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

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

Body adiposity is known to be carefully regulated and to remain relatively stable for long periods of time in most mammalian species. This review summarizes old and recent data implicating insulin and leptin as key circulating signals to the central nervous system, particularly the ventral hypothalamus, in communicating the size and the distribution of body fat stores. This input ultimately alters food intake and energy expenditure to maintain constancy of the adipose depot. The key primary neurons in the arcuate nucleus containing NPY/AgRP and POMC/CART appear be critical constituents of the CNS regulating system, and are shown to contribute to anabolic and catabolic signaling systems to complete the feedback loop. New data to indicate shared intracellular signaling from leptin and insulin is provided. The satiety system for meals, consisting of neural afferents to the hindbrain from the gastrointestinal tract, is described and its effectiveness is shown to vary with the strength of the insulin and leptin signals. This provides an efferent mechanism that plays a key role in a complex feedback system that allows intermittent meals to vary from day to day, but provides appropriate long-term adjustment to need. Recently described contributions of this system to obesity are described and potential therapeutic implications are discussed.
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PMID:Leptin and insulin action in the central nervous system. 1240 80

Neuropeptide Y (NPY(1-36)), a sympathetic cotransmitter and neurohormone, has pleiotropic activities ranging from the control of obesity to anxiolysis and cardiovascular function. Its actions are mediated by multiple Gi/o-coupled receptors (Y1-Y5) and modulated by dipeptidyl peptidase IV (DPPIV/cd26), which inactivates NPY's Y1-agonistic activity but generates the Y2 and Y5-agonist, NPY(3-36). Released by sympathetic activity, NPY is a major mediator of stress, responsible for prolonged vasoconstriction via Y1 receptors. Y1 receptors also mediate NPY's potent vascular growth-promoting activity leading in vivo in rodents to neointima formation. This and the association of a polymorphism of the NPY signal peptide with increased lipidemia and carotid artery thickening in humans strongly suggest NPY's role in atherosclerosis. NPY and DPPIV/cd26 are also coexpressed in the endothelium, where the peptide activates angiogenesis. A similar system exists in immune cells, where NPY and DPPIV/cd26 are coactivated and involved in the modulation of cytokine release and immune cell functions. Thus, NPY, both a messenger and a modulator for all three systems, is poised to play an important regulatory role facilitating interactions among sympathetic, vascular and immune systems in diverse pathophysiological conditions such as hypertension, atherosclerosis and stress-related alterations of immunity.
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PMID:Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? 1271 May 20

The primary aim of the present study was to define central and peripheral physiological differences between dietary obesity-susceptible (DOS) and obesity-resistant (DOR) outbred Sprague Dawley (SD) rats when given a moderate high fat diet containing 32.34% of energy as a fat. After a 9-week feeding period, the DOS-SD rats consumed significantly more feed (11.1%) and had higher abdominal (39.9%) and epididymal (27.5%) fat pads than the DOR-SD rats. In addition, serum leptin and insulin levels were significantly increased in the DOS-SD rats compared with those in the DOR-SD rats. However, we did not observe significant differences in serum triglyceride, cholesterol and glucose. No differences in hypothalamic OB-Ra and Rb mRNA expressions were found between the two groups. In contrast, arcuate NPY immunohistochemical expression was much higher in the DOS-SD rats than in the DOR-SD rats, though NPY expression in the supraoptic and paraventricular nuclei was not different between the two phenotypes. In peripheral tissues, the DOS-SD rats showed noticeably increased acetyl CoA carboxylase (ACC) mRNA expression in the liver, not epididymal fat. However, Western blot of peroxisomal proliferator activated factor gamma (PPAR gamma) in the liver and epididymal fat was not different between the two phenotypes of SD rats. It was concluded that different body weight phenotypes within outbred SD population responded differently to the development of dietary induced obesity via altered anabolic features in the hypothalamus and liver.
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PMID:Physiological difference between dietary obesity-susceptible and obesity-resistant Sprague Dawley rats in response to moderate high fat diet. 1280 84

Neurons of the arcuate nucleus of the hypothalamus (ARH) appear to be sites of convergence of central and peripheral signals of energy stores, and profoundly modulate the activity of the melanocortin circuits, providing a strong rationale for pursuing these circuits as therapeutic targets for disorders of energy homeostasis. Recently, tremendous advances have been made in identifying genes and pathways important to regulating energy homeostasis, particularly the hormone leptin and its receptor. This hormone/receptor pair is expressed at high levels in the so-called satiety centers in the hypothalamus, and at lower levels elsewhere in the body. Recent studies in our lab and those of our collaborators have shown that leptin modulates different populations of hypothalamic cells in different ways, rapidly activating POMC neurons and inhibiting NPY/AgRP neurons. In this report, we outline an integrated model of leptin's action in the arcuate nucleus of the hypothalamus, derived from our electrophysiological studies of brain slice preparations taken from transgenic mice that have been bred to express a variety of fluorescent proteins in specific cell types. We also discuss the recently withdrawn obesity drug fenfluramine, which appears to act on POMC neurons via the serotonin 2C receptor. Nutrient-sensing serotonin neurons may project from the raphe nuclei in the brainstem to the hypothalamus; within the arcuate nucleus, serotonin signals are integrated with others such as leptin, ghrelin, and peptide YY(3-36) from the gut, to produce a coordinated response to nutrient state. Finally, we review the current inquiries into the ability of the hormone ghrelin to stimulate appetite by its action of NPY neurons and inhibition of POMC neurons.
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PMID:Electrophysiological actions of peripheral hormones on melanocortin neurons. 1285 14

Ghrelin is a peptydil hormone that has recently been discovered through an unusual reverse pharmacology pathway. Ghrelin is produced mainly in the stomach, but its expression has also been demonstrated in many other organs such as pituitary, hypothalamus, bowel, kidney, heart, pancreas, testis. It is active on the central nervous system, where it is involved in the regulation of GH secretion, mainly through a GHRH-independent mechanism and directly at the pituitary level. Furthermore, ghrelin controls energy balance, enhancing fat mass deposition and food intake through the activation of the hypothalamic nuclei and the promotion of NPY (neuropeptide Y) and AGRP (Agouti related protein) expression; since it stimulates weight gain, ghrelin is considered a possible important factor in the etiology of obesity. Besides these main actions, ghrelin is active in the cardiovascular, reproductive and endocrine systems, and displays antineoplastic activity. Even though most studies have been conducted in humans and rats, there is increasing interest in the role of ghrelin in domestic species. We have integrated the first studies on ghrelin action with recent data on its involvement in modulating several central and peripheral activities.
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PMID:Ghrelin: central and peripheral effects of a novel peptydil hormone. 1296 Sep 36

To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.
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PMID:Impaired glucose homeostasis in mice lacking the alpha1b-adrenergic receptor subtype. 1458 80

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

The thrifty genotype hypothesis postulates that the genetically determined ability to grow obese and insulin resistant in times of food abundance confers a survival advantage in times of famine. Obviously, this ability poses a major health threat in modern times, where food is always available in large quantities. In the last 10-15 years, many genes encoding pathways that orchestrate energy balance and fuel flux have been discovered. This paper summarizes the evidence that diminished dopaminergic tone in hypothalamic nuclei contributes to the "thrifty" genotype/phenotype. Reduced dopaminergic neurotransmission in the suprachiasmatic nucleus of seasonally obese animals appears to drive noradrenalin and NPY mediated transmissions in other nuclei to induce the obesity syndrome at the appropriate time of year. Treatment with dopamine D(2) receptor agonists can fully reverse the metabolic syndrome in these animals. Similar mechanisms are operative in non-seasonal obese animal models. In man, treatment with dopamine D(2) receptor antagonists induces obesity and type 2 diabetes mellitus, whereas dopamine D(2) receptor activation ameliorates the metabolic profile in obese nondiabetic and diabetic humans. Various loss of function mutations of the dopamine D(2) receptor gene are associated with overweight in humans. In concert, the data support the notion that diminution of dopaminergic (dopamine D(2) receptor mediated) transmission in relevant hypothalamic nuclei sets the stage for efficient partitioning of ingested nutrients to contribute to a phenotype that is not so thrifty anymore.
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PMID:Reduced dopaminergic tone in hypothalamic neural circuits: expression of a "thrifty" genotype underlying the metabolic syndrome? 1462 56

Prader-Willi syndrome (PWS) is a genetic disorder characterized by mild mental retardation, short stature, abnormal body composition, muscular hypotonia and distinctive behavioural features. Excessive eating causes progressive obesity with increased cardiovascular morbidity and mortality. In the PWS genotype loss of one or more normally active paternal genes in region q11-13 on chromosome 15 is seen. It is supposed that the genetic alteration leads to dysfunction of several hypothalamic centres and growth hormone (GH) deficiency (GHD) is common. PWS is well described in children, in whom GH treatment improves body composition, linear growth, physical strength and agility. Few studies have focused on adults. We examined a cohort of 19 young adults with clinical PWS (13 with positive genotype) and mean BMI of 35 kg/m2. At baseline the activity of the GH-insulin-like growth factor-I (IGF-I) system was impaired with low GH values, low total IGF-I and in relation to the obesity low levels of free IGF-I and non-suppressed IGF-binding-protein-1 (IGFBP-1). 2/3 were hypogonadal. Bone mineral density (BMD) was low. Four patients had impaired glucose tolerance and nine patients high homeostasis model assessment (HOMA) index, indicating insulin resistance. Seven patients had a moderate dyslipidemia. The 13 patients with the PWS genotype were shorter and had significantly lower IGF-I. Seventeen (9 men and 8 women), subsequently completed a 12 months GH treatment trial, and GH had beneficial effects on body composition without significant adverse effects. The effects were more pronounced in the patients with the PWS genotype. Analysis of peptides involved in appetite regulation showed that leptin levels were high reflecting obesity and as a consequence NPY levels were low. In relation to the patients obesity circulating oxytocin levels were abnormally low and ghrelin levels abnormally high. Thus, oxytocin and ghrelin might be involved in the hyperphagia. NPY, leptin and ghrelin did not change during GH treatment. In conclusion this pilot study showed that adults with PWS have a partial GH deficiency, and GH treatment has beneficial effects on body composition in adult PWS without significant side-effects. Larger and longer term studies on the effect of GH replacement in adult PWS are encouraged.
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PMID:Endocrine and metabolic aspects of adult Prader-Willi syndrome with special emphasis on the effect of growth hormone treatment. 1470 May 52


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