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

It has been suggested that super-sensitivity to, or overactivity of, endogenous opioid systems, particularly the dynorphin system, may be important in the development of obesity in the obese mouse (ob/ob). We have investigated the possibility that an increase in sensitivity to kappa agonists may also play a role in the development of obesity in another mutant rodent, the Zucker rat. The effects of the selective kappa agonist PD-117302 were investigated in both lean and obese Zucker rats. The lean animals appeared to be more sensitive to the initial hyperphagic effects of PD-117302 than their obese littermates, although this initial hyperphagia was followed by a subsequent decrease in food intake so that by the end of the six-hour test period the animals treated with PD-117302 had eaten less than the saline-treated controls. These changes in food intake were paralleled by increases and decreases in the duration of time spent feeding throughout the experiment. At the doses used in this study PD-117302 had no effect on locomotor activity. It is concluded that obese Zucker rats are not more sensitive to the hyperphagic effects of the kappa agonist (PD-117302 than their lean littermates and therefore it seems unlikely that increased sensitivity to an endogenous kappa opioid system plays a major part in the overeating and obesity observed in this strain of rat.
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PMID:The effects of the kappa agonist PD-117302 on feeding behaviour in obese and lean Zucker rats. 285 65

The levels of immunoreactive dynorphin A(1-8) (ir-DYN8) were measured in discrete brain regions of lean Zucker rats subjected to food deprivation for 72 hr and to a high fat diet, and in fatty Zucker rats after food deprivation for 72 hr. Fatty rats showed higher concentrations of ir-DYN8 in the cortex and midbrain, when compared to lean rats fed a stock diet ad lib. Food deprivation increased ir-DYN8 levels in the cortex of lean rats and fatty rats and in the hippocampus of fatty rats, but decreased its content in the striatum of lean rats and in the midbrain of fatty rats. The high fat diet increased ir-DYN8 levels in the cortex and midbrain of lean rats. These results suggest that ir-DYN8 levels in extrahypothalamic structures of Zucker rats could be differentially modified under conditions of hereditary obesity and dietary manipulations.
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PMID:Effects of food deprivation and high fat diet on immunoreactive dynorphin A(1-8) levels in brain regions of Zucker rats. 289 45

Posterior pituitaries of obese mice (ob/ob) contained significantly more immunoreactive dynorphin (P less than .01) and leu-enkephalin (P less than .01) than their lean littermates. Drinking in obese mice was stimulated by 0.3%, and feeding by 10%, of the dose of ethylketocyclazocine, a kappa receptor agonist, needed to produce extra feeding and drinking in lean mice. Obese mice also showed greater and longer lasting suppression of ingestion after MR-2266, a kappa antagonist, than did lean mice. MR-2266 was much more effective than naloxone in suppressing schedule-induced polydipsia in rats. These results indicate that kappa receptors are involved in feeding and drinking and that obesity is associated with changes in these receptors and their ligands.
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PMID:Increased immunoreactive dynorphin and leu-enkephalin in posterior pituitary of obese mice (ob/ob) and super-sensitivity to drugs that act at kappa receptors. 613 56

Recent studies have suggested a role for the kappa opiate receptor and its endogenous ligand, dynorphin, in the central regulation of appetite. In this study we found that the ob/ob mouse was mildly resistant to the ability of three kappa agonists, viz, butorphanol, tifluadom, and ketocyclazocine to induce food intake. In addition, we could find no change in ir-dynorphin levels in 7 areas for the central nervous system. These findings do not provide evidence for a role of kappa opioid feeding system in the pathogenesis of obesity in the ob/ob mouse.
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PMID:The kappa opioid receptor, ingestive behaviors and the obese mouse (ob/ob). 632 Feb 37

Despite the increase in body fat and obesity that occurs with aging, there is a linear decrease in food intake over the life span. This conundrum is explained by decreased physical activity and altered metabolism with aging. Thus, older persons fail to adequately regulate food intake and develop a physiologic anorexia of aging. This physiologic anorexia depends not only on decreased hedonic qualities of feeding with aging (an area that remains controversial) but also on altered hormonal and neurotransmitter regulation of food intake. Findings in older animals and humans have provided clues to the causes of the anorexia of aging. An increase in circulating concentrations of the satiating hormone, cholecystokinin, occurs with aging in humans. In addition, animal studies suggest a decrease in the opioid (dynorphin) feeding drive and possibly in neuropeptide Y and nitric oxide. The physiologic anorexia of aging puts older persons at high risk for developing protein-energy malnutrition when they develop either psychologic or physical disease processes. Despite its high prevalence, however, protein-energy malnutrition in older persons is rarely recognized and even more rarely treated appropriately. Screening tools for the early detection of protein-energy malnutrition in older persons have been developed. Multiple treatable causes of pathologic anorexia have been identified. There is increasing awareness of the importance of depression as a cause of severe weight loss in older persons. Approaches to the management of anorexia and weight loss in older persons are reviewed. Although many drugs exist that can enhance appetite, none of these are ideal for use in older persons currently.
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PMID:Anorexia of aging: physiologic and pathologic. 973 60

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.
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PMID:The MONA LISA hypothesis in the time of leptin. 976 5

Effects of obesity on gene expression for opioid peptides and neuropeptide-Y (NPY) in the arcuate nucleus (ARC), and on opioid peptides and alpha-melanocyte stimulating hormone (alpha-MSH) in the paraventricular nucleus (PVN) were examined in obese Zucker rats (18 weeks old). Obese Zucker rats are insulin-resistant, diabetic and hyperleptinemic as indicated by high serum glucose, insulin and leptin levels. ARC proOpiomelanocortin (POMC) mRNA levels were significantly lower in the obese relative to lean Zucker rats and ARC proNeuropeptide Y (proNPY) mRNA levels were higher (P<0.05). There were no differences in proDynorphin and proEnkephalin mRNA levels in the ARC (0.05). Obese Zucker rats had lower alpha-MSH and dynorphin A(1-17) peptide levels in the paraventricular nucleus (PVN) (P<0.05), but did not have lower PVN beta-endorphin peptide levels (0.05). The decrease in POMC in the ARC and decrease in alpha-MSH in the PVN seen in the obese Zucker rat in the present study suggest that reduced activity of the melanocortin system in the ARC to PVN pathway may contribute to the related hyperphagia. Reduced activity of the melanocortin system in the ARC to PVN pathway may be due to a disturbance of leptin signaling coupling to POMC.
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PMID:ARC POMC mRNA and PVN alpha-MSH are lower in obese relative to lean zucker rats. 1079 63

A spontaneous point mutation in the coding region of the carboxypeptidase E (CPE) gene results in a loss of CPE activity that correlates with the development of late onset obesity (Nagert, J. K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F., Carroll, R. J., Paigen, B. J., and Leiter, E. H. (1995) Nat. Genet. 10, 135-142). Examination of the level of neuropeptides in these mice showed a decrease in mature bioactive peptides as a result of a decrease in both carboxypeptidase and prohormone convertase activities. A defect in CPE is not expected to affect endoproteolytic processing. In this report we have addressed the mechanism of this unexpected finding by directly examining the expression of the major precursor processing endoproteases, prohormone convertases PC1 and PC2 in Cpe(fat) mice. We found that the levels of PC1 and PC2 are differentially altered in a number of brain regions and in the pituitary. Since these enzymes have been implicated in the generation of neuroendocrine peptides (dynorphin A-17, beta-endorphin, and alpha- melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of these peptides in Cpe(fat) and wild type animals. We found a marked increase in the level of dynorphin A-17, a decrease in the level of alpha-melanocyte-stimulating hormone, and an alteration in the level of C-terminally processed beta-endorphin. These results suggest that the impairment in the level of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activities and that this may lead to the development of obesity in these animals.
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PMID:Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice. 1103 63

Orexins (also called hypocretins) are peptide neurotransmitters expressed in neurons of the lateral hypothalamic area (LHA). Mice lacking the orexin peptides develop narcolepsy-like symptoms, whereas mice with a selective loss of the orexin neurons develop hypophagia and severe obesity in addition to the narcolepsy phenotype. These different phenotypes suggest that orexin neurons may contain neurotransmitters besides orexin that regulate feeding and energy balance. Dynorphin neurons are common in the LHA, and dynorphin has been shown to influence feeding; hence, we studied whether dynorphin and orexin are colocalized. In rats, double-label in situ hybridization revealed that nearly all (94%) neurons expressing prepro-orexin mRNA also expressed prodynorphin mRNA. The converse was also true: 96% of neurons in the LHA containing prodynorphin mRNA also expressed prepro-orexin mRNA. Double-label immunohistochemistry confirmed that orexin-A and dynorphin-A peptides were highly colocalized in the LHA. Wild-type mice and orexin knock-out mice showed abundant prodynorphin mRNA-expressing neurons in the LHA, but orexin/ataxin-3 mice with a selective loss of the orexin neurons completely lacked prodynorphin mRNA in this area, further confirming that within the LHA, dynorphin expression is restricted to the orexin neurons. These findings suggest that dynorphin-A may play an important role in the function of the orexin neurons.
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PMID:Orexin (hypocretin) neurons contain dynorphin. 1156 79

Sprague-Dawley rats selectively bred for diet-induced obesity (DIO) or diet resistance (DR) were characterized on diets of differing energy content and palatability. Over 10 wk, DR rats on a high-energy (HE) diet (31% fat) gained weight similarly to DR rats fed chow (4.5% fat), but they became obese on a palatable liquid diet (Ensure). DIO rats gained 22% more weight on an HE diet and 50% more on Ensure than chow-fed DIO rats. DIO body weight gains plateaued when switched from HE diet to chow. But, Ensure-fed DIO rats switched to chow spontaneously reduced their intake and weight to that of rats switched from HE diet to chow. They also reduced their hypothalamic proopiomelanocortin and dynorphin but not neuropeptide Y mRNA expression by 17-40%. When reexposed to Ensure after 7 wk, they again overate and matched their body weights to rats maintained on Ensure throughout. All Ensure-fed rats had a selective reduction in dynorphin mRNA in the ventromedial hypothalamic nucleus. Thus genetic background, diet composition, and palatability interact to produce disparate levels of defended body weight and central neuropeptide expression.
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PMID:Defense of body weight depends on dietary composition and palatability in rats with diet-induced obesity. 1174 22


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