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)

Feeding animals cafeteria diets causes increased sympathetic activity to brown adipose tissue and this is believed to be responsible for the concomitant activation of thermogenesis. Because chronic catecholamine stimulation in other systems leads to a desensitization of beta-adrenergic receptors, we examined lipolysis and cAMP production in brown adipocytes of hamsters eating cafeteria diets for evidence of diminished beta-adrenergic responses. Basal cAMP levels were similar in chow- and cafeteria-fed hamsters. However, adipocytes from overfed animals formed less cAMP in response to isoproterenol than those of control animals. Isoproterenol-stimulated adenylate cyclase activity was similarly decreased in membrane preparations from cafeteria-fed hamsters. However, when the diterpene forskolin was used, equal amounts of cAMP were formed in cells and membrane preparations from control and overfed animals. In contrast to the reduced responses of the cAMP system to isoproterenol stimulation observed in overfed hamsters, isoproterenol-stimulated lipolysis was greater in cells from overfed animals than in cells from control animals. These results are consistent with a desensitization of the adenylate cyclase system in brown adipocytes occurring during chronic hyperphagia. Because eating cafeteria diets has been reported to increase sympathetic activity to brown fat depots, the apparent desensitization of brown adipocytes observed in this study may result from a persistent stimulation of the brown fat with norepinephrine in vivo. Our data also suggest the existence of mechanisms that preserve lipolysis in the face of low cAMP levels.
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PMID:cAMP metabolism and lipolysis in brown adipocytes of hamsters consuming a cafeteria diet. 298 83

Ten women with low estriol excretion received hyperalimentation prior to induction of labor. Six received an amino acid mixture (5% Aminofusin) and 25% dextrose, two received the amino acid mixture, and two received 25% dextrose. Amniotic fluid obtained before and after hyperalimentation was assayed for fetal surfactant production, thyroid, pituitary, and carbohydrate regulating hormones. In the combined amino acid/dextrose infusion group the amniotic fluid palmitic acid levels increased significantly post infusion; rT3 also increased significantly but T3 and T4 showed no significant change. The pituitary hormones growth hormone, prolactin, and ACTH showed no significant change, but beta-endorphin-like activity was significantly elevated. No thyroid-stimulating hormone was detected in any of the samples. All the carbohydrate regulating hormones, insulin, cortisol, and cAMP, showed significant increases but cGMP showed a significant decrease. The amino acid and dextrose only groups gave similar results. Seven of the infants showed some degree of intrauterine growth retardation but no neonatal complications attributable to the hyperalimentation.
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PMID:Amniotic fluid endocrine changes during maternal hyperalimentation. 608 68

Insulin stimulates the production of superoxide and hydrogen peroxide in various tissues. Hydrogen peroxide has been proposed to be an intracellular second messenger for insulin and a moderator of cellular proliferation and differentiation. We previously found that cell proliferation is increased in small intestinal mucosa of streptozotocin-diabetic rats. The current study was undertaken to determine if superoxide dismutase (SOD), the enzyme that converts superoxide to hydrogen peroxide, is altered in the mucosa of the alimentary tract and renal cortex of the diabetic rat, and if so, whether SOD responds to insulin treatment. Total SOD and cyanide-insensitive [manganese-containing SOD (Mn SOD)] SOD were measured by the nitroblue tetrazolium inhibition assay. We studied ad libitum fed animals, where diabetics are hyperphagic and pair-fed animals, where hyperphagia is not present. Since cyclic nucleotides appear to control cell proliferation in some tissues, we also measured cAMP and cGMP in mucosa of the small intestine. In ad libitum fed animals, total SOD was depressed in the mucosa of duodenum, jejunum, and ileum, but not in the cecum or colon of the streptozotocin-diabetic rats. The level of Mn-SOD was not affected by diabetes or insulin treatment, but the cyanide-sensitive [copper- and zinc containing SOD (Cu-Zn SOD] SOD was depressed in the small intestine and colon of diabetic rats. Insulin treatment restored total and Cu-Zn SOD activity in the small intestine to normal and increased Cu-Zn SOD activity in the colon to normal. Pair-fed animals showed the same changes in the SOD activity of jejunal mucosa that were found in ad libitum fed animals. In renal cortex, diabetes did not alter total SOD, but increased Mn SOD and decreased Cu-Zn SOD. Both responses were reversed by insulin treatment. Cyclic nucleotide concentrations were not affected by diabetes. We conclude that SOD enzymes re altered in diabetes, at least in proliferating tissues. Responses are tissue specific. The mucosa of the small intestine and colon show decreased Cu-Zn SOD, the SOD of the cecum is unaffected, and the kidney shows increased Mn SOD and decreased Cu-Zn SOD. The SOD responses of diabetics are reversed by insulin treatment.
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PMID:Superoxide dismutase activity in the intestine of the streptozotocin-diabetic rat. 704 72

The uncoupling protein (UCP) or thermogenin is a 33 kDa inner-membrane mitochondrial protein exclusive to brown adipocytes in mammals that functions as a proton transporter, allowing the dissipation as heat of the proton gradient generated by the respiratory chain and thereby uncoupling oxidative phosphorylation. Thermogenesis (heat production) in brown adipose tissue, which is activated in response to cold exposure or chronic overeating, depends largely on UCP activity. Norepinephrine, released from sympathetic terminals and acting via beta-adrenoceptors and cAMP, is the main positive regulator of both UCP synthesis and activity. Brown fat thermogenesis plays a critical role in thermoregulation and in overall energy balance, at least in rodents. Manipulation of thermogenesis, whether through UCP or through analogous uncoupling proteins, could be an effective strategy against obesity.
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PMID:The uncoupling protein, thermogenin. 959 49

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.
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PMID:A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. 975 29

Melanin-concentrating hormone (MCH), a neuropeptide highly expressed in the lateral hypothalamus, has an important role in the regulation of energy balance and body weight in rodents. We examined whether mutations in the two known MCH receptors might be associated with obesity-related phenotypes in humans. Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in MCHR1: Y181H and R248Q. Neither of these was found in 192 normal weight controls. R248Q cosegregated with obesity across two generations; family data were unavailable for Y181H. When expressed in HEK293 cells, R248Q showed no evidence of constitutive activation or ligand hypersensitivity for extracellular signal-regulated kinase phosphorylation. In addition, R248Q showed no enhanced suppression of cAMP generation. Two common single-nucleotide polymorphisms were found to be in linkage disequilibrium: g.-114A>G and c.39C>T. No association between either of these single-nucleotide polymorphisms and obesity-related phenotypes was found among a population cohort of 541 whites. Only two rare noncoding variants were found in MCHR2. In conclusion, mutations in the MCH receptors are not commonly found in humans with severe early onset obesity. Clarification of the relationship of these variants to obesity must await study in other populations and/or in genetically modified mice.
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PMID:Melanin-concentrating hormone receptor mutations and human obesity: functional analysis. 1516 93

The hypothalamic paraventricular nucleus (PVN) integrates preautonomic and neuroendocrine control of energy homeostasis, fluid balance, and the stress response. We recently demonstrated that glucocorticoids act via a membrane receptor to rapidly cause endocannabinoid-mediated suppression of synaptic excitation in PVN neurosecretory neurons. Leptin, a major signal of nutritional state, suppresses CB(1) cannabinoid receptor-dependent hyperphagia (increased appetite) in fasting animals by reducing hypothalamic levels of endocannabinoids. Here we show that glucocorticoids stimulate endocannabinoid biosynthesis and release via a Galpha(s)-cAMP-protein kinase A-dependent mechanism and that leptin blocks glucocorticoid-induced endocannabinoid biosynthesis and suppression of excitation in the PVN via a phosphodiesterase-3B-mediated reduction in intracellular cAMP levels. We demonstrate this rapid hormonal interaction in both PVN magnocellular and parvocellular neurosecretory cells. Leptin blockade of the glucocorticoid-induced, endocannabinoid-mediated suppression of excitation was absent in leptin receptor-deficient obese Zucker rats. Our findings reveal a novel hormonal crosstalk that rapidly modulates synaptic excitation via endocannabinoid release in the hypothalamus and that provides a nutritional state-sensitive mechanism to integrate the neuroendocrine regulation of energy homeostasis, fluid balance, and the stress response.
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PMID:Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release. 1677 53

E-6837 is a novel, selective and high-affinity 5-HT(6) receptor ligand (pK(i): 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT(6) receptor and full agonism at a constitutively active human 5-HT(6) receptor by monitoring the cAMP signaling pathway.The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg(-1), p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg(-1), p.o.), while its maximal effect was greater, that is -15.7 versus -11.0%.E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (-6.6%) remained lower than after sibutramine (-3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. These results show that the 5-HT(6) receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.
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PMID:Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats. 1678 8

Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT(4)R) in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT(4)R antagonist or siRNA-mediated 5-HT(4)R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT(4)R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT(4)R. Using 5-HT(4)R knockout mice, we demonstrate that 5-HT(4)R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT(4)R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT(4)R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy.
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PMID:Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens. 1791 92

Agouti lethal yellow (A(y)) mice express agouti ectopically because of a genetic rearrangement at the agouti locus. The agouti peptide is a potent antagonist of the melanocortin 4 receptor (MC4R) expressed in neurons, and this leads to hyperphagia, hypoactivity, and increased fat mass. The MC4R signals through Gs and is thought to stimulate the production of cAMP and activation of downstream cAMP effector molecules such as PKA. Disruption of the RIIbeta regulatory subunit gene of PKA results in release of the active catalytic subunit and an increase in basal PKA activity in cells where RIIbeta is highly expressed. Because RIIbeta is expressed in neurons including those in the hypothalamic nuclei where MC4R is prominent we tested the possibility that the RIIbeta knockout might rescue the body weight phenotypes of the A(y) mice. Disruption of the RIIbeta PKA regulatory subunit gene in mice leads to a 50% reduction in white adipose tissue and resistance to diet-induced obesity and hyperglycemia. The RIIbeta mutation rescued the elevated body weight, hyperphagia, and obesity of A(y) mice. Partial rescue of the A(y) phenotypes was even observed on an RIIbeta heterozygote background. These results suggest that the RIIbeta gene mutation alters adiposity and locomotor activity by modifying PKA signaling pathways downstream of the agouti antagonism of MC4R in the hypothalamus.
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PMID:Disruption of the RIIbeta subunit of PKA reverses the obesity syndrome of Agouti lethal yellow mice. 1817 98


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