Neuro-hormonal control of food intake; basic mechanisms and clinical implications

Obesity is one of the most common metabolic diseases and the greatest threats of the health because of possibility of numerous complications. In order to design effective drugs or apply the helpful surgical procedure it is essential to understand physiology of appetite control and pathophysiology of obesity. According to the first law of thermodynamics, the energy input in the form of food, equals energy expenditure through exercise, basal metabolism, thermogenesis and fat biosynthesis. The control of body weight actually concerns the control of adipose tissue with the key role of hypothalamus, possessing several neuronal centers such as that in lateral hypothalamic nuclei considered to be "hunger" center and in ventromedial nuclei serving as the "satiety" center. In addition, paraventricular and arcuate hypothalamic nuclei (ARC) are the sites where multiple hormones, released from the gut and adipose tissue, converge to regulate food intake and energy expenditure. There are two distinct types of neurons in ARC that are important in control of food intake; (1) preopiomelanocortin (POMC) neurons activated by anorexigenic hormones and releasing a-melanocyte-stimulating hormone (alpha-MSH) in satiety center and (2) neurons activated by orexigenic peptides such as ghrelin that release the substances including neuropeptide Y (NPY) and Agouti-Related Peptide (AgRP) in hunger center. ARC integrates neural (mostly vagal) and humoral inputs such as enteropeptides including orexigenic (ghrelin and orexins) and anorexigenic peptides (cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin and others) that exert a physiological role in regulating appetite and satiety. The peripherally (gut, adipose tissue) and centrally expressed modulators of appetitive behavior act through specific receptors in the afferent (mostly vagal) nerves and hypothalamic neurons implicated in adiposity signaling and regulation of food intake

Helicobacter pylori and its involvement in gastritis and peptic ulcer formation

Modern gastroenterology started in early 19th century with the identification by W. Prout of the inorganic (hydrochloric) acid in the stomach and continued through 20th century with the discoveries by I.P. Pavlov of neuro-reflex stimulation of gastric secretion for which he was awarded first Nobel Prize in 1904. When concept of nervism or complete neural control of all digestive functions reached apogeum in Eastern Europe, on the other side of Europe (in United Kingdom), E. Edkins discovered in 1906 that a hormone, gastrin, may serve as chemical messenger in stimulation of gastric acid secretion, while L. Popielski revealed in 1916 that histamine is the most potent gastric secretagogue. K. Schwartz, without considering neural or hormonal nature of gastric secretory stimulation, enunciated in 1910 famous dictum; “no acid no ulcer” and suggested gastrectomy as the best medication for excessive gastric acid secretion and peptic ulcer. In early 70s, J.W. Black, basing on earlier L. Popielski’s histamine concept, identified histamine-H2 receptors (H2-R) and obtained their antagonists, which were found very useful in the control of gastric acid secretion and ulcer therapy for which he was awarded in 1972 second Nobel Prize in gastrology. With discovery by G. Sachs in 1973 of proton pumps and their inhibitors (PPI), even more effective in gastric acid inhibition and ulcer therapy than H2-R antagonists, gastric surgery, namely gastrectomy, practiced since first gastric resection in 1881 by L. Rydygier, has been considered obsolete for ulcer treatment. Despite of the progress in gastric pharmacology, the ulcer disease remained essentially “undefeated” and showed periodic exacerbation and relapses. The discovery of spiral bacteria in the stomach in 1983 by B.J. Marshall and R.J. Warren, Australian, clinical researches, awarded in 2005 the Nobel Prize for the third time in gastrology, has been widely considered as a major breakthrough in pathophysiology of gastritis and peptic ulcer, which for the first time can be definitively cured by merely eradication of germ infecting stomach. This overview presents the mechanism of induction of gastritis and peptic ulcer by the H. pylori infection and describes accompanying changes in gastric acid and endocrine secretion as well as the effects of germ eradication on gastric secretory functions and gastroduodenal mucosal integrity

Impact of Helicobacter pylori and nonsteroidal anti-inflammatory drugs on gastric ulcerogenesis in experimental animals and in humans

Helicobacter pylori (H. pylori) and nonsteroidal anti-inflammatory drugs (NSAID) are the most common pathogens in the gastroduodenal mucosa in animals and humans, but their relationship in ulcerogenesis has been little studied. According to some authors, H. pylori infection in humans does not act synergistically with NSAID on ulcer healing, therefore, there is no need to eradicate the germ. This notion is supported by the finding that the eradication of H. pylori does not affect NSAID-induced gastropathy treated with omeprazole and that H. pylori infection induces a strong cyclooxygenase-2 expression resulting in excessive biosynthesis of gastroprotective prostaglandins, which should in turn counteract NSAID-induced gastropathy and heal the existing ulcer. Other investigators claim that H. pylori infection acts synergistically with NSAID on ulcer development, therefore, H. pylori should be eradicated, particularly at the start of long-term NSAID therapy. Maastricht 2-2000 consensus also recommends eradication prior to NSAID treatment, but this eradication does not appear to accelerate ulcer healing or to prevent the recurrent ulcers in NSAID users. Our studies in almost 6000 dyspeptic patients undergoing upper endoscopy and [13C]-urea breath test (UBT) revealed that about 70% of these patients are H. pylori (+) and about 30.6% of these develop gastroduodenal ulcers. Of these ulcers, over 70% were H. pylori (+) positive, 12% NSAID (+), 8% were both H. pylori (+) and NSAID (+), while 22% ulcers were H. pylori (−) and NSAID (−) or “idiopathic” ulcers. Basically, our results support Hawkey's concept and this also agrees with our findings in the rat model showing that: (1) there is no synergistic interaction between H. pylori infection and NSAID on gastric ulcer development, (2) H. pylori and NSAID are independent risk factors for peptic ulceration, and (3) NSAID therapy in H. pylori positive patients attenuates the ulcer development possibly due to direct inhibitory action of these drugs on H. pylori