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

Given the current global epidemic of obesity there is a demand for new anti-obesity drugs to overcome the problem. Many pharmacological agents reduce food intake and significantly decrease body mass when administered to animals but affect feeding behaviour in a profoundly different way indicating the variety of biological mechanisms by which such agents act (appetite verses non-appetite). More limited clinical data demonstrates that some of the same drugs produce decreases in food intake and weight loss in humans. A few of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). These drugs that modify the daily flux of appetite could be considered as 'appetite suppressants' with clinical potential as anti-obesity agents. Drugs that can be considered suitable candidates for appetite suppressants are agents that enhance peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin, CART and Melanocortins) or monoamine neurotransmitters (such as serotonin, nor-adrenaline and possibly dopamine). Recently, the hormone leptin has become regarded as a key hormonal signal linking adipose tissue status with a number of key central nervous system circuits (NPY, CART, CRF, Melanocortins and possibly Orexins). This tonic system may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, such modulation of appetite will involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with life style changes and dietary intervention may be critical in dealing with the rising world epidemic of obesity.
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PMID:Pharmacology of appetite suppression: implication for the treatment of obesity. 1173 37

The OLETF rat, lacking CCK-A receptors, provides an important model for identifying roles for CCK in the controls of food intake and body weight. OLETF rats are obese and diabetic and express deficits in the control of the size of individual meals. Meal size in OLETF rats is doubled and although meal number is decreased, the decrease is not sufficient to prevent hyperphagia. Analyses of patterns of hypothalamic gene expression in OLETF rats indicate the presence of a primary deficit in DMH NPY signaling. These data suggest an important role for CCK in controlling NPY expression in a population of non-leptin regulated hypothalamic neurons. In the absence of this control, NPY is overexpressed, contributing to hyperphagia and obesity. Thus, the obesity in the OLETF rats may be the outcome of two regulatory disruptions, one depending upon a peripheral within meal satiety pathway and the other depending upon a central pathway critical to overall energy balance.
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PMID:Actions of CCK in the controls of food intake and body weight: lessons from the CCK-A receptor deficient OLETF rat. 1235 7

Background. We have previously shown that polymorphism in the promoter region of the human cholecystokinin type-A receptor ( CCKAR) gene is a genetic factor affecting obesity. However, there have not yet been any reports of analysis of the promoter activity of CCKAR genes, and thus almost nothing is known about CCKAR transcriptional regulation. Methods. Using STC-1 cells, an enteroendocrine tumor cell line, we measured the promoter activity of the human CCKAR gene by a transient transfection method. Results. We showed that STC-1 cells expressed CCKAR as well as its peptide-ligand, CCK. Analysis of a series of 5'-deleted promoter constructs showed that the proximal 622-base region upstream from the initiation site, which contained two GC-box motifs, was important as a regulatory region for the transcriptional activity. However, no significant differences were found for the promoter activities of polymorphic promoter constructs. Conclusions. These results suggest that the reported polymorphism may not play a role in transcriptional regulation.
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PMID:Promoter analysis of human cholecystokinin type-A receptor gene. 1242 65

K cells are a subpopulation of enteroendocrine cells that secrete glucose-dependent insulinotropic polypeptide (GIP), a hormone that promotes glucose homeostasis and obesity. Therefore, it is important to understand how GIP secretion is regulated. GIP-producing (GIP/Ins) cell lines secreted hormones in response to many GIP secretagogues except glucose. In contrast, glyceraldehyde and methyl pyruvate stimulated hormone release. Measurements of intracellular glucose 6-phosphate, fructose 1,6-bisphosphate, and pyruvate levels, as well as glycolytic flux, in glucose-stimulated GIP/Ins cells indicated that glycolysis was not impaired. Analogous results were obtained using glucose-responsive MIN6 insulinoma cells. Citrate levels increased similarly in glucose-treated MIN6 and GIP/Ins cells. Thus pyruvate entered the tricarboxylic acid cycle. Glucose and methyl pyruvate stimulated 1.4- and 1.6-fold increases, respectively, in the ATP-to-ADP ratio in GIP/Ins cells. Glyceraldehyde profoundly reduced, rather than increased, ATP/ADP. Thus nutrient-regulated secretion is independent of the ATP-dependent potassium (K(ATP)) channel. Antibody staining of mouse intestine demonstrated that enteroendocrine cells producing GIP, glucagon-like peptide-1, CCK, or somatostatin do not express detectable levels of inwardly rectifying potassium (Kir) 6.1 or Kir 6.2, indicating that release of these hormones in vivo may also be K(ATP) channel independent. Conversely, nearly all cells expressing chromogranin A or substance P and approximately 50% of the cells expressing secretin or serotonin exhibited Kir 6.2 staining. Compounds that activate calcium mobilization were potent secretagogues for GIP/Ins cells. Secretion was only partially inhibited by verapamil, suggesting that calcium mobilization from intracellular and extracellular sources, independent from K(ATP) channels, regulates secretion from some, but not all, subpopulations of enteroendocrine cells.
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PMID:Studies with GIP/Ins cells indicate secretion by gut K cells is KATP channel independent. 1267 50

Neuropeptides play an important role in the regulation of feeding behavior and obesity. The mechanisms for controlling food intake involve a complicated interplay between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monamines (serotonin, dopamine, norepinephrine). In addition to regulating eating behavior, a number of CNS neuropeptides participate in the regulation of neuroendocrine pathways. Thus, clinical studies have evaluated the possibility that CNS neuropeptide alterations may contribute to dysregulated secretion of the gonadal hormones, cortisol, thyroid hormones and growth hormone in the eating disorders. Most of the neuroendocrine and neuropeptide alterations apparent during symptomatic episodes of AN and BN tend to normalize after recovery. This observation suggests that most of the disturbances are consequences rather than causes of malnutrition, weight loss and/or altered meal patterns. Still, an understanding of these neuropeptide disturbances may shed light on why many people with AN or BN cannot easily "reverse" their illness and even after weight gain and normalized eating patterns, many individuals who have recovered from AN or BN have physiological, behavioral and psychological symptoms that persist for extended periods of time.
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PMID:A review of neuropeptide and neuroendocrine dysregulation in anorexia and bulimia nervosa. 1276 12

Obesity is associated with many comorbid conditions including diabetes, hyperlipidemia, and gallstones. However, the interaction among these modalities remains unclear. We recently demonstrated that both leptin-deficient and leptin-resistant obese mice have impaired biliary motility. These obese mice also are diabetic and hyperlipidemic. Therefore, we tested the hypothesis that serum glucose, insulin, cholesterol, and triglyceride levels would correlate with gallbladder contractility. Thirty-four lean control, 10 lean heterozygous leptin-deficient, 18 obese homozygous leptin-deficient, and 12 obese homozygous leptin-resistant mice were fed a nonlithogenic chow diet while nine lean control and nine obese homozygous leptin-deficient mice were fed a high-cholesterol diet for 4 weeks. In vitro gallbladder responses to cholecystokinin (CCK; 10(-8) mol/L), acetylcholine (ACh; 10(-5) mol/L), and neuropeptide Y (NPY; 10(-6) mol/L) were measured. Serum glucose, insulin, cholesterol, and triglyceride levels were measured from pooled serum from an additional 704 animals. Gallbladder responses were greatest for CCK, intermediate for ACh, and least for NPY. Serum glucose, insulin, cholesterol, and triglyceride levels and body weight all correlated similarly, negatively, and significantly (P<0.001) with gallbladder contractility. Hyperglycemia, insulin-resistance, hyperlipidemia, and body weight in obese mice with leptin dysfunction are associated with poor gallbladder contractility, which in turn may contribute to the association between obesity and gallstone formation.
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PMID:Diabetes and hyperlipidemia correlate with gallbladder contractility in leptin-related murine obesity. 1459 58

Obese subjects are at risk of developing gallstones both by being overweight and by reducing their body weight. The aim of the present study was to investigate factors related to disturbances in gallbladder emptying measured by ultrasound. Detailed information about weight loss attempts, age at onset of obesity, parity, presence of menopause, use of contraceptive or hormonal replacement drugs, and phase of menstrual cycle was obtained. Smoking habits, alcohol use, dietary intake, and physical activity were recorded. Body composition and fat distribution were assessed by anthropometry. Blood samples were taken for CCK, lipids, glucose, and insulin. Mean (SD) fasting gallbladder volume was 30.0 (12.6) ml. The residual volume was 12.5 (9.8) ml 90 min after a test meal. CCK levels increased from a basal 1.64 (0.8) pM to a peak value of 2.9 (1.0) pM. Fasting gallbladder volumes were closely related to residual and ejection volumes. Body weight and fasting insulin levels explained 35.2% of the variance in fasting volume, lean body mass and insulin explained 28.1% of the residual volume, and waist circumference 23.6% of the ejection volume. None of the other factors were related to gallbladder emptying. Subjects with the largest fasting gallbladders had the largest residual and least emptying gallbladders, scored the highest in every aspect of body size, composition, and fat distribution, and also had the highest insulin levels. Body weight, lean body mass, central fat distribution, and insulin levels were the main determinants of gallbladder kinetics. Fasting and residual gallbladder volumes were closely related and both determined by obesity and its metabolic complication of hyperinsulinemia.
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PMID:Determinants of gallbladder kinetics in obesity. 1499 28

The regulation of body weight is a complex process which relies on a balance between supply of nutrients and demand on these nutrients in the form of energy expenditure. Various central and peripheral mechanisms play a crucial role in maintaining this balance. While various neuropeptides in the central nervous system (CNS), particularly in the hypothalamus, maintain the necessary harmony between hyperphagia and anorexia, peripheral signals arising from the gastrointestinal tract (cholecystokinin-8 [CCK-8], amylin), pancreas (insulin) and adipose tissue (leptin) provide the necessary stimuli or a feedback inhibition for the synthesis and secretion of these hypothalamic neuropeptides. Various metabolites of the carbohydrate and fat metabolism are also involved in regulating the neuronal activity in the hypothalamus which ultimately leads to a release of key neuropeptides. In addition to the central mechanisms, peripheral mechanisms that regulate energy expenditure, particularly in the brown adipose tissue and skeletal muscle, are critical in maintaining the overall balance. Insight into these mechanisms sets the stage for developing novel strategies in the treatment of emerging childhood diseases such as obesity, anorexia nervosa, and bulimia. Further, delineation of these processes in the fetus and newborn sets the stage for investigating their role in molding the adult phenotype due to intrauterine adaptations.
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PMID:Neurohumoral regulation of body weight gain. 1501 96

Little is known regarding satiety effects of systemically administered cholecystokinin (CCK-8) in propensity or resistance to dietary-induced obesity (DIO), and of its effect under conditions of melanocortin-3/4R blockade. We found that CCK-8 exerted greater satiety effects in DIO-prone but not DIO-resistant rats, and this occurred only when the rats were placed on a high-fat (HF) diet, when DIO-prone rats failed to compensate for the greater energy density of the diet. CCK-8 also suppressed intake stimulated by melanocortin-3/4R antagonist, SHU9119, but only after 24h of increased feeding. This suggests that under both of these conditions, responsiveness to CCK's satiety effect is not so much affected by a HF diet or significant increases in body weight per se, but by a failure to rapidly limit food intake to that needed only for metabolic need. Identification of an early feeding mediator that is most strongly activated by a HF diet or by an acute challenge to energy homeostasis should provide an ideal anti-obesity target adjunct to CCK-8.
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PMID:Change in CCK-8 response after diet-induced obesity and MC3/4-receptor blockade. 1506 12

Although cholecystokinin A (CCK-A) receptors (CCK-AR) mediate the feeding inhibitory actions of CCK in both rats and mice, the absence of CCK-AR results in species-specific phenotypes. The lack of CCK-AR in Otsuka Long-Evans Tokushima fatty (OLETF) rats results in hyperphagia and obesity. We have suggested that demonstrated increases in meal size and elevated levels of dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) gene expression may contribute to this phenotype. In contrast to OLETF rats, CCK-AR(-/-) mice have normal total daily food intake and do not develop obesity. To assess the basis underlying the different phenotypes in rats and mice lacking CCK-AR, we characterized meal patterns in CCK-AR(-/-) mice and determined whether CCK-AR(-/-) mice exhibited an alteration in DMH NPY gene expression. We demonstrate that although CCK-AR(-/-) mice show a similar dysregulation in meal size as OLETF rats, they do not have an elevation in DMH NPY mRNA expression levels. In fact, intact mice have no CCK-AR in the DMH. Furthermore, in intact rats, NPY and CCK-AR are colocalized in DMH neurons, and parenchymal injection of CCK into the DMH reduces food intake and down-regulates DMH NPY mRNA expression. These results suggest that although CCK-AR plays a role in the mediation of CCK actions in the control of meal size in both rats and mice, CCK-AR seems to contribute to modulating DMH NPY levels only in rats. The deficit in CCK's action in the control of DMH NPY gene expression may play a major role in the obese phenotype in OLETF rats.
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PMID:Differential roles for cholecystokinin a receptors in energy balance in rats and mice. 1512 37


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