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

Obesity, a condition already at epidemic proportions in the developed world, is largely attributable to an indulgent lifestyle. Biologically we feel hunger more acutely than feeling "full-up" (satiety). The discovery over a decade ago of leptin, an adiposity signal, revolutionised our understanding of hypothalamic mechanisms underpinning the central control of ingestive behaviour. The structure and function of many hypothalamic peptides (Neuropeptide Y (NPY), Melanocortins, Agouti related peptide (AGRP), Cocaine and amphetamine regulated transcript (CART), Melanin concentrating hormone (MCH), Orexins and endocannabinoids) have been characterised in rodent models. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Short-term signal hormones including Cholecystokinin (CCK), Ghrelin, Peptide YY (PYY(3-36)) and Glucagon-like peptide 1 (GLP-1) control meal size via pathways converging on the hypothalamus. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems among others, implicated in hypothalamic appetite regulation all provide potential "drugable" targets by which to treat obesity.
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PMID:The hypothalamus and obesity. 1577 92

The worsening global epidemic of obesity has increased the urgency of research aimed at understanding the mechanisms of appetite regulation. An important aspect of the complex pathways involved in modulating energy intake is the interaction between hormonal signals of energy status released from the gut in response to a meal, and appetite centres in the brain and brainstem. In particular, the gut peptides cholecystokinin, peptide YY, glucagon-like peptide 1, oxyntomodulin and pancreatic polypeptide have been implicated in signaling satiety post-prandially. The ultimate goal of work in this field is the development of effective treatments for obesity, and manipulation of these gut-brain axes offers potentially useful strategies for the conquest of this significant cause of morbidity and mortality and future burden on healthcare systems worldwide.
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PMID:Gut feeling--the secret of satiety? 1584 7

In the present paper, we summarise the data supporting the following hypothesis: dietary inulin-type fructans extracted from chicory root may modulate the production of peptides, such as incretins, by endocrine cells present in the intestinal mucosa, this phenomenon being involved in the regulation of food intake and/or systemic effects. To test this hypothesis, male Wistar rats received for 3 weeks either a standard diet or the same diet supplemented with 10 % inulin-type fructans with different degrees of polymerisation. All the effects were most pronounced with the diet containing oligofructose, and consisted of (i) a decrease in mean daily energy intake and in epididymal fat mass; (ii) a higher caecal pool of the anorexigenic glucagon-like peptide-1 (7-36) amide (GLP-1), and peptide YY (PYY), due to caecal tissue proliferation; (iii) an increase in GLP-1 and of its precursor - proglucagon mRNA - concentrations in the proximal colon; (iv) an increase in portal serum level of GLP-1 and PYY; (v) a decrease in serum orexigenic peptide ghrelin. Moreover, oligofructose supplementation improved glucose homeostasis (i.e. decreased glycaemia, increased pancreatic and serum insulin content) in diabetic rats previously treated with streptozotocin, a phenomenon that is partly linked to the reduction in food intake and that correlates with the increase in colic and portal GLP-1 content. Based on these results it appears justified to test, in human subjects, the hypothesis that dietary inulin-type fructans could play a role in the management of obesity and diabetes through their capacity to promote secretion of endogenous gastrointestinal peptides involved in appetite regulation.
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PMID:Impact of inulin and oligofructose on gastrointestinal peptides. 1587 89

Energy balance is largely regulated by the central nervous system (CNS), which senses metabolic status from a wide range of humoral and neural signals, and controls energy intake. Accumulating evidence supports the model that stimulation of leptin- and ghrelin-responsive pathways, including the central melanocortin system, in the hypothalamus, contributes to the maintenance of body weight. Ghrelin is the brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach and acts as an afferent signal to the hypothalamus and hindbrain. Leptin, the adipocyte hormone, is believed to tonically act as an afferent signal from adipose tissue to the brain, in particular hypothalamus, as a part of negative feedback loop regulating the size of energy stores and energy balance. Dysregulation of these pathways is a marker of changes in energy balance. Ghrelin is negatively correlated with weight and obese subjects have lower ghrelin levels than lean subjects, consistent with a compensatory rather than causal role for ghrelin in obesity. On the contrary, circulating leptin levels correlate in proportion to adiposity being high in obesity suggesting that human obesity is associated with insensitivity to leptin. The leptin resistance in diet-induced obesity emphasizes that environmental factors can modulate leptin sensitivity. It is speculated that through hypothalamic/pituitary axis ghrelin and leptin operate as a metabolic switch. Ghrelin actually transfers information from the stomach to the hypothalamus in cooperation with leptin and provides calories that growth hormone (GH) needs for growth and repair. Pharmacological manipulations of circulating hormone levels may work well in "cheating" the brain regarding information from the periphery. It might also be necessary to combine two or three agents to fight obesity. A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3-36) might have a chance of achieving sustained weight loss. The administration of exogenous satiety hormone peptide YY 3-36 (PYY) may prevent the action of appetite-stimulating hypothalamic circuits on the anorexigenic melanocortin pathways.
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PMID:Brain somatic cross-talk: ghrelin, leptin and ultimate challengers of obesity. 1590 62

The significant burden of overweight and obesity on our society necessitates the development of lifestyle strategies that facilitate successful long-term body weight management. Recently, the discovery of novel cellular modulators of the brain-gut axis have generated much interest in possible therapeutic manipulation of these and other hormones that regulate energy intake. These modulators include the enterohormones ghrelin, peptide YY 3-36, and cholecystokinin, and the adipocyte-derived hormone leptin. There is some evidence that dietary macronutrient composition can influence concentrations of these hormones, which could impact sensations of hunger, satiety, and ultimately energy intake. The purpose of this review is to provide background information on these four peripheral hormones involved in energy intake regulation, to discuss what is currently known about their mechanism of action, and to present research findings related to the effect of macronutrient composition on concentrations and efficacy of these hormones. Potential applications of this information are also discussed.
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PMID:Dietary influences on peripheral hormones regulating energy intake: potential applications for weight management. 1598 31

Neuropeptide Y (NPY) is a 36 amino acid amidated peptide with high sequence homology to the endocrine peptides, peptide YY (PYY) and pancreatic polypeptide (PP). They appear to interact with a family of receptors that possess high affinity for one or more of these peptides. Five members of the receptor family have been cloned, with several additional members postulated through pharmacological evidence. All are members of the seven transmembrane domain-G-protein coupled receptor family. The Y1 receptor is the best characterised, with several nonpeptide antagonists available. This receptor appears to mediate a constriction of the peripheral vasculature and the 'anxiolytic' effects of centrally administered NPY. Less is known about the other receptors in the family. The Y2 receptor is believed to be presynaptic and mediates a reduction in neurotransmitter release. The Y4 receptor appears to be the receptor for pancreatic polypeptide, with high amounts of mRNA for this receptor found in the periphery, but lower levels in the brain. The Y5 receptor is expressed in the hypothalamus and has been postulated to be the receptor which mediates the increased food consumption seen following centrally administered NPY. Finally, the Y6 receptor has been cloned in the mouse and other species, but does not appear to encode a functional gene product in humans. Several types of nonpeptide Y1 and a series of Y5 antagonists have been described in the patent literature, though these compounds have limitations that will confine their use to preclinical studies. Nevertheless, considerable progress has been made in understanding the role of NPY and its receptors in experimental obesity. The next step will be the discovery of potent and selective nonpeptide antagonists, to add further credence to the therapeutic potential.
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PMID:Neuropeptide Y receptor antagonists in obesity. 1598 83

Appetite regulation is part of a feedback system that controls the energy balance, involving a complex interplay of hunger and satiety signals, produced in the hypothalamus as well as in peripheral organs. Hunger signals may be generated in peripheral organs (e.g. ghrelin) but most of them are expressed in the hypothalamus (neuropeptide Y, orexins, agouti-related peptide, melanin concentrating hormone, endogenous opiates and dopamine) and are expressed during situations of energy deficiency. Some satiety signals, such as cholecystokinin, glucagon-like peptide 1, peptide YY and enterostatin are released from the digestive tract in response to food intake. Others, such as leptin and insulin, are mobilized in response to perturbations in the nutritional state. Still others are generated in neurones of the hypothalamus (alpha-melanocyte-stimulating hormone and serotonin). Satiety signals act by inhibiting the expression of hunger signals and/or by blunting their effect. Palatable food, i.e. food rich in fat and sugar, up-regulates the expression of hunger signals and satiety signals, at the same time blunting the response to satiety signals and activating the reward system. Hence, palatable food offsets normal appetite regulation, which may explain the increasing problem of obesity worldwide.
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PMID:How palatable food disrupts appetite regulation. 1599 51

Recent advances in obesity research focused on neuroendocrine control of food intake, appetite and body weight balance. Gut hormones, which are sequentially released from different regions of the gut, send signals to the areas of appetite control in the central nervous system causing a release of counter-regulatory hormones also originating from the gastrointestinal system. Ghrelin, a peptide secreted from the gastric fundus is released just before meal intake and stimulates hunger and food intake. Recently, peptide YY has been suggested to counteract ghrelin by inducing satiety and reducing appetite and caloric intake. While the effects of PYY on various gastrointestinal functions are well described, its action on weight loss is less known. Controversial results on the effect of exogenous administration of PYY(3-36) opened the discussion on the respective roles of PYY and/or PYY(3-36) in body weight homeostasis in man.
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PMID:News in gut-brain communication: a role of peptide YY (PYY) in human obesity and following bariatric surgery? 1600 43

In the clinic, obesity and anorexia constitute prevalent problems whose manifestations are encountered in virtually every field of medicine. However, as the command centre for regulating food intake and energy metabolism is located in the brain, the basic neuroscientist sees in the same disorders malfunctions of a model network for how integration of diverse sensory inputs leads to a coordinated behavioural, endocrine and autonomic response. The two approaches are not mutually exclusive; rather, much can be gained by combining both perspectives to understand the pathophysiology of over- and underweight. The present review summarizes recent advances in this field including the characterization of peripheral metabolic signals to the brain such as leptin, insulin, peptide YY, ghrelin and lipid mediators as well as the vagus nerve; signalling of the metabolic sensors in the brainstem and hypothalamus via, e.g. neuropeptide Y and melanocortin peptides; integration and coordination of brain-mediated responses to nutritional challenges; the organization of food intake in simple model organisms; the mechanisms underlying food reward and processing of the sensory and metabolic properties of food in the cerebral cortex; and the development of the central metabolic system, as well as its pathological regulation in cancer and infections. Finally, recent findings on the genetics of human obesity are summarized, as well as the potential for novel treatments of body weight disorders.
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PMID:Brain regulation of food intake and appetite: molecules and networks. 1616 70

The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY(1-36) to PYY(3-36) was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY(3-36) was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY(3-36) in humans caused a graded reduction in food intake (R2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY(3-36) on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY(3-36). Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY(3-36) infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity.
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PMID:Attenuated peptide YY release in obese subjects is associated with reduced satiety. 1636 39


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