Leptin,gut, and food intake

Hyperphagia (overeating) is often associated with energy over-storage and obesity, which may lead to a myriad of serious health problems, including heart disease, hypertension, and type 2 diabetes. Thus, understanding the complex pathological mechanisms underlying hyperphagia and obesity has an important clinical significance. Leptin, or ob protein, is a key element in the long-term regulation of food intake and body weight homeostasis. It circulates in the blood at levels correlated with body fat mass. Leptin binds to specific receptors in the hypothalamus to mediate events that regulate feeding behavior. In light of new evidence, the initial view that leptin is an adipocyte-derived signal, which acts centrally to decrease body weight, has been modified. It has been shown that leptin may also have specific functions in the gastrointestinal tract, suggesting that feeding and energy homeostasis is regulated by both central and peripheral signals. Evidence supports the view that leptin integrates short-term, meal-related signals from the gut into long-term regulation of energy balance. In addition, the gastric leptin level is altered by the nutritional state and the administration of cholecystokinin. This commentary aims to review the evidence of the role of leptin as a peripherally acting signal in the gut in the regulation of nutrient intake, adiposity, and body weight. Based on currently available data, some potential future studies are suggested.     

Carotid occlusion increases the release of endogenous GABA in the nucleus of the solitary tract

Summary In anaesthetized cats, the nucleus of the solitary tract was bilaterally superfused through push-pull cannulae with artificial cerebrospinal fluid (CSF) and the effect of carotid occlusion on the release of endogenous GABA was investigated.Bilateral carotid occlusion led to a rise in blood pressure which was associated with a very pronounced increase in the release rate of GABA in the nucleus of the solitary tract. The results demonstrate the hypertensive function of GABA in the nucleus of the solitary tract and the importance of GABAergic neurons of this nucleus for the central cardiovascular control.This work was supported by the Fonds zur Fbrderung der wissenschaftlichen Forschung Send offprint requests to A. Philippu at the above address     

The role of the brain renin–angiotensin system in hypertension: Implications for new treatment

Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin–angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine–vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150 — the prototype of a new class of centrally acting antihypertensive agents.     

Inhibition of swallowing reflex following phosphorylation of extracellular signal-regulated kinase in nucleus tractus solitarii neurons in rats with masseter muscle nociception

Pain is associated with swallowing abnormalities in dysphagic patients. Understanding neuronal mechanisms underlying the swallowing abnormalities associated with orofacial abnormal pain is crucial for developing new methods to treat dysphagic patients. However, how the orofacial abnormal pain is involved in the swallowing abnormalities is not known. In order to evaluate neuronal mechanisms of modulation of the swallows by masticatory muscle pain, here we first induced swallows by topical administration of distilled water to the pharyngolaryngeal region. The swallowing reflex was significantly inhibited after capsaicin (10, 30 mM) injection into the masseter muscle compared to vehicle injection. Moreover the number of phosphorylated extracellular signal-regulated kinase-like immunoreactive (pERK-LI) neurons in the nucleus tractus solitarii (NTS) was significantly increased in the rats with capsaicin injection into the masseter muscle compared to that with vehicle injection. Rostro-caudal distribution of pERK-LI neurons in the NTS was peaked at the obex level. The capsaicin-induced inhibitory effect on swallowing reflex was reversed after intrathecal administration of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor, PD98059. The present findings suggest that phosphorylation of ERK in NTS neurons may be involved in capsaicin-induced inhibition of swallowing reflex.     

The effects of nicotine on the alpha-7 and beta-2 nicotinic acetycholine receptor subunits in the developing piglet brainstem

Exposure to cigarette smoke is a major risk factor for sudden infant death syndrome (SIDS). We tested the hypothesis that nicotine increases expression of the nicotinic acetylcholine receptor (nAChR) subunits α7 and β2 in a piglet model. Piglets exposed to 2 mg/kg/day nicotine for 14 days postnatally (n = 14) were compared to non-exposed controls (n = 14), (equal gender proportions). Immunohistochemistry was performed to identify and quantify changes in, α7 and β2 nAChR subunits in 8 nuclei of the medulla at both the rostral and caudal levels. Compared to controls, nicotine exposed piglets had decreased α7 in the rostral dorsal motor nucleus of the vagus (rDMNV) (p = 0.01), and increased β2 in the caudal DMNV (cDMNV) (p = 0.05), caudal nucleus of the spinal trigeminal tract (cNSTT) (p = 0.03) and caudal nucleus of the solitary tract (cNTS) (p = 0.04). Analysis by gender showed that in the control group, compared to males, females had higher β2 in the caudal hypoglossal (cXII) (p < 0.01) and caudal inferior olivary (p = 0.04) nuclei, while in the nicotine group females had higher β2 in the cDMNV (p = 0.02). Compared to control males, nicotine exposed males had lower β2 in the cXII (p < 0.01). Overall, changes in α7 were specific to nicotine exposure with no gender differentiation. Changes in β2 were more widespread but showed gender-specific effects. These findings provide evidence that early postnatal exposure to nicotine significantly affects nAChR subunit expressions in the developing brainstem.     

The origin of nausea in migraine–A PET study

Background

Nausea is a common and disabling symptom of migraine. The origin of nausea is not well understood although functional connections between trigeminal neurons and the nucleus tractus solitarius may explain occurrence of nausea with pain. However, nausea occurs as a premonitory symptom in about a quarter of patients, suggesting that a primary brain alteration unrelated to the experience of pain may be the reason for nausea.

Methods

We performed positron emission tomography scans with H₂¹⁵O PET in premonitory phase of nitroglycerin-induced migraine and compared patients with and without nausea.

Results

The results showed activation in rostral dorsal medulla and periaqueductal grey (PAG) in the nausea group, which was absent in the no nausea group. The rostral dorsal medullary area included the nucleus tractus solitarius, dorsal motor nucleus of the vagus nerve and the nucleus ambiguus, all of which are thought to be involved in brain circuits mediating nausea.

Conclusions

The results demonstrate that nausea can occur as a premonitory symptom in migraine, independent of pain and trigeminal activation. This is associated with activation of brain structures known to be involved in nausea. We conclude that nausea is a centrally driven symptom in migraine.     

Gut hormones and appetite control

Many peptides are synthesized and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut-brain signaling regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Recent research suggests that gut hormones can be manipulated to regulate energy balance in humans, and that obese subjects retain sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective and well-tolerated treatment for obesity.     

PRESSOR RESPONSES TO SEROTONIN INJECTED INTO THE NUCLEUS TRACTUS SOLITARIUS OF SPRAGUE-DAWLEY RATS AND SPONTANEOUSLY HYPERTENSIVE RATS

Previous studies in rats have shown that injection of nanomoles of serotonin (5-hydroxytryptamine; 5HT) into the nucleus tractus solitarius (NTS) acts on 5HT3 receptors to increase arterial pressure (AP). We investigated the effect of 5HT in Sprague-Dawley (SD) rats and in spontaneously hypertensive rats (SHR). Injection of nanomoles of 5HT into the NTS of chloralose-anesthetized SD rats increased AP. This effect was inhibited by prior injection of 5HT3 receptor antagonist ondansetron. The GABA_A receptor antagonist bicuculline did not inhibit the effect of 5HT. Bilateral injection of 5HT or ondansetron did not affect the baroreflex sensitivity. Bilateral injection of ondansetron did not alter AP. The pressor effect of 5HT was exaggerated in SHR. These results suggest that stimulation of 5HT3 receptors in the NTS increases AP independently of activation of GABAA receptors and the baroreflex sensitivity. Furthermore, this serotonergic system is supersensitive in the NTS of SHR.     

Olanzapine treatment decreases the density of muscarinic M2 receptors in the dorsal vagal complex of rats

In this study, we investigated the effects of antipsychotic drugs, olanzapine and haloperidol, on the density of the muscarinic M2 receptors in the dorsal vagal complex (DVC) and hypoglossal nucleus (HN). Female Sprague Dawley rats were treated with olanzapine, haloperidol or vehicle (control) for 1 (short-term) or 12 weeks (long-term). Quantitative autoradiography was used to investigate the M2 receptor density in the DVC and HN using a muscarinic antagonist [(3)H] AF-DX384. Olanzapine, but not haloperidol, treatment induced a significant decrease in the binding density of M2 receptors in the DVC compared to control groups. Although the HN showed a higher density of [(3)H] AF-DX384 binding than the DVC, treatment with both olanzapine and haloperidol did not induce any significant changes in [(3)H] AF-DX384 binding in the HN. These results suggest that olanzapine-induced body weight gain may be associated with functional changes in the muscarinic neurotransmission in the DVC.