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

Early postnatal overnutrition is a risk factor for obesity in juvenile and adult life. Underlying pathophysiological mechanisms are still unclear. Hypothalamic neuropeptides are decisively involved in the regulation of body weight and food intake. In this study, we investigated consequences of early postnatal overnutrition, as compared to normo-and undernutrition, on NPY within the arcuate nucleus and paraventricular nucleus (PVN). The normal litter size of Wistar rats was adjusted on the third day of life from 10 pups (normal litters, NL; normonutrition) to only three newborns (small litters, SL; overnutrition) or 18 pups per mother (large litters, LL; undernutrition). SL rats developed clear overweight until the day 21 of life (P<0.0001), as well as hyperleptinaemia (P<0.001), and hyperinsulinaemia (P<0.01). LL rats were underweight and had decreased leptin and insulin concentrations. Using radioimmunoassay, NPY contents were determined in hypothalamic micropunches, and immunocytochemistry for NPY was performed in serial hypothalamic sections on day 21 of life. While in the underweight, hypoleptinaemic, and hypoinsulinaemic LL rats increased concentrations of NPY in the arcuate nucleus and PVN were observed, no decrease in NPY content was found in the overweight, hyperleptinaemic, and hyperinsulinaemic SL rats. Moreover, the percentage of NPY-immunopositive neurones per total number of neurones was increased not only in the LL rats, but also in the SL rats. Since the NPY system is functionally mature already at this age, these findings might indicate an acquired resistance of the hypothalamic NPY system to increased levels of insulin and/or leptin in early postnatally overfed SL rats.
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PMID:Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats. 1044 11

Leptin is a satiety factor which acts within the hypothalamus to decrease the levels of several neuropeptides stimulating food intake (among them, neuropeptide Y [NPY]), while increasing those that inhibit food intake. These effects of leptin bring about decreased body weight. In vivo, leptin potentiates basal and insulin-stimulated glucose utilization, presumably its oxidation, and decreases fat storage. Leptin increases sympathetic-mediated energy dissipation, and the expression of uncoupling proteins-1, -2, and -3. In peripheral tissues (muscles, adipose, others), leptin decreases triglyceride content by increasing fatty acid oxidation, decreasing the activity/expression of esterification and lipogenic enzymes, and favoring lipolysis. It decreases the lipogenic activity of insulin. Ultimately, leptin depletes fat stores and promotes leanness. NPY, taken as one example of what an orexigenic agent may produce, increases food intake and body weight. It favors fat storage in adipose tissue by stimulating lipogenic activity. It decreases glucose utilization by muscles, making more glucose carbon available for lipogenesis. Effects of NPY result from vagus nerve-mediated hyperinsulinemia and overactivity of the hypothalamo-pituitary-adrenal axis. Thus, NPY favors fat stores, and ultimately obesity. Glucocorticoids are necessary for NPY effects to occur, because central administration of the neuropeptide in adrenalectomized animals is ineffective. Glucocorticoids also have genuine effects when administered centrally to normal rats. They increase the hypothalamic content of NPY and decrease that of CRH. This double neuro-peptidic change stimulates food intake, insulin output, adipose tissue storage ability, decreases the expression of uncoupling proteins-1 and -3, and increases body weight. Body weight homeostasis appears to require a finely tuned regulation of both leptin and glucocorticoids, with their respective opposite effects.
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PMID:Neuroendocrine regulation of nutrient partitioning. 1084 67

Despite a rising worldwide epidemic of obesity there is currently only a very small number of anti-obesity drugs available to manage the problem. Large numbers of differing pharmacological agents reliably produce a reduction in food intake when administered acutely to animals, and when administered chronically they result in a significant decrease in body mass. Behavioural analysis of drug-induced anorexia in animals demonstrates that various compounds profoundly effect feeding behaviour in differing ways. This indicates the variety of mechanisms by which pharmacological agents can induce changes in food intake, body weight and eventually body composition. Some of the same drugs produce decreases in food intake and weight loss in humans. Some 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). Such drugs can be considered as "appetite suppressants" with clinical potential as anti-obesity agents. Other drugs induce changes in food intake and body weight through various physiological mechanisms inducing feelings of nausea or even by side effect related malaise. Of the drugs considered suitable candidates for appetite suppressants are agents which act via peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), or alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin and Melanocortins) or levels of the key CNS appetite monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NA). Recently, the hormone leptin has been regarded as a hormonal signal linking adipose tissue status with a number of key central nervous system circuits. The peptide itself stimulates leptin receptors and it links with POMC and MC-4 receptors. These receptors 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, modulation of appetite may 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 lifestyle changes and dietary intervention may be useful in dealing with the rising world epidemic of obesity.
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PMID:Pharmacology of appetite suppression. 1085 85

In the past few years, there has been exponential growth in our knowledge of genes that control food intake and metabolism. Most of this research has demonstrated either an increased or decreased expression of these "obesity genes" in response to changes in nutritional status. Ultimately, these changes reflect modifications in the rate of gene transcription, mRNA stability, translation initiation, or posttranslational processing. Few laboratories have examined specifically which of these molecular mechanisms are responsible for obesity gene regulation, and thus, the field is wide open for exploration. In addition, it is possible that some forms of human obesity may be caused by inherited mutations in transcription factors or other regulatory molecules rather than base pair mutations in the obesity genes themselves. This article focuses on the regulation of the leptin receptor, NPY, and POMC genes, and explores what is known about the regulation of these obesity genes in response to food intake or changes in body fat stores. Connections between regulation of these genes and some inherited forms of human obesity are made.
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PMID:How tight are your genes? Transcriptional and posttranscriptional regulation of the leptin receptor, NPY, and POMC genes. 1086 Jun 73

Recent experimental evidence supports the role of glucocorticoids in the neuroendocrine control of food intake and energy expenditure. In particular, glucocorticoids promote food consumption directly through stimulation of NPY and inhibition of CRH and melanocortin release. CRH and NPY are also functionally linked by a mutual regulation. CRH is anorexigenic when secreted acutely while it exerts the opposite effect when, upon sustained secretion, it stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The orexigenic effects of glucocorticoids are counteracted by a steroid-induced rise in leptin levels that closes a regulatory loop regarding food consumption. Furthermore, glucocorticoids may alter body fat distribution, increasing truncal adiposity both directly and by inhibition of growth hormone secretion. No clearcut alterations of the HPA function are apparent in obesity as a whole. However, subtle and specific abnormalities may be noted in subsets of obese patients. Indeed, obesity, mostly visceral type, is associated with an increased cortisol clearance and 11-beta hydroxysteroid dehydrogenase activity in the omental fat. In the same vein, an increased cortisol rise following a mixed meal has been observed in obese subjects. Finally, it has been proposed that adrenal incidentalomas, often characterized by enhanced cortisol secretion, might be a clinical expression of the X syndrome.
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PMID:Glucocorticoids and neuroendocrine function. 1099 15

The aim of the present study was to determine whether the anorexic and thermogenic effects of leptin were attenuated in overweight aged rats following intracerebroventricular (i.c.v.) injection of murine leptin. Male F344/BN rats of two ages (6 months: young (n=20) and 24 months: old (n=18)) were divided into three groups (control, pair-fed and leptin) and were treated with either vehicle (artificial cerebrospinal fluid) or leptin (15.6 microgram/day) for 3 days. There was an age-related increase in basal food intake (20+/-2%), serum leptin levels (363+/-106%) and leptin (OB) mRNA (72+/-16%) in perirenal white adipose tissue (PWAT). In contrast, basal expression of hypothalamic NPY mRNA and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) mRNA was reduced significantly (-35+/-4% and -51+/-5%, respectively) with age. I.c.v. leptin treatment had a significantly greater effect in reducing food intake (-42+/-5% vs. -23+/-4%), serum leptin levels (-55+/-7% vs. 10+/-2%) and PWAT OB mRNA (-46+/-2% vs. 10+/-5%) in young than in old rats. Similarly, central leptin treatment also had a greater effect in suppressing hypothalamic NPY mRNA expression in young (-23+/-4%) than in old (-8+/-4%) rats compared with their age-matched pair-fed treated rats. The stimulatory effect of i.c.v. leptin treatment on BAT UCP1 mRNA expression was also significantly greater in young rats (45+/-8%) than in old rats (10+/-6%) compared with age-matched pair-fed rats. Our previous report indicated that these overweight aged rats were resistant to peripheral administered leptin. The present data extend those findings and demonstrate that the impaired anorexic and metabolic effects of leptin are centrally mediated. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both. The development of leptin resistance with age may contribute to the hyperphagia, hyperleptinemia and impaired energy balance with age.
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PMID:Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats. 1102 67

Food intake is regulated by the central nervous system depending on macronutrients and environmental changes. The hypothalamus is the target of hunger and satiety signals arising from the peripheral organs and the brain. Noradrenaline-neuropeptide Y and opioid-galanine are involved in carbohydrate and fat intake, respectively, while serotonin-CCK-insulin and dopamine-cyclic dipeptides systems inhibit them. Histamine and proinflammatory cytokines are involved in stress- and sickness-induced anorexia. Leptin accelerated intrahypothalamic anorexic mechanisms executed by POMC/CART and CRH but suppresses orexigenic mechanisms promoted by NPY and orexin. Although these mechanisms elegantly regulate appetite and feeding behavior, disruption of weight control has been accelerated and the incidence of obesity and eating disorder are dramatically increasing recent years in our modern society. New approach may be necessary to solve the problems of weight control.
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PMID:[Physiology of appetite and feeding behavior: introduction]. 1126 85

Mice lacking NPY Y1 receptors develop obesity without hyperphagia indicating increased energy storage and/or decreased energy expenditure. Then, we investigated glucose utilization in these animals at the onset of obesity. Fasted NPY Y1 knockouts showed hyperinsulinemia associated with increased whole body and adipose tissue glucose utilization and glycogen synthesis but normal glycolysis. Since leptin modulates NPY actions, we studied whether the lack of NPY Y1 receptor affected leptin-mediated regulation of glucose metabolism. Leptin infusion normalized hyperinsulinemia and glucose turnover. These results suggest a possible mechanism for the development of obesity without hyperphagia via dysfunction in regulatory loops involving NPY, leptin and insulin.
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PMID:Increased insulin concentrations and glucose storage in neuropeptide Y Y1 receptor-deficient mice. 1128 97

Leptin and its principal mediators, NPY and alpha-MSH are postulated to play a pivotal role in energy balance. To determine the possibility of the disturbance in neuropeptides in human obesity and their consequent changes in response to negative energy balance, we evaluated plasma and cerebrospinal fluid (CSF) leptin, NPY, and alpha-MSH levels in obese women before and after weight loss in comparison with normal control women. Subjects included 16 obese women [mean body mass index (BMI), 35.6 kg/m(2)] before and after weight loss induced by a 2-wk very low caloric diet (800 kcal/d) and 14 normal weight women (mean BMI, 20.4 kg/m(2)). The CSF to plasma leptin ratio in normal weight subjects was 2.3-fold higher than that in obese subjects. After weight loss in obese subjects, plasma leptin levels decreased by 40% and CSF levels decreased by 51%. There was a positive linear correlation between CSF and plasma leptin levels at baseline in obese subjects (r = 0.74, P < 0.05) and a positive logarithmic correlation in normal weight subjects (r = 0.89, P < 0.05) and in obese subjects after weight loss (r = 0.64, P < 0.05). The BMI was negatively correlated with the CSF to plasma leptin ratio (r = -0.86, P < 0.05) in all subjects. Neither the baseline plasma levels nor the baseline CSF levels of NPY were different between normal weight subjects and obese subjects. After weight loss, the CSF NPY level decreased significantly compared with baseline values in obese subjects. The alpha-MSH levels in plasma and CSF did not differ significantly from controls in obese subjects at baseline or after weight loss. Baseline CSF leptin level correlated with neither the baseline CSF NPY level nor the baseline CSF alpha-MSH level. In conclusion, this study demonstrated that the efficiency of brain leptin delivery is reduced in human obesity and central nervous system leptin uptake involves a combination of a saturable and an unsaturable mechanism. CSF NPY and alpha-MSH did not differ from controls in human obesity, and the CSF NPY level decreased significantly whereas alpha-MSH did not differ after weight loss in obese subjects compared with baseline. There was no significant correlation between CSF leptin and CSF NPY or alpha-MSH. This could be the result of leptin resistance present in human obesity and/or the more complex mechanisms involved in modulating appetite and regulating energy balance in human obesity.
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PMID:Cerebrospinal fluid and plasma concentrations of leptin, NPY, and alpha-MSH in obese women and their relationship to negative energy balance. 1160 May 52

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 microg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.
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PMID:Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy. 1170 92


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