Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.

Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.

Proinsulin C-peptide activates vagus efferent output in rats.

The aim of this study was to examine the effect of proinsulin C-peptide on the autonomic nervous systems in rats. Intravenous administration of C-peptide gradually increased electrophysiological activity of the vagus nerves into the stomach and pancreas for at least 90 min. It also slightly increased gastric acid secretion that was suppressed by the treatment with atropine. Intraperitoneal injection of C-peptide did not affect the basal and stress-induced norepinephrine (NE) turnover rate, a biochemical index of sympathetic nerve activity. These results indicate that C-peptide increases parasympathetic nerve activity without affecting sympathetic nerve activity. This could explain, at least in part, the ameliorating effects of C-peptide on impaired cardiac autonomic nerve functions in patients with type 1 diabetes.

Is the degree of sensitivity to nondepolarizing muscle relaxants related to requirements for postoperative ventilation in patients with myasthenia gravis?

The purpose of this study was to examine whether the degree of sensitivity to nondepolarizing muscle relaxants is related to the requirement for postoperative ventilatory support in patients with myasthenia gravis. Thirty-six patients with myasthenia gravis undergoing trans-sternal thymectomy were monitored by electromyography in order to assess the neuromuscular response to vecuronium. After calibration to 100% of baseline electromyographic response values using an EMG monitor, incremental doses of 5, 10 and 20 microg/kg of vecuronium were administrated to produce 95% neuromuscular blockade and to obtain a cumulative dose-response curve for each patient. A univariable logistic regression with odds ratio was used to examine the predictive variables of prolonged postoperative ventilation. Depending on their postoperative ventilatory needs, patients were divided into an early extubation group and a prolonged ventilatory group. There were no significant differences between the two groups in terms of vecuronium ED95 (prolonged ventilation group: 23.2 +/- 18 microg/kg; early extubation group: 23.2 +/- 18 microg/kg P=0.129) and vecuronium requirement to maintain less than 25% neuromuscular blockade (prolonged ventilation group: 24 +/- 1.7 mg/kg; early extubation group: 3.8 +/- 4.5 mg/kg P=0.249). There were, however, significant differences in the incidence of a history of previous respiratory crises and the presence of bulbar palsy between the early extubation and prolonged ventilation groups. History of previous respiratory crisis (odds ratio (OR), 3.5; 95% confidence interval (CI), 1.0-13; P=0.03) and presence of bulbar palsy (OR, 3.7; 95%CI, 0.9-15; P=0.049) were associated with the need for prolonged postoperative ventilation. However, we failed to demonstrate that the degree of sensitivity to nondepolarizing muscle relaxants was related to an increased requirement for postoperative ventilation in patients with myasthenia gravis.

Histidine induces lipolysis through sympathetic nerve in white adipose tissue.

BACKGROUND: Hypothalamic neuronal histamine has been shown to increase lipolysis in white adipose tissue. The present study aimed to clarify whether peripheral loading with L-histidine, a precursor of neuronal histamine, may affect lipid metabolism in adipose tissue. MATERIALS AND METHODS: The in vivo microdialysis study was used to assess lipolysis in rat epididymal adipose tissue by measuring the release of glycerol in response to administration of L-histidine. In addition, electrophysiological measurements were performed to record changes in activity of sympathetic nerve innervating adipose tissue following histidine treatment. RESULTS: Sequential administration of isoproterenol, a beta-adrenoceptor agonist, through the microdialysis cannula at concentrations of 10(-)8 to 10(-6) M increased the glycerol concentration in the dialysate dose-dependently (P < 0.05). Intraperitoneal administration of L-histidine at a dosage of 0.35 mmol kg(-1) also increased the glycerol concentration compared to that of phosphate buffered saline (P < 0.05). Concomitantly, the administration of histidine increased the serum concentration of free fatty acid compared to control treatment (P < 0.05). The accelerating effects of histidine on lipolysis were mimicked by the infusion of 10(2) nmol rat(-1) L-histamine into the third cerebroventricle (P < 0.05). Electrophysiological measurement demonstrated that administration of histidine at a dosage of 0.35 mmol kg(-1) increased the activity of efferent sympathetic nerve, innervating adipose tissue more than the infusion of phosphate buffered saline (P < 0.05). CONCLUSION: The present results indicate that histidine accelerates lipolysis in white adipose tissue through activation of the sympathetic nerve. The regulation of lipolysis may therefore involve histamine neurons in the brain, probably through the conversion of L-histidine to histamine in the hypothalamus.

Hepato-vagal pathway associated with nicotine's anorectic effect in the rat.

Nicotine reduces appetite and body weight. Because the hepato-portal area senses different types of nutrients that transmit signals via vagal afferent nerves to the hypothalamus to modify food intake and feeding pattern, we investigated the effect of nicotine on a hepato-vagal-hypothalamic pathway. Low doses of nicotine (< 10 ng) injected into portal vein (i.p.v.) decreased, while high doses of nicotine increased (> or = 10 ng) electrophysiological activity of hepatic vagal afferents. Stimulatory effect of high dose of nicotine on vagal hepatic afferents was blocked by a prior i.p.v. injection of curare (30 microg) or hexamethonium (1 mg). Furthermore, activities of gastric vagal and adrenal sympathetic efferents were suppressed by low-dose, but stimulated by high-dose i.p.v. nicotine. These reflex effects did not occur in hepatic vagotomized rats. Results of experiments demonstrate that in addition to nicotine's anorectic effect being mediated via a direct central action, nicotine also acts peripherally via hepatic vagal afferents from sensors of nicotine in the hepato-portal region.

Effect of L-carnosine on the hyperglycemia caused by intracranial injection of 2-deoxy-D-glucose in rats.

Effects of a chicken essence and one of its components, L-carnosine, on the hyperglycemia caused by intracranial injection of 2-deoxy-D-glucose (2DG-hyperglycemia) in unanesthetized rats were examined. The chicken essence inhibited the 2DG-hyperglycemia. Central or peripheral administration of specific doses of L-carnosine reduced the 2DG-hyperglycemia. L-carnosine inhibited neural activities of sympathetic efferent nerves innervating the adrenal gland and liver and facilitated the activity of vagal celiac nerve innervating the pancreas in urethane anesthetized rats. Specific doses of histamine also suppressed the 2DG-hyperglycemia, and thioperamide eliminated the inhibiting actions of both histamine and L-carnosine on the 2DG-hyperglycemia. Considering mammalian muscles contain L-carnosine, these facts suggest a possibility that L-carnosine might be an endogenous control factor of the blood glucose level through autonomic nerves via H3-receptor.

Effect of lysine on afferent activity of the hepatic branch of the vagus nerve in normal and L-lysine-deficient rats.

Amino acid deficiency was modeled by feeding rats a diet deficient in the essential L-amino acid, L-lysine (L-lys). There is a rapid anorectic response to such a diet, and a strong preference for L-lys develops during the deficiency. While the brain appears to trigger this preference, the peripheral pathways that inform the brain about the deficiency are not well understood. One possible information pathway may utilize an "amino acid sensor" in the hepatoportal region. In the present study, we measured in vivo neural activity in normal and L-lys-deficient rat. Compared to the normally fed controls, we found an approximately 100-fold increase in the firing sensitivity of the L-lys sensors in vagal afferent fibers from the hepatoportal region of the L-lys-deficient rats. Injection of 10 mM L-lys into the hepatoportal circulation, but not D-lysine (D-lys), evoked an increase in afferent activity. While L-lys deficiency enhanced the sensitivity of the L-lys sensors, the sensitivity due to other small amino acid sensors remained unchanged. Finally, we observed a time-dependent response of the lysine sensors to lysine deficiency. It required 3-4 days of maintenance on the lysine-deficient diet for the sensitivity of the L-lys sensors to change. Taken together, these results provide additional data to support the existence of putative L-amino acid sensors in the hepatoportal circulation. Additionally, they describe several characteristics of the L-lys sensors and show that these sensors may contribute to the adaptation to dietary L-lys deficiency and to maintenance of L-amino acid homeostasis.

Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake.

To reveal brain regions and transmitter systems involved in control of pancreatic hormone secretion, specific vagal and sympathetic denervation were combined with injection of a retrograde transsynaptic tracer, pseudorabies virus (PRV), into the pancreas. After sympathetic or vagal transsection first-order neurons were revealed in the dorsal motor nucleus of the vagus (DMV) or in preganglionic spinal cord neurons (SPN), respectively. Careful timing of the survival of the animals allowed the detection of cell groups in immediate control of these DMV or SPN neurons. A far larger number of cell groups is involved in the control of DMV than of SPN neurons. Examples are given of a high level of interaction between the sympathetic and parasympathetic nervous system. Several cell groups project to both branches of the autonomic nervous system, sometimes even the same neurotransmitter is used, e.g., oxytocin neurons in the paraventricular nucleus and melanin-concentrating hormone and orexin neurons in the lateral hypothalamus project to both the DMV and SPN neurons. Moreover, the appearance of third-order neurons located in the sympathetic SPN after complete sympathectomy and in the DMV after complete vagotomy illustrates the possibility that motor neurons of the sympathetic and parasympathetic system may exchange information by means of interneurons. The presence of second-order neurons in prefrontal, gustatory, and piriform cortex may provide an anatomic basis for the involvement of these cortices in the cephalic insulin response. The observation that second-order neurons in both vagal and sympathetic control of the pancreas contain neuropeptides that are known to play a role in food intake indicates a direct association between behavioral and autonomic functions. Finally, the observation of third-order neurons in the suprachiasmatic nucleus and ventromedial hypothalamus shows the modulatory action of the time of the day and metabolic state, respectively.

Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.

BACKGROUND & AIMS: : Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, was recently identified in the rat stomach. We examined the effects of the gastric peptide ghrelin on energy balance in association with leptin and vagal nerve activity. METHODS: : Food intake, oxygen consumption, gastric emptying, and hypothalamic neuropeptide Y (NPY) messenger RNA expression were measured after intra-third cerebroventricular or intraperitoneal injections of ghrelin in mice. The gastric vagal nerve activity was recorded after intravenous administration in rats. Gastric ghrelin gene expression was assessed by Northern blot analysis. Repeated coadministration of ghrelin and interleukin (IL)-1 beta was continued for 5 days. RESULTS: : Ghrelin exhibited gastroprokinetic activity with structural resemblance to motilin and potent orexigenic activity through action on the hypothalamic neuropeptide Y (NPY) and Y(1) receptor, which was lost after vagotomy. Ghrelin decreased gastric vagal afferent discharge in contrast to other anorexigenic peptides that increased the activity. Ghrelin gene expression in the stomach was increased by fasting and in ob/ob mice, and was decreased by administration of leptin and IL-1 beta. Peripherally administered ghrelin blocked IL-1 beta-induced anorexia and produced positive energy balance by promoting food intake and decreasing energy expenditure. CONCLUSIONS: : Ghrelin, which is negatively regulated by leptin and IL-1 beta, is secreted by the stomach and increases arcuate NPY expression, which in turn acts through Y(1) receptors to increase food intake and decrease energy expenditure. Gastric peptide ghrelin may thus function as part of the orexigenic pathway downstream from leptin and is a potential therapeutic target not only for obesity but also for anorexia and cachexia.

The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor.

Glucagon-like peptide-1 (7-36)amide (tGLP-1), a representative humoral incretin, released into the portal circulation in response to a meal ingestion, exerts insulinotropic action through binding to the tGLP-1 receptor known to be a single molecular form thus far. We previously reported that the hepatic vagal nerve is receptive to intraportal tGLP-1, but not to non-insulinotropic full-length GLP-1-(1-37), through a mechanism mediated by specific receptor to the hormone. In the present study, we aimed to examine how modification of the receptor function alters this neural reception of tGLP-1, by using the specific agonist, exendin-4, and the specific antagonist, exendin (9-39)amide, of the receptor at doses known to exert their effects on the insulinotropic action of tGLP-1. Intraportal injection of 0.2 or 4.0 pmol tGLP-1, a periphysiological and pharmacological dose, respectively, facilitated significantly the afferent impulse discharge rate of the hepatic vagus in anesthetized rats, as reported previously. However, unexpectedly, intraportal injection of exendin-4 at a dose of 0.2 or 4.0 pmol, or of even 40.0 pmol, did not facilitate the afferents at all. Moreover, intraportal injection of exendin (9-39)amide at 100 times or more molar dose to that of tGLP-1, either 5 min before or 10 min after injection of 0.2 or 4.0 pmol tGLP-1, failed to modify the tGLP-1-induced facilitation of the afferents. The present results suggest that the neural reception of tGLP-1 involves a receptor mechanism distinct from that in the well-known humoral insulinotropic action.

Reflex effects of oral, gastrointestinal and hepatoportal glutamate sensors on vagal nerve activity.

Glutamate sensors in the oral cavity, gastrointestinal canal and hepatoportal region are thought to function in the reflex regulation of vagal activity to the gastrointestinal tract and pancreas. In support of this notion, the findings summarized in this report demonstrate that the infusion of monosodium glutamate (MSG) into the stomach (150 mmol/L, 3 mL), duodenum (150 mmol/L, 3 mL) and portal vein (10 mmol/L, 0.1 mL) increases afferent activity in the vagal gastric, celiac and hepatic nerves, suggesting the existence of glutamate sensors in the gastric wall, intestinal wall and hepatoportal region. Further, oral, gastric and intestinal infusions of MSG (150 mmol/L, isotonic solution) and the infusion of MSG (10 mmol/L, 0.1 mL) into the portal vein resulted in reflex activation of the efferent gastric and pancreatic branches of the vagus. The intravenous injection of 10 mmol/L MSG (0.1 mL) also induced a reflex activation of the efferent discharges of the gastric branch of the vagus; however, in hepatic and celiac vagotomized rats, the intravenous injection of MSG (1 or 3mol/L, 1 mL) produced no effect on gastric vagal activity. The results of these experiments demonstrate the importance of the afferent nerve signals from visceral glutamate sensors in generating the reflex activation of gastrointestinal and pancreatic functions in response to MSG administration.

Leptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats.

We investigated the effects of leptin on central and/or peripheral feeding-related neuronal networks in Wistar male rats either normal (350-450 g) or Zucker obese (500-800 g). Low doses (1-10 pg) of leptin inhibited glucose-sensitive vagal hepatic afferent discharges and facilitated sympathetic efferent discharges to brown and white adipose tissue. Most (40-75%) neurons in the arcuate nucleus were significantly inhibited by superperfusion with leptin (0.1 nM-10 pM) under in vitro conditions. In anesthetized animals, leptin was applied electrophoretically to single hypothalamic neurons. Both glucose-sensitive neurons (GSNs) and non-GSNs in the feeding center (LHA) were significantly inhibited. Most glucoreceptor neurons in the satiety center (VMH) were significantly excited. Their depolarization was confirmed by activation of Na+ and K+ channels by 10(-11) M leptin using the perforate blind patch-clamp method. Although leptin excited GSNs in the parvocellular part of the paraventricular nucleus, the effects of leptin on such neuronal activity were slight or absent in Zucker obese rats. These results suggest that the feeding-suppression effects of leptin are mediated by its effects on signal transduction through both the central and the peripheral nervous systems.

Reflex effects from leptin sensors in the white adipose tissue of the epididymis to the efferent activity of the sympathetic and vagus nerve in the rat.

Efferent nerve signals were recorded from the central cut end of the small nerve filament dissected from the sympathetic nerve innervating the white adipose tissue (WAT) of epididymis, inter scapular brown adipose tissue (BAT), pancreas, liver, adrenal medulla, and vagus nerve innnervating the pancreas and liver. Injection of leptin (2 ng, 0.2 ml) into the white adipose tissue of the either side of the epididymis evoked reflex activation of the sympathetic nerve activity and suppression in vagus nerve activity. These observations suggest that leptin sensors in the white adipose tissue of the epididymis play a role in reflex regulation of metabolic functions of the body through the modulatory change in sympathetic and vagal outflow.

Effect of bilateral lesions of the suprachiasmatic nucleus on hyperglycemia caused by 2-deoxy-D-glucose and vasoactive intestinal peptide in rats.

In mammals, the brain usually uses glucose as a sole energy source. Thus, under a central glucopenic condition after intracranial injection of 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, it has been shown that rats elevate their blood glucose level through excitation of the sympathetic nerves. Experiments were conducted with rats to examine the role of the hypothalamic suprachiasmatic nucleus (SCN) in the hyperglycemic response to intracerebroventricular injection of either 2DG or vasoactive intestinal peptide (VIP). It was observed that, (1) intracerebroventricular injection of a VIP-antagonist inhibited the hyperglycemic and hyperglucagonemic responses to the intracranial injection of 2DG; (2) bilateral electrolytic lesioning of the SCN suppressed the hyperglycemic and hyperglucagonemic responses to intracranial injection of 2DG, and intracerebroventricular injection of VIP restored these responses to 2DG; and (3) bilateral electrolytic lesioning of the SCN also suppressed the hyperglycemic and hyperglucagonemic responses to the VIP injection, and additional intracerebroventricular injection of 2DG caused hyperglycemia. These findings indicate that in rats with bilateral lesions of the SCN intracranial injection of 2DG is able to elicit hyperglycemia when VIP was administered intracranially, and suggest that neurons containing VIP-like immunoreactive substance (VIP-neurons) in the SCN have an important role in the mechanism of hyperglycemia elicitation following intracranial injection of 2DG. Moreover, these findings show that 2DG and VIP are able to realize their functions through acting on the brain sites outside the SCN.

Effect of infusion of vasoactive intestinal peptide (VIP)-antisense oligodeoxynucleotide into the third cerebral ventricle above the hypothalamic suprachiasmatic nucleus on the hyperglycemia caused by intracranial injection of 2-deoxy-D-glucose in rats.

We examined the effect of the infusion of a vasoactive intestinal peptide (VIP) antisense oligodeoxynucleotide into the third cerebral ventricle above the hypothalamic suprachiasmatic nucleus (SCN) using osmotic minipump for 3 days (0.2 nmol/ml per h) on the hyperglycemic response to intracerebroventricular injection of 2-deoxy-D-glucose (2DG) (80 micromol) in rats. After the infusion of the VIP antisense the inhibition of VIP expression in the SCN was observed in association with suppressions of the hyperglycemia, hyperglucagonemia and relative hypoinsulinemia due to the 2DG injection. Furthermore, additional intracranial injection of VIP (4 nmol) restored these responses to the 2DG injection in rats treated with the VIP antisense. These findings suggest that VIP neurons in the SCN are involved in the regulation of glucose metabolism.

Afferent signals from leptin sensors in the white adipose tissue of the epididymis, and their reflex effect in the rat.

Afferent nerve signals were recorded from a peripheral cut end of the small nerve bundle innervating the white adipose tissue (WAT) of the epididymis in the anesthetized rat. An injection of leptin (2 ng, 0.2 ml) into the white adipose tissue facilitated the afferent activity. The response was dose dependent and the least effective dose was 100 pg (0.1 ml). An injection of 2 ng (0.2 ml) leptin into the one side of the WAT resulted in a reflex activation of efferent activity of the sympathetic nerve innervating the WAT of the bilateral epididymis. The observations suggest the existence of leptin sensors in WAT which send afferent signals from the WAT to the central nervous system and evoke a reflex activation of sympathetic outflow to the WAT which may accelerate lipolysis. This WAT to WAT reflex can explain a part of the effect of leptin on metabolic function of the fatty tissue such as the reduction of body weight and increase in energy expenditure as a negative feed-back reflex response.

Acidic fibroblast growth factor activates adrenomedullary secretion and sympathetic outflow in rats.

Effects of exogenous acidic fibroblast growth factor (aFGF), which is increased in the brain by food intake, on the plasma levels of catecholamines and on sympathetic efferent outflow were examined in anesthetized rats. A guide cannula was inserted into the cerebral third ventricle, and a vascular indwelling catheter was inserted into the right atrium from the jugular vein. Plasma epinephrine (Epi) and norepinephrine (NE) increased markedly in a dose-dependent manner for up to 120 min after intracerebroventricular or intravenous administration of aFGF (6-667 fmol/rat). Concomitant increases occurred in the efferent activity in the sympathetic nerves supplying the adrenal, spleen, and interscapular brown adipose tissue after the above administrations of aFGF. Both intravenous and intracerebroventricular administration of 10 ng basic FGF (bFGF) also increased sympathetic adrenal efferent activity and plasma Epi and NE concentrations. However, the increases induced by 10 ng bFGF were smaller than those induced by 10 ng aFGF. Bilateral splanchnicotomy completely prevented the increases in Epi induced by intracerebroventricular or intravenous aFGF but had less effect on the increases in NE. Pretreatment with an antibody against corticotropin-releasing factor (CRF), given via the intracerebroventricular route, significantly attenuated the increases in Epi and NE evoked by intracerebroventricular or intravenous administration of aFGF. Hepatic vagotomy also greatly reduced the increases in both catecholamines and the increases in sympathetic efferent firing rates evoked by intravenous administration of aFGF. These findings indicate that 1) aFGF administered intracerebroventricularly activates adrenomedullary secretion and sympathetic outflow via CRF release and 2) aFGF injected intravenously also induces sympathoadrenomedullary activation via centrally released CRF. The idea is discussed that sympathetic activation induced either by endogenous aFGF after feeding or by exogenously administered aFGF may play roles both in energy expenditure after overeating and in the modulation of immune functions.

Impaired vagus nerve-mediated control of insulin secretion in Wistar fatty rats.

It has been reported that hyperglycemia in the portal venous blood suppresses afferent activity of the hepatic branch of the vagus nerve, which in turn accelerates efferent activity of the pancreatic branch of the vagus nerve to stimulate insulin secretion. The present study examined this neural control mechanism in genetically obese diabetic male Wistar fatty (fa/fa) rats. Adult (aged 12 to 14 weeks) Wistar fatty rats were obese, hyperinsulinemic, and hyperglycemic. Young (aged 5 to 6 weeks) Wistar fatty rats were slightly obese and hyperinsulinemic, but were euglycemic compared with the lean littermates. In both adult and young lean littermates, the plasma insulin response after an intragastric glucose load (1 g/kg) was diminished by intracerebroventricular (i.c.v.) atropine methylbromide (methylatropine 10 nmol) pretreatment, and a transient increase in plasma insulin was observed after selective hepatic vagotomy, as reported in normal rats. In contrast, in both adult and young Wistar fatty rats, the plasma insulin response after an intragastric glucose load was not diminished by i.c.v. methylatropine pretreatment, and plasma insulin decreased slightly after selective hepatic vagotomy. Further, afferent discharges of the hepatic vagal branch decreased and efferent discharges of the celiac/pancreatic vagal branch increased when 10 mg glucose was infused into the portal vein in the 9-week-old lean littermates, as reported in normal rats. In 7-week-old Wistar fatty rats, afferent discharges of the hepatic vagal branch decreased but efferent discharges of the celiac/pancreatic vagal branch did not increase after intraportal glucose infusion. It is concluded that the vagus nerve-mediated regulation of insulin secretion is impaired from an early stage of life in Wistar fatty rats. Efferent discharges of the vagus nerve to the pancreas seem not to be suppressed by afferent discharges from the hepatic vagus branch, which may lead to insufficient insulin secretion in response to nutrient ingestion followed by a delayed peak. These abnormalities may thus lead to the insulin resistance and fasting hyperinsulinemia that characterize the Wistar fatty rat model.