Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of body fat stores is a problem of energy and nutrient balance that can be most readily viewed as a feedback system. Several elements are involved in any feedback system, including afferent signals, a controller that senses the afferent signals and transduces their information and then activates efferent controls that regulate the controlled system. The recent discovery of leptin has provided a major missing link in the feedback control system. This afferent signal is produced exclusively in fat cells of nonpregnant mammals but can be produced in the placenta as well. This circulating peptide has a very strong relationship to the level of body fat and its absence experimentally and clinically produces massive obesity. In the controller, or brain, several anatomic regions play a central role in regulating fat stores. Damage to the ventromedial nucleus (VMH) or the paraventricular nucleus (PVN) in the hypothalamus produces massive obesity in mammals and birds. Injury to the central nucleus of the amygala will also produce obesity. In contrast, damage to the lateral hypothalamus reduces body fat. The syndrome of leptin deficiency or defects in the leptin receptors produce a massive obesity that is metabolically similar to the VMH or PVN lesion syndromes of obesity, suggesting that leptin may have its metabolic effects through these medial hypothalamic centers. Support for this idea has come from studies showing that damage to the PVN or VMH will block the effects of leptin. A number of neuropeptides and monoamines are involved with modulating of food intake and fat stores. Both serotonin, acting through 5-HT2C receptors, and norepinephrine, acting through beta 2 and/or beta 3 receptors, reduce food intake. A variety of peptides also influence food intake and body fat. Neuropeptide Y, dynorphin, galanin, and melanocyte-stimulating hormone all increase food intake. In contrast, a large number of peptides--including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, insulin, leptin, alpha-MSH, and TRH--reduce food intake. Chronic administration of neuropeptide Y, acting through Y-5 receptors, can produce chronically increased food intake and obesity. This syndrome is similar to the VMH syndrome and suggests that NPY must be acting as an inhibitor of a feeding system. The melanocortin receptor system may be particularly important because a mouse that does not express MC4 receptors is massively overweight. These central systems modulate food intake and fat stores by the controlled system. Glucocorticoids from the adrenal gland are important in obesity, since adrenalectomy will reverse or prevent the development of all forms of obesity. The sympathetic nervous system is also important because low sympathetic activity is associated with experimental and clinical obesity. The reciprocal relationship between food intake and sympathetic activity has been a robust relationship, suggesting that beta receptors in the periphery or brain may be involved in feeding control. In one model of dietary obesity resulting when animals eat a high-fat diet, the syndrome is blocked by inhibitory adrenal steroid activity. These animals show a lower level of sympathetic activity and a low level of brain serotonin. Finally, they show an enhanced sensitivity to essential fatty acids when these are applied to the tongue or given into the gut. In this chapter, the control of energy stores as fat is viewed as a feedback system. Leptin is perceived as a key afferent signal and glucocorticoids and the sympathetic nervous system through beta receptors as essential elements of this control system.
 ...
PMID:The MONA LISA hypothesis in the time of leptin. 976 5

Rats maintained on high-fat diets often exhibit increased food intake and weight gain. We hypothesized that high-fat diets might result in reduced sensitivity to hormonal signals responsible for terminating food intake--satiety signals. The intestinal hormone cholecystokinin (CCK) and the gastrointestinal neuropeptide, bombesin (BBS) both have been proposed as satiety signals. To determine whether maintenance on high-fat diets alters sensitivity to satiating effects of CCK and bombesin (BBS), rats were maintained on a low fat diet (LF), a high-fat diet that was isocaloric with the low-fat diet (HF), or one of two hypercaloric high-fat diets (HF-1, HF-2) that differed from HF and LF in fat, fiber, and total caloric content. CCK and bombesin reduced food intake significantly less in rats maintained on high-fat diets, compared to those on the low fat diet. Neither high caloric intake, which was associated with increased body weight gain on the two hypercaloric diets, nor fiber content of the diet accounted for the reduced response of HF rats to CCK. Rather, reduced sensitivity to CCK was related only to the high proportion of calories taken as fat. We also determined whether reduced CCK sensitivity was due to the maintenance on a particular diet or to the diet eaten during a CCK test. After CCK, rats maintained on LF reduced food intake more (49%) than rats maintained on HF (22%), regardless of whether they ate HF or LF during the CCK test itself. These findings indicate that maintenance of rats on high-fat diets reduces sensitivity to some peptide satiety signals. Reduced sensitivity to satiety signals might contribute to overeating and obesity often observed when rats are maintained on high-fat diets.
 ...
PMID:Rats maintained on high-fat diets exhibit reduced satiety in response to CCK and bombesin. 980 56

Cholecystokinin (CCK) is one of the first discovered gastrointestinal hormones and one of the most abundant neuropeptides in the brain. Two types of CCK receptors have been identified: (1) CCK-A receptors are mainly located in the periphery, but are also found in some areas of the CNS; and (2) CCK-B receptors are widely distributed in the brain. Major biological actions of CCK are the reduction of food intake and the induction of anxiety-related behavior. Inhibition of feeding is mainly mediated by the A-type receptors, whereas anxiety-like behavior is induced by stimulating B-type receptors. This paper presents new findings on the effects of the biologically active CCK agonists, CCK-8S, CCK-4, and A71378. The results reviewed suggest that the hypophagic effects of CCK are strongly dependent on the experimental design, sex, and age of the rats. For example, food intake measured during the night or after food deprivation is reduced by CCK-8S in young adult and aged rats, whereas, under fixed feeding conditions, CCK-8S does not inhibit food intake in young adult rats. The sensitivity to the hypophagic CCK effect increases with age in male and female rats; however, female rats are less sensitive to the CCK action. Further, using a nongenetic and non-stressful model of obesity due to unspecific postnatal overfeeding, the satiating effect of moderate CCK-8S doses is weaker in obese than in normal rats. Again, the hypophagic effect is more pronounced in male than in female obese and normal rats. Considering that aversive reactions in rats are markedly influenced by strain and breeding-line variations, research results in this area are critically reviewed. It is shown that anxiety-like symptoms can only be induced by a selectively acting CCK-B agonist, whereas mixed CCK-A and -B agonists and selective CCK-A agonists fail to change behavior in anxiety tests. CCK-4 induces stable and reproducible anxiogenic-like behavior only in certain rat strains. Moreover, CCK-4 effects can be demonstrated in the conflict test, in the ultrasonic vocalization test in rat pups, on the elevated plus maze, and in the black and white box, but not in the social interaction test. CCK has also been reported to modulate memory processes. On the one hand, CCK-8S and CCK-4 enhanced habituation to the novelty of a hole board. On the other hand, repeated administration of CCK-8S did not improve maze performance in aged rats. The literature on the behavioral pharmacology of CCK is rife with inconsistency and contradiction. The major biological actions of CCK depend on the receptor selectivity of the CCK fragments used and on organismic and procedural variables. All these variables potentially influence behavioral responses in rats. Therefore, in CCK research more attention should be paid to the importance of these methodological factors.
 ...
PMID:Major biological actions of CCK--a critical evaluation of research findings. 983 94

Cholecystokinin (CCK) is suggested to be involved, e.g. in the central nervous modulation of food intake, possibly by acting within specific hypothalamic nuclei. Perinatal overnutrition predisposes to permanent obesity and hyperphagia, while underlying mechanisms are unclear. By reducing the litter size from the 3rd to 21st day of life, early overnutrition was induced in newborn rats. At weaning, clear overweight (P < 0.001), hyperglycaemia (P < 0.05), hyperinsulinaemia (P < 0.001), and insulin resistance (P < 0.001) occured. These early signs of obesity were associated with a significantly decreased number of CCK-positive neurons in the paraventricular hypothalamic nucleus (P < 0.002). In conclusion, due to neonatal overfeeding malformation of CCKergic neurons at the end of the critical hypothalamic differentiation period occurs. Long-term consequences on CCK-related neuroendocrine regulations could be suggested, including those affecting food intake and body weight gain.
 ...
PMID:Reduction of cholecystokinin-8S-neurons in the paraventricular hypothalamic nucleus of neonatally overfed weanling rats. 987 40

This review is dealing with currently available medications used in the treatment of obesity. Unfortunately currently available drugs did not prove effective in the long term treatment of obese patients. Fenfluramin and D-Fenfluramin has been withdrawn from the market because of severe side effects as pulmonary hypertension and valvular heart disease. Sibutramin, a serotonin noradrenalin reuptake inhibitor, will be available this year. Orlistat, an inhibitor of pancreatic lipases, has proven effective for weight reduction in obese patients. New drugs as alpha 2-adrenergic antagonists, cholecystokinin, neuropeptide y, bombesin and leptin are in the pipeline.
 ...
PMID:[Drug therapy of obesity]. 987 89

Environmental manipulations during early development can induce permanent alterations in hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stressors. However, little is known about the impact of early life experiences on appetitive responses. The present investigation assessed the effects of brief handling/separation or protracted separation from the dams, on feeding and anxiety responses during development. During the first 3 weeks post-partum, Sprague-Dawley rat pups were exposed daily to either brief (15 min) handling/isolation (H), a more protracted (3 h) period of maternal separation (MS), or were not handled (NH). When tested on the elevated plus-maze (at 5-6 weeks) H groups displayed less anxiety than NH gender-matched controls. Surprisingly, so did the MS females. At weaning (Day 22), the MS rats weighed significantly less than both the H and NH animals; the difference between the H and MS was more robust and persisted throughout the experiment (D 62). The H animals of both genders, and the females of the MS group, consumed more of the palatable 'snack' than their NH counterparts. The feeding suppressant response to the various satiety peptides (bombesin, cholecystokinin, and amylin) was not affected by the early life experience, with exception of cholecystokinin (CCK) effects, which were more pronounced in H and MS males. These results suggest that early life events may contribute to anxiety and/or ingestive disorders such as anorexia nervosa, bulimia and obesity.
 ...
PMID:Short- and long-periods of neonatal maternal separation differentially affect anxiety and feeding in adult rats: gender-dependent effects. 1006 79

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A weak indication for linkage was obtained between the Isl-1 locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or another nearby gene) lies on chromosome 5q should be determined by further analyses.
 ...
PMID:A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q. 1033 20

Adult Otsuka Long-Evans Tokushima fatty (OLETF) rats lack functional cholecystokinin A (CCK-A) receptors, are diabetic, hyperphagic, and obese, and have patterns of ingestion consistent with a satiety deficit secondary to CCK insensitivity. Because dietary fat potently stimulates CCK release, we examined how dietary fat modulates feeding in adult male OLETF rats and their lean [Long-Evans Tokushima (LETO)] controls. High-fat feeding produced sustained overconsumption of high-fat diet (30% corn oil in powdered chow) over a 3-wk period in OLETF but not LETO rats. We then assessed the ability of gastric gavage (5 ml, 1-2 kcal/ml x 15 s) or duodenal preloads (1 kcal/ml, 0.44 ml/min x 10 min) of liquid carbohydrate (glucose), protein (peptone), or fat (Intralipid) to suppress subsequent 30-min 12.5% glucose intake in both strains. In OLETF rats, gastric and duodenal fat preloads were significantly less effective in suppressing subsequent intake than were equicaloric peptone or glucose. These results demonstrate that OLETF rats fail to compensate for fat calories and suggest that their hyperphagia and obesity may stem from a reduced ability to process nutrient-elicited gastrointestinal satiety signals.
 ...
PMID:Decreased responsiveness to dietary fat in Otsuka Long-Evans Tokushima fatty rats lacking CCK-A receptors. 1051 56

Palatable cephalic stimuli induce a simultaneous activation of gastrointestinal motility, gastric acid and pancreatic enzyme secretion, as well as, release of the gastrointestinal hormones gastrin and pancreatic polypeptide. Cholinergic neural input is the dominant mediator of these responses with cholecystokinin and gastrin acting as additional stimulatory modulators. Central cholinergic circuits, neuropeptide Y, and thyrotropin releasing hormone are candidate central stimulators of the cephalic phase. There are good arguments for glucagon-like peptide-1 and peptide YY to be physiological inhibitors of cephalic-phase responses with these peptides being released in the intestinal phase of digestion and putatively contributing to termination of the cephalically stimulated pattern. Cephalic-phase responses are used clinically as diagnostic tests to assess completeness of selective proximal vagotomy and to explore autonomic neuropathy. Pancreatic polypeptide secretion with sham feeding is an appropriate test of abdominal vagal function. Cephalically stimulated motor and secretory activity contribute greater than 50% of overall postprandial responses. Pharmacological inhibition of cephalic-vagal stimulation, resulting in reduced food intake, may be a novel approach to obesity management. Glucagon-like peptide-1 is a particular candidate because it inhibits the cephalic phase of digestion, diminishes food intake, and reduces the glycemic excursion after a meal by retarding gastric emptying, stimulating insulin and lowering glucagon release.
 ...
PMID:Nutritional implications of cephalic phase gastrointestinal responses. 1074 9

A number of epidemiological studies has established obesity as a risk factor for gallstone disease. More recently, studies have suggested a relationship between gallstone disease and the metabolic syndrome linked to central adiposity, whose cardinal feature is represented by hyperinsulinaemia. Studies on fasting gall-bladder volume in obese subjects show that this parameter correlates with weight, body mass index (BMI) and body surface area; however, this is also true for large-sized non-obese subjects. Gall-bladder volume also correlates with abdominal fat and with impaired glucose tolerance. In contrast to the well-established role of bile supersaturation in the pathogenesis of gallstones in obesity, data are controversial on whether gall-bladder motor function is defective in obese subjects. However, studies were heterogeneous for subjects' BMI, emptying stimulus, technique used and parameters assessed to evaluate gall-bladder motor function. Also, differences in baseline gall-bladder volume may lead to wide differences in bile 'washout' effect despite apparently similar percentage changes in volume or content. Although post-prandial plasma levels of cholecystokinin (CCK) are normal in obese subjects, there is some evidence that a sub-group of obese subjects could have decreased sensitivity to CCK, possibly mediated by hyperinsulinaemia. Further studies using standard physiological stimuli and controlling for glucose tolerance, fasting insulin levels and baseline gall-bladder volume are needed to establish the role of gall-bladder motor function in the pathogenesis of gallstone disease in obesity.
 ...
PMID:Review article: gall-bladder motor function in obesity. 1090 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>