas the effects of BA increased ASNA extremely weakly. Furthermore, pre-treatment with the histaminergic H1-receptor antagonist diphenhydramine eliminated the effects of TMT on ASNA. These findings suggest that TMT odor affects autonomic neurotransmission via histaminergic neurons. Exposure to TMT odor likely regulates the controlling autonomic function and output to a motor system simultaneously, evoking behavioral stress responses.

Effects of Eucommia leaf extracts on autonomic nerves, body temperature, lipolysis, food intake, and body weight.

Eucommia ulmoides Oliver leaf extracts (ELE) have been shown to exert a hypolipidemic effect in hamsters. Therefore, it was hypothesized that ELE might affect lipid metabolism via changes in autonomic nerve activities and causes changes in thermogenesis and body weight. We examined this hypothesis, and found that intraduodenal (ID) injection of ELE elevated epididymal white adipose tissue sympathetic nerve activity (WAT-SNA) and interscapular brown adipose tissue sympathetic nerve activity (BAT-SNA) in urethane-anesthetized rats and elevated the plasma concentration of free fatty acids (FFA) (a marker of lipolysis) and body temperature (BT) (a marker of thermogenesis) in conscious rats. Furthermore, it was observed that ID administration of ELE decreased gastric vagal nerve activity (GVNA) in urethane-anesthetized rats, and that ELE given as food reduced food intake, body and abdominal adipose tissue weights and decreased plasma triglyceride level. These findings suggest that ELE stimulates lipolysis and thermogenesis through elevations in WAT-SNA and BAT-SNA, respectively, suppresses appetite by inhibiting the activities of the parasympathetic nerves innervating the gastrointestinal tract, including GVNA, and decreases the amount of abdominal fat and body weight via these changes.

Effect of an intraduodenal injection of fat on the activities of the adrenal efferent sympathetic nerve and the gastric efferent parasympathetic nerve in urethane-anesthetized rats.

Nutrient information from the gastrointestinal tract to the brain plays a critical role in the regulation of appetite and energy homeostasis. The autonomic nervous system controls the functions of several tissues to regulate the energy homeostasis of the whole body. Autonomic nerve activity is influenced by environmental or exogenous changes in even a single tissue. In the present study, we investigated the effect of an intraduodenal injection of fat on the activities of the autonomic nerves innervating the adrenal gland and stomach in urethane-anesthetized rats. An intraduodenal injection of corn oil suppressed adrenal efferent sympathetic nerve activity (ASNA) and stimulated gastric efferent vagal nerve activity (GVNA). A lipase inhibitor, epsilon-polylysine, coinjected with corn oil completely suppressed the corn oil-induced changes in ASNA and GVNA. Further, an intraduodenal injection of fatty acid (linoleic acid) moderately suppressed ASNA and significantly stimulated GVNA; these results indicate that fat may affect autonomic nerve activity partly through the chemoreception of free fatty acids (FFAs), which are produced during the hydrolysis of fat (corn oil) by a pancreatic lipase, in the intestinal lumen. Furthermore, an intraduodenal injection of an intravenous fat emulsion with the same pH and osmotic pressure as the body fluid affected ASNA and GVNA in a similar manner as corn oil. These results suggest that intraduodenal fat suppresses ASNA and stimulates GVNA partly via the chemoreception of FFAs-the degradation products of fats-in the intestinal lumen.

Effects of flavangenol on autonomic nerve activities and dietary body weight gain in rats.

In a previous report, evidence was presented that flavangenol supplementation has an anti-ischemic effects in rats. In the study presented here, we examined the autonomic effects of intraduodenal (ID) injection of flavangenol in urethane-anesthetized rats and found that it increased sympathetic nerve activity innervating brown adipose tissue (BAT-SNA) in a dose-dependent manner, while it suppressed gastric vagal nerve activity (GVNA). In addition, intra-oral (IO) injection of flavangenol elevated brown adipose tissue temperature (BAT-T). Furthermore, flavangenol drinking for 15 d reduced body weight gain in rats fed a high-fat diet. These results thus suggest that flavangenol supplementation exerts its reducing action on body weight through changes in autonomic neurotransmission.

Effect of 4G-alpha-glucopyranosyl hesperidin on brown fat adipose tissue- and cutaneous-sympathetic nerve activity and peripheral body temperature.

Changes in the activity of the autonomic nervous system are good indicators of alterations in physiological phenomena such as the body temperature, blood glucose, blood pressure. Hesperidin, a flavanone known as vitamin P, has been shown to reduce the levels of serum lipids, cholesterol, and blood pressure. However, hesperidin is not water-soluble and is not well absorbed from the intestine. G-hesperidin (4G-alpha-glucopyranosyl hesperidin) is more water-soluble and more rapidly absorbed than hesperidin. In order to clarify the functions of G-hesperidin, we examined the effects of oral administration of G-hesperidin on interscapular brown adipose tissue-sympathetic nerve activity (BAT-SNA) and cutaneous sympathetic nerve activity (CASNA) in rats weighing about 300 g. In this study, we found that oral administration of 60 mg of G-hesperidin increased the BAT-SNA but decreased the CASNA in urethane-anesthetized rats. Since an elevation in BAT-SNA increases heat production (i.e. body temperature (BT)) and a decrease in CASNA increases cutaneous perfusion, we examined whether oral administration of G-hesperidin had an effect on the peripheral BT in rats. Consequently, we observed that the subcutaneous BT at the caudal end of the back after oral administration of 60 mg of G-hesperidin was significantly higher than the subcutaneous BT after oral administration of water in conscious rats. These findings suggest that G-hesperidin enhances the BAT-SNA and suppresses the CASNA resulting in an increase in the peripheral BT, probably by an increase in the thermogenesis in the BAT and an elevation in the cutaneous blood flow.

Effects of L-arginine and L-lysine mixtures on splenic sympathetic nerve activity and tumor proliferation.

Oral supplementations of L-arginine and L-lysine show tumor inhibition abilities. The splenic sympathetic nerve is involved in central modulation of cellular immunity and suppresses splenic natural killer cell activity in rats. An intravenous administration of a mixture of 10 mM L-arginine and L-lysine decreased splenic sympathetic nerve activity (splenic-SNA). We examined the effect of L-arginine and L-lysine mixtures on splenic-SNA in urethane-anesthetized rats by administration of 1 ml mixtures of 2 mM, 10 mM, and 50 mM L-arginine and L-lysine. We also studied the effect of the above mixtures on human colon cancer cell proliferation in athymic nude mice. An increase in splenic-SNA and tumor volume (2 mM), no effect (10 mM), and a decrease in both values (50 mM) were seen. Bivariate correlation analysis revealed a positive correlation between changes in splenic-SNA and tumor volume, indicating the tumor suppressing ability of weakened splenic-SNA.

Effect of the culture extract of Lentinus edodes mycelia on splenic sympathetic activity and cancer cell proliferation.

The spleen is an important organ for tumor immunity, and the splenic sympathetic nerve has a suppressive effect on splenic natural killer (NK) cytotoxicity. On the basis of this and reports that Lentinus edodes (Shiitake mushroom) has tumor-inhibitory effects, the authors hypothesized that an extract of a mycelial culture of L. edodes grown in a solid medium of sugar-cane bagasse and defatted rice bran-L.E.M-might affect the sympathetic splenic sympathetic nerve activity (Splenic-SNA) and thus inhibit tumor proliferation. Thus, the effect of L.E.M on Splenic-SNA and human cancer cell proliferation was examined. Splenic-SNA was found to be suppressed by an intraduodenal L.E.M injection in urethane-anesthetized rats, which significantly inhibited increases in the tumor volume of human colon and breast cancer cells implanted in athymic nude mice. These findings suggest that L.E.M has an inhibitory effect on tumor proliferation possibly via a reduction in NK cytotoxicity through the suppression of Splenic-SNA.

High-fat diet-induced obesity is attenuated by probiotic strain Lactobacillus paracasei ST11 (NCC2461) in rats.

SUMMARY: In a recent study, we obtained some evidences that probiotic strain Lactobacillus affects the autonomic nerve activities and regulates blood glucose and cardiovascular function. In the study presented here, we found that long-term ingestion of the lactobacillus strain Lactobacillus paracasei ST11 (NCC2461) reduced body weight and abdominal fat weight. To investigate possible role of autonomic nerves in anti-obesity action of NCC2461, we examined the effects of intraduodenal (ID) injection of the lactobacillus strain L. paracasei ST11 (NCC2461) on sympathetic nerve activity innervating white adipose tissue (WAT-SNA) in urethane-anesthetized rats, and found that it accelerated WAT-SNA. Moreover, intraduodenal (ID) injection of NCC2461 increased in sympathetic nerve activity innervating brown adipose tissue (BAT-SNA) and decreased in hepatic vagal nerve activity (HVNA). In addition, using conscious rats, we examined the effects of intra-gastric (IG) injection of NCC2461 on lipolysis and BAT thermogenesis, and observed that it clearly elevated the plasma FFA level, BAT temperature and abdominal temperature. Thus, these data suggest that the NCC2461 affects autonomic nerves, enhances lipolysis, and reduces body weight in rats.: