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)

The effect of intracerebroventricular administration of dizocilpine on feeding behaviour and adrenal corticrotropic hormone (ACTH)-induced anorexia in elevated plus maze was examined. Dizocilpine (10, 20 and 40 nmol/rat, i.c.v.) showed a dose-dependent increase in food intake in 16 h food deprived rats. Dopamine receptor antagonists such as SCH 23390 (0.25 and 0.5 mg/kg, i.p.), pimozide (0.5 and 1 mg/kg, i.p.) and haloperidol (0.25 and 0.5 mg/kg, i.p.) dose-dependently blocked dizocilpine (40 nmol)-induced potentiation of food intake. Brain dopamine depletion by pretreatment with reserpine (5 mg/kg, i.p.) and alpha-methyl-p-tyrosine (200 mg/kg, i.p.) decreased food intake in rats. Similarly, pretreatment with reserpine and alpha-methyl-p-tyrosine (AMPT) reversed the hyperphagic effect of dizocilpine (20 and 40 nmol). Intracerebroventricular administration of ACTH (5 microgram/rat) produced significant diminution of feeding duration and increased tasting latency and feeding latency in elevated plus maze which was reversed by dizocilpine (40 nmol). SCH 23390 (0.25 mg/kg), pimozide (0.5 mg/kg) and haloperidol (0.25 mg/kg) reversed the effect of dizocilpine on ACTH-induced behaviours in elevated plus maze. The present observations support and extend the hypothesis that endogenous excitatory aminoacids (EAAs) play a role in the control of food intake. Further, dizocilpine-induced hyperphagia and dizocilpine-induced reversal of ACTH effect on feeding behaviour in elevated plus maze involve DAergic mediation.
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PMID:Dopamine receptor sensitive effect of dizocilpine on feeding behaviour. 981

Insulin receptor substrate (IRS)-1 and IRS-2, which mediate phosphatidylinositol (PI) 3-kinase activation, play essential roles in insulin-induced translocation of GLUT4 and in glycogen synthesis. In this study, we investigated the process of PI 3-kinase activation via binding with IRS-1 and -2 in liver, muscle, and fat of high-fat-fed rats, a model of insulin-resistant diabetes. In the liver of high-fat-fed rats, insulin increased the PI 3-kinase regulatory subunit p85alpha and the PI 3-kinase activities associated with IRS-1 3.6- and 2.4-fold, and with IRS-2, 4.7- and 3.0-fold, respectively, compared with those in control rats. The tyrosine phosphorylation levels of IRS-1 and IRS-2 were not significantly altered, however. In contrast with the liver, tyrosine phosphorylation levels and associated PI 3-kinase proteins and activities were decreased in the muscle and adipose tissue of high-fat-fed rats. Thus, high-fat feeding appears to cause insulin resistance in the liver by a mechanism different from the impaired PI 3-kinase activation observed in muscle and adipose tissue. Taking into consideration that hepatic PI 3-kinase activation is severely impaired in obese diabetic models such as Zucker fatty rats, it is possible that the mechanism by which a high-fat diet causes insulin resistance is quite different from that associated with obesity and overeating due to abnormality in the leptin system. This is the first report to show increased PI 3-kinase activation by insulin in an insulin-resistant diabetic animal model. These findings may be important for understanding the mechanism of insulin resistance in human NIDDM, since a high-fat diet is considered to be one of the major factors exacerbating insulin insensitivity in humans.
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PMID:Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats. 989 38

Insulin resistance is central to the pathophysiology of type 2 diabetes. It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. We studied the molecular basis of insulin resistance in mice in which injection with gold thioglucose led to the development of hyperphagia, obesity and insulin resistance over a 4-month period. We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. We investigated different mechanisms by which defects in the components of the insulin signalling cascade could emerge, including down-regulation and abnormal phosphorylation of signal molecules. In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. Increased IRS-1 phosphorylation on serine and threonine residues affects tyrosine phosphorylation. Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice.
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PMID:Molecular mechanisms of insulin action in normal and insulin-resistant states. 1032 50

Serum tyrosine concentration, Phe/Tyr scores and psychomotor/mental development scores were analysed in 32 children with phenylketonuria (PKU) and 39 with mild hyperphenylalaninaemia. Observation period included the first 6 years of life. Tendency to tyrosine deficiency was observed; stronger in dietary treated PKU patients than in those with mild hyperphenylalaninaemia. Statistically significant differences between patient groups were found only in 3 and 6 years old children (lower tyrosine values in PKU patients). It was observed that evaluation of Phe/Tyr score value might be usefull in differentiation between PKU and mild hyperphenylalaninaemia. Moreover, the above score may help in the evaluation of hypo- and hyperalimentation state in the course of dietary treatment. The level of tyrosine deficiency in the analysed patient groups did not influence their normal intellectual development.
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PMID:[Serum tyrosine in children with phenylketonuria and mild hyperphenylalaninemia]. 1101 57

Hyperphagia followed both central neuropeptide Y (NPY) administration and the presumed increase of endogenous NPY activity after food deprivation. NPY induced greater hyperphagia in cold-adapted than non-adapted rats; fasting of comparable severity caused similar hyperphagia in the two groups. NPY-receptor-antagonist D-Tyr(27,36), D-Thr32-NPY(27,36) or functional NPY-antagonist D-myo-inositol-1,2,6-trisphosphate attenuated the hyperphagic effect of both NPY and fasting in non-adapted rats. However, while completely preventing the NPY-hyperphagia, they did not influence the fasting-induced hyperphagia in cold-adapted rats. With cold-adaptation the sensitivity to NPY and to its antagonists increases, but the hypothalamic NPY loses from its fundamental role in the regulation of food intake, and the hyperphagia seen in cold-adaptation may need some other explanation.
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PMID:Effects of neuropeptide Y antagonists on food intake in rats: differences with cold-adaptation. 1604 Jan 56

Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity involved in regulating the degradation of receptor tyrosine kinases. We have recently reported that c-Cbl(-/-) mice exhibit a lean phenotype and enhanced peripheral insulin action likely due to elevated energy expenditure. In the study reported here, we examined the effect of a high-fat diet on energy homeostasis and glucose metabolism in these animals. When c-Cbl(-/-) mice were fed a high-fat diet for 4 weeks, they maintained hyperphagia, higher whole-body oxygen consumption (27%), and greater activity (threefold) compared with wild-type animals fed the same diet. In addition, the activity of several enzymes involved in mitochondrial fat oxidation and the phosphorylation of acetyl CoA carboxylase was significantly increased in muscle of high-fat-fed c-Cbl-deficient mice, indicating a greater capacity for fat oxidation in these animals. As a result of these differences, fat-fed c-Cbl(-/-) mice were 30% leaner than wild-type animals and were protected against high-fat diet-induced insulin resistance. These studies are consistent with a role for c-Cbl in regulating nutrient partitioning in skeletal muscle and emphasize the potential of c-Cbl as a therapeutic target in the treatment of obesity and type 2 diabetes.
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PMID:Casitas b-lineage lymphoma-deficient mice are protected against high-fat diet-induced obesity and insulin resistance. 1650 34

SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.
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PMID:Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. 1723 96

Leptin regulates energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. However, the whole spectrum of signaling actions through the 3 cytoplasmic tyrosines of mouse Ob-Rb remains to be completely defined in vivo. Here, we generated 2 knockin lines of mice expressing mutant leptin receptors with phenylalanine substitution for all 3 tyrosines (Y123F) or for Tyr(1138) alone (Y3F). Y123F animals developed overt obesity similar to that of Y3F animals with abrogated hypothalamic activation of STAT3 by leptin, but they exhibited more severe impairment in glucose tolerance. In striking contrast to db/db mice, however, both Y123F and Y3F mice showed attenuated adiposity with reduced hyperphagia, marked improvement in physical activity and adaptive thermogenesis, and significantly ameliorated glycemic control. Further, Y123F mice had hypothalamic neuropeptide Y/agouti-related protein expression maintained at prominently lower levels compared with db/db mice. Thus, these results provide direct physiological evidence that Ob-Rb exerts crucial metabolic actions not only through tyrosine-dependent, but also tyrosine-independent mechanisms in control of energy balance and glucose homeostasis.
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PMID:Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis. 1901 22

Ghrelin and peptide tyrosine tyrosine (PYY) are known to affect appetite and body weight, but the acute effects of fat-rich and carbohydrate-rich meals on plasma ghrelin, PYY response, and appetite remain unclear. We hypothesized that obese individuals had impaired postprandial ghrelin and PYY response based on macronutrient content of meals, affecting appetite and energy intake. We conducted a randomized crossover trail comparing fasting ghrelin and PYY concentrations, postprandial ghrelin and PYY responses, and subjective appetite in 15 obese and 12 lean Chinese young adults after they consumed isocaloric high-carbohydrate [HC; 88% energy carbohydrate, 4% energy fat, 8% energy protein] and high-fat (HF; 25% energy carbohydrate, 71% energy fat, 4% energy protein) meals. Ghrelin concentrations over time differed between HC and HF meals (P < 0.01) via repeated measures of ANOVA, with lower postprandial ghrelin suppression after HF meals, especially among obese participants. PYY response differed between meals among lean participants, with a delayed and higher postprandial PYY peak after the HF meal (P < 0.01); however, PYY response did not differ among obese participants. The incremental area under the curve of PYY was higher in lean than in obese participants after the HF meal (P < 0.01). These results suggest that impaired ghrelin response after HF meals may contribute to reduced satiety and overeating, especially among obese individuals. Whether an attenuated response of PYY in obese participants after a HF meal bears any physiological consequences warrants further study.
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PMID:Impaired ghrelin response after high-fat meals is associated with decreased satiety in obese and lean Chinese young adults. 1945 28

Insulin resistance and type 2 diabetes (T2D) are closely linked to obesity. Numerous prospective studies have reported on weight gain, insulin resistance, and insulin signaling in experimental animals, but not in humans. We examined insulin signaling in adipocytes from lean volunteers, before and at the end of a 4-wk period of consuming a fast-food, high-calorie diet that led to weight gain. We also examined adipocytes from patients with T2D. During the high-calorie diet, subjects gained 10% body weight and 19% total body fat, but stayed lean (body mass index = 24.3 kg/m(2)) and developed moderate systemic insulin resistance. Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. Unlike the T2D subjects, in subjects on the high-calorie diet, likely owing to the ongoing weight-gain, phosphorylation of MAP-kinases ERK1/2 became hyperresponsive to insulin. To our knowledge this study is the first to investigate insulin signaling during overeating in humans, and it demonstrates that T2D effects on intracellular insulin signaling already occur after 4 wks of a high-calorie diet and that the effects in humans differ from those in laboratory animals.
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PMID:Short-term overeating induces insulin resistance in fat cells in lean human subjects. 1959 6


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