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)

Ghrelin, an orexigenic peptide produced in the stomach, is increased in streptozotocin (STZ)-induced diabetic (DM) mice. This study clarifies the regulation of ghrelin levels by leptin in STZ-DM mice. STZ-DM mice had higher plasma ghrelin concentrations and greater ghrelin mRNA expression than control mice. Changes in ghrelin levels were dose dependently attenuated by the subcutaneous injection of leptin (0-27 nmol x kg(-1) x day(-1) over 7 days). Leptin treatment also partially reversed the hyperphagia and hyperglycemia observed in STZ-DM mice, but not the hypoinsulinemia, and there was a decrease in plasma ghrelin concentrations and ghrelin mRNA levels compared with STZ-LEP pair-fed mice. These results indicate that leptin treatment partially reverses elevated plasma ghrelin levels in STZ-DM mice independent of food intake and insulin, and suggest that hypoleptinemia in STZ-DM mice upregulates ghrelin.
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PMID:Leptin downregulates ghrelin levels in streptozotocin-induced diabetic mice. 1610 2

Leptin is thought to be related to vegetative symptoms of depression such as alterations in food intake and weight. Fifty-seven drug-free patients and 26 healthy controls were enrolled in this study. We have found that the serum leptin levels were higher in patients with atypical depressive disorder than in controls, but not in patients with non-atypical depressive disorder, however, body mass index, age, and gender were not significantly different between these groups. Probably, these findings seem to be associated with some features of the atypical depressive disorders such as weight gain, a result of hyperphagia.
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PMID:High serum leptin levels in depressive disorders with atypical features. 1640 Dec 52

Leptin is an obese gene product, and leptin-deficient ob/ob mice develop hyperphagia and reduced locomotor activity. Leptin is thought to be related to brain development, because leptin receptors are widely expressed in the brain, and because brain weight as well as brain protein and DNA contents were reduced in adult ob/ob mice. In this study, we investigated the effect of leptin on the fetal cingulate cortex, since the leptin receptor is expressed in the neurons of the cingulate cortex, which is involved in emotion as well as in sensory, motor, and cognitive processes. The ob/ob fetuses had more pycnotic cells than wild-type fetuses in the cingulate cortex at embryonic day (E) 18. Many pycnotic cells were observed in the intermediate zone of the cingulate cortex. Most cells observed in this area were neuronal lineage cells, while few undifferentiated cells and oligodendrocyte precursor cells were found. At E18 there was no significant difference in the rostrocaudal length of the corpus callosum, which contains the neuronal projection from the cingulate cortex, between ob/ob and wild-type fetuses. We also showed that the length of the cerebrum was greater and the width of the cerebrum and cerebellum were lesser in ob/ob fetuses than in wild-type at E16. These results suggest an increased cell death in neuronal lineage cells in the intermediate zone of the cingulate cortex in leptin-deficient ob/ob mice. Leptin deficiency may also alter the gross morphology of the brain in development, but not the formation of the corpus callosum.
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PMID:Leptin deficiency causes pycnotic change in fetal cingulate cortical cells. 1664 94

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

This study examined the importance of direct central nervous system (CNS) actions and increased adrenergic activity in mediating the chronic antidiabetic and cardiovascular actions of leptin. Insulin-deficient rats (streptozotocin, 50 mg/kg) were used to examine the effects of leptin on glucose homeostasis independent of changes in insulin. Male Sprague-Dawley rats were instrumented with arterial and venous catheters and intracerebroventricular cannula for 24-h/day blood pressure (BP) and heart rate (HR) monitoring and intravenous and intracerebroventricular infusions. Insulin-deficient diabetes was associated with marked hyperglycemia, hyperphagia, decreased BP, and pronounced fall in HR. Leptin treatment, intravenous or intracerebroventricular, completely restored to control values plasma glucose levels (384+/-58 to 102+/-28 and 307+/-38 to 65+/-7 mg/dl, respectively), food intake, BP, and HR (304+/-8 to 364+/-7 and 317+/-13 to 423+/-9 bpm, respectively). Combined blockade of alpha1-, beta1-, and beta2-adrenergic receptors attenuated the rise in HR by 30 to 50% but had no effect on the antidiabetic and dietary actions of leptin. Blockade of beta3-adrenergic receptors did not attenuate the chronic cardiovascular or metabolic effects of leptin. These data demonstrate that leptin, via its direct actions in the CNS, has powerful antidiabetic actions in insulin-deficient rats independent of increased peripheral alpha1, beta1, beta2, and beta3-adrenergic activity. Leptin also exerts important long-term cardiovascular actions that are partially mediated via alpha1- and beta1/beta2-adrenergic activation. These findings provide new insights into novel pathways for long-term control of glucose homeostasis and cardiovascular regulation.
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PMID:Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity. 1677 68

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.
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PMID:Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. 1679 35

Following the chemically-induced lesion of the ventromedial nucleus, gold-thioglucose treated rodents display hypothalamic leptin resistance, hyperphagia, hyperinsulinemia and obesity. Despite the exuberant hyperinsulinemia following gold-thioglucose treatment, systemic insulin sensitivity is preserved during the early phase of the obesity syndrome, resulting in extensive fat production and markedly increased leptin levels. Leptin and adiponectin levels are inversely associated in vivo. However, the reciprocal relationship between leptin and adiponectin can not be explained by in vitro observations, suggesting the involvement of the central nervous system. We measured leptin and adiponectin expression levels in gold-thioglucose obese and control mice. In this study, we show that gold-thioglucose treatment causes a profound reduction in the number of hypothalamic glucokinase transcripts in rodents. Also, we demonstrate that the adiponectin expression levels and protein content are increased in gold-thioglucose treated animals, which can explain the increased insulin sensitivity during the early phase of the obesity syndrome. Furthermore, as the increased leptin production in gold-thioglucose obese mice is not paralleled by reduced adiponectin production, our data suggest that the inverse regulation between leptin and adiponectin levels is, at least partially, mediated via the hypothalamus.
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PMID:Adiponectin expression is paradoxically increased in gold-thioglucose-induced obesity. 1694 Dec 72

Obesity is typically associated with increased tumor susceptibility, whereas caloric restriction, a regimen resulting in leanness, inhibits carcinogenesis. The link between adiposity and malignancies suggests that adipose tissue may influence carcinogenesis. An adipose tissue hormone, leptin, could be procarcinogenic because it stimulates proliferation in various tissues and tumor cell lines. Leptin may contribute to the correlation between adiposity and malignancies as its levels are usually increased in obese subjects and reduced by caloric restriction. We hypothesized that leptin deficiency, despite obesity, would inhibit carcinogenesis in leptin-null ob/ob mice and tested this hypothesis in two models: (a) two-stage skin carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and (b) p53 deficiency. Contrary to a typical association between obesity and enhanced carcinogenesis, obese ob/ob mice developed induced skin papillomas and spontaneous p53-deficient malignancies, mostly lymphomas, similarly to their lean littermates. Surprisingly, lipodystrophic (ZIP) mice that had very little both adipose tissue and leptin were highly susceptible to carcinogenesis. Hyperphagia, hyperinsulinemia, and hyperglycemia are unlikely to have contributed significantly to the enhancement of carcinogenesis in ZIP mice because similarly hyperphagic, hyperinsulinemic, and hyperglycemic ob/ob mice had normal susceptibility to carcinogenesis. Our data suggest that, in contrast to a well-known correlation between obesity and cancer, the direct effect of adipose tissue may rather be protective.
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PMID:Susceptibility to induced and spontaneous carcinogenesis is increased in fatless A-ZIP/F-1 but not in obese ob/ob mice. 1695 Dec 7

Leptin, a product of the ob gene, is a pleiotropic signal implicated in regulation of multiple physiological functions in the periphery and centrally, including hypothalamic integration of energy homeostasis. Recessive mutations of ob gene result in early onset of hyperphagia, morbid obesity, metabolic disorders, early mortality and shortened life-span. Intracerebroventricular injection of recombinant adeno-associated virus vector (rAAV) encoding the leptin gene in adult obese ob/ob mice enhanced leptin transgene expression only in the hypothalamus, normalized food intake, body weight and more than doubled the life-span as compared to control cohorts and extended it to near that of normal wild type mice. These life-extending benefits were associated with drastic reductions in visceral fat, and blood glucose and insulin levels, but elevated ghrelin levels, the anti-aging biomarkers. Thus, bioavailability of leptin transduced by ectopic gene in the hypothalamus alone is both necessary and sufficient to normalize life-span. Evidently, site-specific ectopic gene expression with rAAV is durable and safe for alleviating neural disorders that stem from missing or functional disruption of a single gene.
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PMID:Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin. 1701 Oct 78

Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases.
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PMID:Brain adipocytokine action and metabolic regulation. 1713 Jun 38


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