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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. beta-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.
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PMID:Afferent signals regulating food intake. 1099 53

Cholecystokinin (CCK) and gastrin (G) and their receptors (CCK1 and CCK2) are involved in multiple physiological functions. Notably, CCK1R plays a role in the regulation of food intake whereas both CCK1R and CCK2R play a role in the regulation of pancreatic endocrine function. CCK1R and CCK2R may therefore serve as pharmacological targets in diabetes and obesity and genes encoding these receptors may be candidate genes in the pathogenesis of the diseases. In this study, we used single nucleotide polymorphism analysis and allele specific amplification for mutation screening of the CCK2 receptor gene and family linkage study. Mutated receptors were constructed, expressed in COS-7 cells for analysis of their binding and functional properties. V125I-CCK2 receptor variant was found in 2 out of 18 type 2 diabetes mellitus families tested. V125I mutation co-segregated in those 2 initial families, but further association studies showed that this mutation was not associated with diabetes or early age at diagnosis of the disease. V125I-CCK2 receptor high affinity sites exhibited a 2-fold enhanced binding affinity for CCK which was correlated to a slightly increased potency in coupling to inositol phosphate production. Since CCK2 receptor is expressed in pancreatic glucagon-producing cells in humans and is involved in secretion of glucagon, an increase of binding affinity of the mutated CCK2 receptor could enhance glucagon secretion in patients bearing V125I mutation. We also characterized a mutant of the CCK1 receptor which was previously identified in an obese patient. This mutant, V365I-CCK1, demonstrated a decreased level of expression (26%) and efficacy (25%) to stimulate inositol phosphates. It can therefore be expected that in humans bearing V365I mutation, decreases in CCK1 receptor expression and coupling efficiency may affect CCK-induced regulation of satiety. Polymorphism or mutations in the CCK receptors may be involved in type 2 diabetes mellitus and obesity. However, further studies are necessary to precisely evaluate this role in humans.
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PMID:Genetic, pharmacological and functional analysis of cholecystokinin-1 and cholecystokinin-2 receptor polymorphism in type 2 diabetes and obese patients. 1177 61

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal base and include breast, prostate, endometrium, colon and gallbladder cancers. As the basis for understanding the problem of obesity has advanced, a number of new ideas have emerged about the relationship of obesity to cancer. The conversion of androstenedione secreted by the adrenal gland into estrone by aromatase in adipose tissue stroma provides an important source of estrogen for the postmenopausal woman. This estrogen may play an important role in the development of endometrial and breast cancer. Of interest is that experimental animals lacking aromatase or the estrogen receptor alpha are obese. Leptin is one of the many products produced by fat cells and has given rise to the ideas that the fat cell is an endocrine cell and that adipose tissue is an endocrine organ. The increased release of cytokines from this tissue may play a role in the inflammatory state that is associated with obesity. The gut also plays an important role in signaling satiety in response to food intake. Colon cancer is an important human disease, and experimental mice lacking gastrin are obese and have an increased risk of developing colon cancer in response to carcinogenic drugs. Efforts to control obesity through preventive strategies and treatment can be expected to have a benefit in reducing the risk of cancer.
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PMID:The underlying basis for obesity: relationship to cancer. 1242 69

The first hormone discovered in the gastrointestinal tract was secretin, isolated from duodenal mucosa. Some years later, two additional gastrointestinal hormones, gastrin and cholecystokinin (CCK), were discovered, but it was not until the 1970s that gastrointestinal endocrinology studies became more prevalent, resulting in the discovery of many more hormones. Here, we examine the role of gut hormones in energy balance regulation and their possible use as pharmaceutical targets for obesity.
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PMID:Gut hormones ghrelin, PYY, and GLP-1 in the regulation of energy balance [corrected] and metabolism. 1662 93

The role of cholecystokinin (CCK) as a satiety factor has been extensively documented. Although most work implies that CCK1 receptor mediates the control of food intake, a contributing role for CCK2 receptor (CCK2R) in the CCK-induced satiety cannot be totally excluded. The hypothesis that CCK2R invalidation disrupts regulatory pathways with impact on feeding behavior was examined in CCK2R(-/-) mice. CCK2R(-/-) mice developed obesity that was associated with hyperphagia. Obesity was related with increased fat deposition resulting from adipocyte hypertrophy. Expression of several adipokines was dysregulated consistently with obesity. Moreover, obesity was associated with disturbed glucose homeostasis as revealed by increased fasting glycemia and insulinemia, impaired glucose tolerance, and hepatic insulin resistance in CCK2R(-/-) mice. In vitro analysis of isolated adipocytes metabolism was consistent with increased storage but preserved insulin sensitivity. Suppression of feeding and concomitant increased expression of hypothalamic proopiomelanocortin after intracerebroventricular injection of gastrin into control mice demonstrates that hypothalamic CCK2 receptors mediate inhibition of food intake. Comparative analysis of hypothalamic mediator gene expression in fed knockout and control mice demonstrated overexpression of ghrelin receptors in CCK2R(-/-) mice, indicating up-regulation of orexigenic pathways. This effect was also observed after body weight normalization, indicating a causative role in the development of hyperphagia and obesity of CCK2R(-/-) mice. Our results give evidence that CCK2 receptor activity plays a contributing regulatory role in the control of food intake.
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PMID:Involvement of cholecystokinin 2 receptor in food intake regulation: hyperphagia and increased fat deposition in cholecystokinin 2 receptor-deficient mice. 1712 76

Metabolic syndrome (MS), defined as central obesity, hyperinsulinemia, insulin resistance, hypertension, dyslipidemia and glucose intolerance, has been associated with inflammatory biomarkers and cardiovascular diseases. This study was carried out on three groups of women; lean controls, moderately obese with MS (OB-MS) and morbidly obese with MS (MOB-MS). The main objectives were: 1. to analyze the plasma levels of total and acylated ghrelin, peptide YY(3-36) (PYY(3-36)), cholecystokinin (CCK), gastrin and insulin levels under basal conditions and in response to a standard mixed meal, and 2. to elucidate the relationship between the plasma levels of these gut peptides and metabolic syndrome parameters. Plasma levels of the gut hormones were measured by radioimmunoassays at time 0 just before the meal and at 30, 60 and 120 min after a meal ingestion. Traditional lipid profile and high-sensitivity C reactive protein (hs-CRP), the strongest biomarker of inflammation were also determined in OB-MS and MOB-MS. When compared to OB-MS, MOB-MS exhibited much higher anthropometric parameters such as waist circumference, higher fat mass and higher plasma levels of low density lipoprotein-cholesterol (LDL-C) and hs-CRP. Both these obese groups revealed significantly higher values of body mass index (BMI), fat mass, total cholesterol (TC), LDL-C, fasting glucose, fasting insulin, insulin resistance (IR) calculated from homeostatic model assessment (HOMA) and hs-CRP compared to the values recorded in lean subjects. Fasting PYY(3-36) level was lower, while fasting acylated ghrelin was higher in MOB-MS than in OB-MS. Plasma total and acylated ghrelin levels were significantly lower in OB-MS compared to lean women. In MOB-MS women the fasting PYY(3-36) levels were lower compared to lean controls and OB-MS, whilst postprandially in both OB-MS and MOB-MS, it was much lower than in lean women. The fasting plasma levels of total and acylated ghrelin and their postprandial decrease were significantly smaller in both obese groups compared to lean subjects. Plasma hs-CRP levels correlated positively with BMI, waist circumference, fat mass, fasting glucose, HOMA IR and fasting active ghrelin, whilst it negatively correlated with plasma fasting and total ghrelin. Moreover, plasma fasting acylated ghrelin correlated positively with fat mass. Fasting total ghrelin correlated positively with BMI, HDL-C and negatively with HOMA IR. We conclude that MS features of obesity are closely related to fasting and postprandial alterations of concentrations of PYY(3-36), CCK and ghrelin, suggesting that determination of gut hormones controlling food intake might be considered as a valuable tool to assess the progression of MS to comorbidities of obesity.
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PMID:Basal and postprandial plasma levels of PYY, ghrelin, cholecystokinin, gastrin and insulin in women with moderate and morbid obesity and metabolic syndrome. 1744 25

The phenomenon of pancreatic regeneration in mammals has been well documented. It has been shown that pancreatic tissue is able to regenerate in several species of mammal after surgical insult. This tissue is also known to have the potential to maintain or increase its beta-cell mass in response to metabolic demands during pregnancy and obesity. Since deficiency in beta-cell mass is the hallmark of most forms of diabetes, it is worthwhile understanding pancreatic regeneration in the context of this disease. With this view in mind, this article aims to discuss the potential use in clinical strategies of knowledge that we obtained from studies carried out in animal models of diabetes. Approaches to achieve this goal involve the use of biomolecules, adult stem cells and gene therapy. Various molecules, such as glucagon-like peptide-1, beta-cellulin, nicotinamide, gastrin, epidermal growth factor-1 and thyroid hormone, play major roles in the initiation of endogenous islet regeneration in diabetes. The most accepted hypothesis is that these molecules stimulate islet precursor cells to undergo neogenesis or to induce replication of existing beta-cells, emphasizing the importance of pancreas-resident stem/progenitor cells in islet regeneration. Moreover, the potential of adult stem cell population from bone marrow, umbilical cord blood, liver, spleen, or amniotic membrane, is also discussed with regard to their potential to induce pancreatic regeneration.
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PMID:Approaches towards endogenous pancreatic regeneration. 1749 91

Gastrin and cholecystokinin (CCK) are two of the oldest hormones and within the past 15 years there has been an exponential increase in knowledge of their pharmacology, cell biology, receptors (CCK1R and CCK2R), and roles in physiology and pathological conditions. Despite these advances there is no approved disease indication for CCK receptor antagonists and only a minor use of agonists. In this review, the important factors determining this slow therapeutic development are reviewed. To assess this it is necessary to briefly review what is known about the roles of CCK receptors (CCK1R and CCK2R) in normal human physiology, their role in pathologic conditions, the selectivity of available potent CCKR agonists/antagonists as well as to review their use in human conditions to date and the results. Despite extensive studies in animals and in humans, recent studies suggest that monotherapy with CCK1R agonists will not be effective in obesity, nor CCK2R antagonists in panic disorders or CCK2R antagonists to inhibit growth of pancreatic cancer. Areas that require more study include the use of CCK2R agonists for imaging tumors and radiotherapy, CCK2R antagonists in hypergastrinemic states especially with long-term PPI use and for potentiation of analgesia as well as use of CCK1R antagonists for a number of gastrointestinal disorders [motility disorders (irritable bowel syndrome, dyspepsia, and constipation) and pancreatitis (acute and chronic)].
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PMID:Progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential. 1799 37

Biliopancreatic diversion (BPD) is a surgical procedure performed in patients with untreatable obesity and insulin resistance. The demonstrated metabolic and hormonal results of this procedure include the reversal of insulin resistance; an increase in diet-induced thermogenesis; and modifications of gut hormones, such as gastrin, enteroglucagon, neurotensin, and cholecystokinin. On the other hand, obesity is a condition of increased oxidative stress; however, few studies have investigated antioxidant systems in obese persons with BPD. To evaluate the metabolic status and antioxidant systems in such patients, we studied a group of 11 morbidly obese patients, aged 28 to 62 years, with a mean body mass index (BMI) of 54.71 +/- 2.52 kg/m(2), before and after successful BPD (mean post-BPD BMI, 44.68 +/- 1.51 kg/m(2)). A control group composed of 10 slightly overweight women, with a mean BMI of 28.5 +/- 0.72 kg/m(2), was also studied. Coenzyme Q(10) (CoQ(10)) levels (also normalized for cholesterol levels) and total antioxidant capacity in blood plasma were assessed in these populations. The most striking datum was the extremely low level of CoQ(10) in postoperative period (0.34 +/- 0.16 vs 0.66 +/- 0.09 mug/mL, P = .04); also, the data corrected for cholesterol levels presented the same pattern, with a more marked significance (152.46 +/- 11.13 vs 186.4 +/- 17.98 nmol/mmol, P = .001). This could be due to lipid malabsorption after surgery. In fact, the pre-BPD data present all the metabolic and hormonal characteristics of severe obesity; and after BPD, there was a net improvement in the metabolic parameters. The first pathophysiologic phenomenon seems to be lipid malabsorption that has been argued to be the cause of insulin resistance reversion. This metabolic interpretation is also confirmed by the absence of significant variations of total antioxidant capacity (57.5 +/- 5.3 vs 66 +/- 5.3). The mechanisms of these phenomena remain to be established. These data suggest the importance of correcting postsurgical metabolic complications, in these clinical populations, with CoQ(10) supplementation.
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PMID:Evaluation of antioxidant systems (coenzyme Q10 and total antioxidant capacity) in morbid obesity before and after biliopancreatic diversion. 1959 73

Circadian and seasonal rhythms are a fundamental feature of all living organisms and their organelles. Biological rhythms are responsible for daily food intake; the period of hunger and satiety is controlled by the central pacemaker, which resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and communicates with tissues via bidirectional neuronal and humoral pathways. The molecular basis for circadian timing in the gastrointestinal tract (GIT) involves interlocking transcriptional/translational feedback loops which culminate in the rhythmic expression and activity of a set of clock genes and related hormones. Interestingly, it has been found that clocks in the GIT are responsible for the periodic activity (PA) of its various segments and transit along the GIT; they are localized in special interstitial cells, with unstable membrane potentials located between the longitudinal and circular muscle layers. The rhythm of slow waves is controlled in various segments of the GIT: in the stomach (about 3 cycles per min), in the duodenum (12 cycle per min), in the jejunum and ileum (from 7 to 10 cycles per min), and in the colon (12 cycles per min). The migrating motor complex (MMC) starts in the stomach and moves along the gut causing peristaltic contractions when the electrical activity spikes are superimposed on the slow waves. GIT hormones, such as motilin and ghrelin, are involved in the generation of MMCs, while others (gastrin, ghrelin, cholecystokinin, serotonin) are involved in the generation of spikes upon the slow waves, resulting in peristaltic or segmental contractions in the small (duodenum, jejunum ileum) and large bowel (colon). Additionally, melatonin, produced by neuro-endocrine cells of the GIT mucosa, plays an important role in the internal biological clock, related to food intake (hunger and satiety) and the myoelectric rhythm (produced primarily by the pineal gland during the dark period of the light-dark cycle). This appears to be an endocrine encoding of the environmental light-dark cycle, conveying photic information which is used by organisms for both circadian and seasonal organization. Motor and secretory activity, as well as the rhythm of cell proliferation in the GIT and liver, are subject to many circadian rhythms, mediated by autonomic cells and some enterohormones (gastrin, ghrelin and somatostatin). Disruption of circadian physiology, due to sleep disturbance or shift work, may result in various gastrointestinal diseases, such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD) or peptic ulcer disease. In addition, circadian disruption accelerates aging, and promotes tumorigenesis in the liver and GIT. Identification of the molecular basis and role of melatonin in the regulation of circadian rhythm allows researchers and clinicians to approach gastrointestinal diseases from a chronobiological perspective. Clinical studies have demonstrated that the administration of melatonin improves symptoms in patients with IBS and GERD. Moreover, our own studies indicate that melatonin significantly protects gastrointestinal mucosa, and has strong protective effects on the liver in patients with non-alcoholic steatohepatitis (NASH). Recently, it has been postulated that disruption of circadian regulation may lead to obesity by shifting food intake schedules. Future research should focus on the role of clock genes in the pathophysiology of the GIT and liver.
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PMID:Gut clock: implication of circadian rhythms in the gastrointestinal tract. 2167 61


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