Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver, and discrete brain regions. Although overexpression of 11 beta-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11 beta-HSD1 null (11 beta-HSD1-/-) mice resist metabolic disease on high-fat (HF) diet, but also show hyperphagia. This suggests 11 beta-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11 beta-HSD1-/- mice express lower hypothalamic mRNA levels of the anorexigenic cocaine and amphetamine-regulated transcript and melanocortin-4 receptor, but higher levels of the orexigenic melanin-concentrating hormone mRNAs than controls (C57BL/6J) on a low-fat diet (11% fat). HF (58% fat) diet promoted transient ( approximately 8 wk) hyperphagia and decreased food efficiency in 11 beta-HSD1-/- mice and decreased melanocortin-4 receptor mRNA expression in control but not 11 beta-HSD1-/- mice. 11 beta-HSD1-/- mice showed a HF-mediated up-regulation of the orexigenic agouti-related peptide (AGRP) mRNA in the arcuate nucleus which paralleled the transient HF hyperphagia. Conversely, control mice showed a rapid (48 h) HF-mediated increase in arcuate 11 beta-HSD1 associated with subsequent down-regulation of AGRP. This regulatory pattern was unexpected because glucocorticoids increase AGRP, suggesting an alternate hyperphagic mechanism despite partial colocalization of 11 beta-HSD1 and AGRP in arcuate nucleus cells. One major alternate mechanism governing selective fat ingestion and the AGRP system is endogenous opioids. Treatment of HF-fed mice with the mu opioid agonist DAMGO recapitulated the HF-induced dissociation of arcuate AGRP expression between control and 11 beta-HSD1-/- mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11 beta-HSD1. These data suggest that 11 beta-HSD1 in brain plays a role in the adaptive restraint of excess fat intake, in part by increasing inhibitory opioid tone on AGRP expression in the arcuate nucleus.
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PMID:11 beta-hydroxysteroid dehydrogenase type 1 induction in the arcuate nucleus by high-fat feeding: A novel constraint to hyperphagia? 1676 61

The increased prevalence of obesity in Western society has been well established for many years, and with this trend, the prevalence of other associated pathologies including insulin resistance, dyslipidaemia, hypertension and the genesis of a proinflammatory and prothrombotic environment within individuals is also rapidly increasing, resulting in a condition known as the~metabolic syndrome. From a physiological perspective, one of the most severe consequences of the metabolic syndrome is a progressive inability of the cardiovascular system to adequately perfuse tissues and organs during either elevated metabolic demand and, if sufficiently severe, under basal levels of demand. For the study of the metabolic syndrome, the OZR (obese Zucker rat) represents an important tool in this effort, as the metabolic syndrome in these animals results from a chronic hyperphagia, and thus can be an excellent representation of the human condition. As in afflicted humans, OZR experience an attenuated functional and reactive hyperaemia, and can ultimately experience an ischaemic condition in their skeletal muscles at rest. The source of this progressive ischaemia appears to lie at multiple sites, as endothelium-dependent vasodilator responses are strongly impaired in OZR, and specific constrictor processes (e.g. adrenergic tone) may be enhanced. Whilst these active processes may contribute to a reduction in blood flow under resting conditions or with mild elevations in metabolic demand, an evolving structural alteration to individual microvessels (reduced distensibility) and microvascular networks (reduced microvessel density) also develop and may act to constrain perfusion at higher levels of metabolic demand. Given that constrained muscle perfusion in the metabolic syndrome appears to reflect a highly integrated, multi-faceted effect in OZR, and probably in humans as well, therapeutic interventions must be designed to address each of these contributing elements.
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PMID:Vascular function in the metabolic syndrome and the effects on skeletal muscle perfusion: lessons from the obese Zucker rat. 1714 86

With the worldwide epidemic of metabolic syndrome (MetS), the proportion of women that are overweight/obese and overfed during pregnancy has increased. The resulting abnormal uterine environment may have deleterious effects on fetal metabolic programming and lead to MetS in adulthood. A balanced/restricted diet and/or physical exercise often improve metabolic abnormalities in individuals with obesity and type 2 diabetes mellitus (T2D). We investigated whether reducing fat intake during the periconceptual/gestation/lactation period in mothers with high-fat diet (HFD)-induced obesity could be used to modify fetal/neonatal MetS programming positively, thereby preventing MetS. First generation (F1) C57BL/6J female mice with HFD-induced obesity and T2D were crossed with F1 males on control diet (CD). These F1 females were switched to a CD during the periconceptual/gestation/lactation period. At weaning, both male and female second generation (F2) mice were fed a HFD. Weight, caloric intake, lipid parameters, glucose, and insulin sensitivity were assessed. Sensitivity/resistance to the HFD differed significantly between generations and sexes. A similar proportion of the F1 and F2 males (80%) developed hyperphagia, obesity, and T2D. In contrast, a significantly higher proportion of the F2 females (43%) than of the previous F1 generation (17%) were resistant (P<0.01). Despite having free access to the HFD, these female mice were no longer hyperphagic and remained lean, with normal insulin sensitivity and glycemia but mild hypercholesterolemia and glucose intolerance, thus displaying a "satiety phenotype." This suggests that an appropriate dietary fatty acid profile and intake during the periconceptual/gestation/lactation period helps the female offspring to cope with deleterious intrauterine conditions.
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PMID:Resistance to high-fat diet in the female progeny of obese mice fed a control diet during the periconceptual, gestation, and lactation periods. 1716 37

Estrogen receptor alpha (ERalpha) plays a pivotal role in the regulation of food intake and energy expenditure by estrogens. Although it is well documented that a disruption of ERalpha signaling in ERalpha knockout (ERKO) mice leads to an obese phenotype, the sites of estrogen action and mechanisms underlying this phenomenon are still largely unknown. In the present study, we exploited RNA interference mediated by adeno-associated viral vectors to achieve focused silencing of ERalpha in the ventromedial nucleus of the hypothalamus, a key center of energy homeostasis. After suppression of ERalpha expression in this nucleus, female mice and rats developed a phenotype characteristic for metabolic syndrome and marked by obesity, hyperphagia, impaired tolerance to glucose, and reduced energy expenditure. This phenotype persisted despite normal ERalpha levels elsewhere in the brain. Although an increase in food intake preceded weight gain, our data suggest that a leading factor of obesity in this model is likely a decline in energy expenditure with all three major constituents being affected, including voluntary activity, basal metabolic rate, and diet-induced thermogenesis. Together, these findings indicate that ERalpha in the ventromedial nucleus of the hypothalamus neurons plays an essential role in the control of energy balance and the maintenance of normal body weight.
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PMID:Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. 1728 95

Pediatric obesity is increasing worldwide and disproportionately affects the economically and socially disadvantaged. Obese children are at risk of developing the (dys)metabolic syndrome, insulin resistance, early-onset type 2 diabetes mellitus, polycystic ovarian syndrome, hypertension, hyperlipidemia, and obstructive sleep apnoea. Those with diabetes may have mixed features of type 1 and type 2 diabetes mellitus. Pediatric obesity is the result of persistent adverse changes in food intake, lifestyle, and energy expenditure. It may be because of underlying a genetic syndrome or a conduct disorder. Children living in urban settings often lack safe, affordable, and accessible recreational facilities. Tight educational schedules mean less free time, while computer games and television have become preferred recreational activities. More families are eating out or eating take-out meals and processed foods at home because of pressures of work and time constraints. Consumer advertising targeted at children and the ready availability of vending machines encourage unwise food choices. Some children eat excessively because they are depressed, anxious, sad, or lonely. Often families and obese children are aware of the need for healthy eating and exercise but are unable to translate knowledge into weight loss. Population-based measures such as public education, school meal reforms, child-safe exercise friendly environments, and school-based and community-based exercise programs have been shown to be successful to varying degrees, but there remain individuals who will need special help to overcome obesity. Overeating (e.g. binge eating) may be a manifestation of disordered coping behavior but may also be because of defects in the neural and hormonal control of appetite and satiety. New pharmacological approaches are targeting these areas. We need a coordinated approach involving government, communities, and healthcare providers to provide a continuum of population-based interventions, focused screening, and personalized multidisciplinary interventions for the obese child and family.
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PMID:An overview of pediatric obesity. 1799 Nov 36

Human (visceral) obesity is associated with alterations hypothalamus-pituitary-adrenal (HPA) axis functioning. It is however not completely clear whether the HPA axis is causally or co-incidentally related to (visceral) obesity. This review summarizes supporting data of an involvement of the HPA axis in the development of (visceral) obesity. First, several DNA polymorphisms related to HPA axis functioning are correlated to the development of obesity. Second, chronic elevation of circulatory glucocorticoid concentrations, as in Cushing's disease, results in increased abdominal adiposity. Third, (visceral) obesity is associated with a diminished capacity of cortisol to suppress its own secretion. HPA axis functioning might affect energy balance through affecting energy intake. Both CRH and cortisol influence physiological, central mechanisms involved in the regulation of food intake. Still, general activation of the HPA axis has shown to have inconsistent effects on food intake in humans. This inconsistency may partially be explained by gender differences, individual differences in the functioning of the HPA axis, as well as differences in attitude towards eating. In particular, women with high scores on dietary restraint are prone to stress-induced hyperphagia. Dietary restraint scores, in turn, are positively correlated to basal and dexamethasone-suppressed cortisol levels, indicating a complex dual relationship between stress, HPA axis functioning, attitude towards eating and the risk for stress-induced hyperphagia. In the Western society, with chronically high ambient levels of stress and the availability of high caloric foods, this relationship may imply a risk for the development of (visceral) obesity and the metabolic syndrome.
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PMID:The hypothalamic-pituitary-adrenal-axis in the regulation of energy balance. 1827 77

Obesity is an excess of fat mass. Fat mass is an energy depot but also an endocrine organ. A deregulation of the sympathetic nervous system (SNS) might produce obesity. Stress exaggerates diet-induced obesity. After stress, SNS fibers release neuropeptide Y (NPY) which directly increases visceral fat mass producing a metabolic syndrome (MbS)-like phenotype. Adrenergic receptors are the main regulators of lipolysis. In severe obesity, we demonstrated that the adrenergic receptor subtypes are differentially expressed in different fat depots. Liver and visceral fat share a common sympathetic pathway, which might explain the low-grade inflammation which simultaneously occurs in liver and fat of the obese with MbS. The neuroendocrine melanocortinergic system and gastric ghrelin are also greatly deregulated in obesity. A specific mutation in the type 4 melanocortin receptor induces early obesity onset, hyperphagia and insulin-resistance. Nonetheless, it was recently discovered that a mutation in the prohormone convertase 1/3 simultaneously produces severe gastrointestinal dysfunctions and obesity.
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PMID:Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome. 1856 42

Overweight and obesity are highly prevalent in patients with bipolar disorder, and metabolic disorders also affect a significant portion of this population. Obesity and metabolic disorders cause significant economic burden and impair quality of life in both the general population and patients with bipolar disorder. This review examines the relationship between bipolar disorder and the metabolic syndrome, and the associated economic impact. The metabolic syndrome and bipolar disorder appear to share common risk factors, including endocrine disturbances, dysregulation of the sympathetic nervous system, and behaviour patterns, such as physical inactivity and overeating. In addition, many of the commonly used pharmacological treatments for bipolar disorder may intensify the medical burden in bipolar patients by causing weight gain and metabolic disturbances, including alterations in lipid and glucose metabolism, which can result in an increased risk for diabetes mellitus, hypertension, dyslipidaemia, cardiovascular disease and the metabolic syndrome. These medical co-morbidities and obesity have been associated with a worse disease course and likely contribute to the premature mortality observed in bipolar patients. Weight gain is also a major cause of treatment noncompliance, increased use of outpatient and inpatient services and, consequently, higher healthcare costs. Prevention of weight gain and metabolic disturbances or early intervention when these are present in bipolar disorder could result in significant health and economic benefits.
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PMID:Bipolar disorder and the metabolic syndrome: causal factors, psychiatric outcomes and economic burden. 1860 4

The Zucker fatty (ZF) rat is a disease model of obesity and metabolic syndrome, such as hyperlipidemia and insulin resistance, resulting from hyperphagia owing to the loss of function of the leptin receptor, but it rarely develops hyperglycemia. We examined the effects of different doses of streptozotocin (STZ). A low dosage of STZ (30 mg/kg body weight, i.p.) elevated blood glucose levels in ZF rats up to 300 mg/dl within a week, and to nearly 500 mg/dl by 5 weeks after injection of STZ. Besides hyperglycemia, STZ-treated ZF (STZ-ZF) rats retained metabolic syndrome features such as hyperlipidemia and hyperinsulinemia. The stimulated insulin secretion in response to orally-loaded glucose disappeared completely in STZ-ZF rats. Although there were no significant differences in the morphology of pancreatic islets between vehicle-treated ZF (Cont-ZF) and STZ-ZF rats, the insulin content was markedly decreased in STZ-ZF rats. The hepatic gene expression for gluconeogenic enzymes was upregulated in STZ-ZF rats compared with Cont-ZF rats. Metformin lowered the blood glucose levels of STZ-ZF rats in a dose-dependent manner. These results suggest that STZ-ZF rats are useful for studies of T2DM and for the evaluation of the efficacy of anti-diabetic drugs.
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PMID:Characterization of STZ-Induced Type 2 Diabetes in Zucker Fatty Rats. 1863 56

In previous work, we observed that N/OFQ-induced hyperphagia is greater in DA rats, animals resistant to metabolic syndrome, than in WOKW animals, which are prone to this disease. We attributed this difference to the fact that these two strains have different Cart gene sequences and expression. As a preliminary approach to pursue this hypothesis, the present work focused on Cart gene expression by developing from DA and WOKW rats various congenic animals with exchanges of metabolic syndrome-related QTL's of different chromosomes (3, 5, 10 and 16), and analyzing their N/OFQ-induced (2.1, 4.2, and 8.4nmol/rat) food intake in terms of their CART gene expression and N/OFQ hypothalamic immunostaining. Two groupings emerged, the first, with strains 3a, 3b, and 5a with elevated N/OFQ-induced feeding similar to that of the DA rats, and the second, with strains 16 and 10, with lower feeding, like the WOKW rats. There was a perfect correlation between Cart gene expression and N/OFQ-induced feeding data at 30min for the strains DA, 3a, 3b, 5 in the first group, and 16 and WOKW for the second, but not for strain 10. As expected, the strains with low content of Cart gene expression had elevated N/OFQ-induced feeding, but contrary to expectations, strain 10, with the lowest Cart gene expression, exhibited low N/OFQ-induced feeding, on the order of that of the WOKW rats. A comparable trend was observed with N/OFQ hypothalamic immunostaining. This anomaly may be due to other satiety-related factors involved in N/OFQ-induced feeding.
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PMID:Nociceptin/orphanin FQ-induced food intake and cocaine amphetamine regulated transcript gene expression in strains derived from rats prone (WOKW) and resistant (Dark Agouti) to metabolic syndrome. 1907 Jun 36


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