Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of leptin, the product of the ob gene, has led to major developments in understanding the regulation of energy balance. It is now recognised that leptin is produced in several organs additional to white adipose tissue, including brown fat, the placenta and fetal tissues (such as heart and bone/cartilage). The hormone has multiple functions-in inhibiting food intake, in the stimulation/maintenance of energy expenditure, as a signal to the reproductive system and as a 'metabolic' hormone influencing a range of processes (for example, insulin secretion, lipolysis, sugar transport). The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production by white fat is envisaged for the sympathetic system, operating through beta3-adrenoceptors. The leptin receptor gene is widely expressed, with the several splice variants exhibiting different patterns of expression. The long form variant (Ob-Rb) is expressed particularly in the hypothalamus, although it is being increasingly identified in other tissues. Leptin exerts its central effects through several neuroendocrine systems, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotrophin releasing hormone (CRH) and cocaine- and amphetamine-regulated transcript (CART). In essence, the leptin system now appears highly complex, the hormone being involved in a range of physiological processes in a manner far transcending the initial lipostatic concept. This complexity may reduce the potential of the leptin system as a target for anti-obesity therapy.
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PMID:Leptin: fundamental aspects. 1019 58

The melanocortin-4 receptor (MC4-R) appears to be an important downstream mediator of the action of leptin. We examined to what extent the anorectic effects of cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1) and corticotrophin releasing factor (CRF) might be mediated via MC4-R. alpha-Melanocyte stimulating hormone (alpha-MSH), the MC4-R agonist, administered intracerebroventricularly (ICV) at a dose of 1 nmol reduced food intake by approximately half. Agouti-related protein (Agrp) (83-132), a biologically active fragment of the endogenous MC4-R antagonist, administered ICV at a dose of 1 nmol completely blocked the anorectic effect of 1 nmol alpha-MSH. CART (55-102) (0.2 nmol), GLP-1 (3 nmol) and CRF (0.3 nmol) produced a reduction in feeding of approximately the same magnitude as 1 nmol alpha-MSH. Agrp (83-132) (1 nmol) administered ICV did not block the anorectic effects of CART (55-102) (1 h food intake, 0.2 nmol CART (55-102), 2.7+/-0.8 g vs. CART (55-102)+Agrp (83-132), 2.6+/-0.6 g, P=0.87; saline control 5.4+/-0.3 g, P<0.001 vs. both groups). Agrp (83-132) also did not block the anorectic effects of GLP-1 or CRF (1 h food intake, 0.3 nmol CRF, 0.7+/-0.3 g vs. CRF+Agrp (83-132), 0.7+/-0.3 g, P=0.91; 3 nmol GLP-1, 1.9+/-0.4 g vs. GLP-1+Agrp (83-132), 1.1+/-0. 5 g, P=0.23; saline control 5.0+/-0.6 g, P<0.001 vs. all four groups). Thus, as previous data suggests, GLP-1 and CRF do not appear to reduce food intake predominantly via MC4-R, we here demonstrate for the first time that CART, in addition to GLP-1 and CRF primarily acts via Agrp independent pathways.
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PMID:Cocaine- and amphetamine-regulated transcript, glucagon-like peptide-1 and corticotrophin releasing factor inhibit feeding via agouti-related protein independent pathways in the rat. 1082 88

Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respond to leptin have not been examined comprehensively. In this study, we explored systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subsets of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was investigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of Fos-IR was observed in hypothalamic nuclei, including the paraventricular nucleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and external lateral subdivisions of the parabrachial nucleus (slPB and elPB, respectively), the supragenual nucleus, and the nucleus of the solitary tract (NTS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found that contained cocaine- and amphetamine-regulated transcript mRNA in several hypothalamic nuclei, including the RCA, Arc, DMH, and PMV. In the Arc and DMH, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Arc also expressed Fos-IR. In the brainstem, we found that cholecystokinin neurons in the slPB and glucagon-like peptide-1 neurons in the NTS were activated by leptin. We also investigated the coexpression of Fos-IR and the long form of the leptin receptor (OBRb) mRNA. We found double-labeled neurons surrounding the median eminence and in the RCA, Arc, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very few double-labeled cells. These results suggest that leptin stimulates brain pathways containing neuropeptides that are involved in the regulation of energy balance, autonomic homeostasis, and neuroendocrine status.
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PMID:Chemical characterization of leptin-activated neurons in the rat brain. 1086 58

The central regulation of the food intake is organized by a long-loop mechanism involving humoral signals and afferent neuronal pathways to the hypothalamus, obligatory processing in hypothalamic neuronal circuits, and descending commands through vagal and spinal neurons to the body. Receptors sensitive to glucose metabolism, body fat reserves, distension of the stomach, as well as neuropeptide and cannabinoid receptors have been identified and localized in the hypothalamus. Five groups of cells in the hypothalamus--arcuate, paraventricular, ventromedial and dorsomedial nuclei, and the dorsolateral hypothalamic area--contain neurons with either anorexic actions (alpha-MSH, CART peptide, corticotropin-releasing hormone, urocortin III, cholecystokinin, glucagon-like peptides) or that stimulate food intake (neuropeptide Y, agouti-related peptide, orexins, melanin concentrating hormone, galanin). Intrahypothalamic neuronal circuits exist between these peptidergic neurons including the arcuate-paraventricular and arcuate-dorsolateral hypothalamic projections. Circulating substances carrying signals connected to changes in body food homeostasis and energy balance (leptin, ghrelin, insulin, glucose) enter the hypothalamus mainly through the arcuate nucleus. Neurons in the medulla oblongata that express leptin and insulin receptors, as well as neuropeptide mediators project to the hypothalamus. Vica versa, hypothalamic neurons give rise to projections to autonomic centers in the brainstem and the spinal cord with potential for stimulation or inhibition of food intake, energy balance and ingestion behavior.
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PMID:Hypothalamic regulation of food intake. 1460 50

The regulation of bodyweight is a complex process involving the interplay of neuronal circuitries controlling food intake and energy expenditure (thermogenesis) with endocrine secretions modulating the activity of the neurons making up those circuitries. The neurons controlling food intake and thermogenesis also modulate the hypothalamic-pituitary-adrenal axis, the role of which in the regulation of energy balance has been acknowledged for some time. These neurons secrete various neuromolecules or neuropeptides including endocannabinoids, neuropeptide Y, agouti-related protein, melanin-concentrating hormone, orexins (hypocretins), melanocortins, cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, corticotropin-releasing hormone, and urocortins. Among those peptides, neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, orexins, and endocannabinoids have been classified as being anabolic molecules whereas melanocortins, cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, and corticotropin-releasing hormone are referred to as catabolic peptides. The expression and secretion of these neuromolecules are known to be affected by the anabolic (corticosteroids and ghrelin) and catabolic (leptin, insulin, and glucagon-like peptide 1) peripheral hormones. A link is made between the pathways regulating energy balance and those modulating the activity of the hypothalamic-pituitary-adrenal axis.
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PMID:Circuitries involved in the control of energy homeostasis and the hypothalamic-pituitary-adrenal axis activity. 1533 Jun 75

Although the orexigenic action of peptide hormones such as ghrelin and growth hormone releasing peptide is different between chickens and mammals, the anorexigenic action of peptide hormones is similar in both species. For example, central administration of peptide hormones such as leptin, cholecystokinin or glucagon has been shown to suppress food intake behavior in chickens and mammals. Central administration of insulin suppresses food intake in mammals. However, the anorexigenic action of insulin in chickens has not yet been identified. In the present study, we investigated the effects of central administration of insulin on food intake in chicks. Intracerebroventricular administration of insulin in chicks significantly suppressed food intake. Central administration of insulin significantly upregulated mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART) and corticotropin-releasing factor (CRF), but did not influence mRNA levels of neuropeptide Y and agouti-related protein in the hypothalamus. These results suggest that alpha-melanocyte stimulating hormone (alpha-MSH, an anorexigenic peptide from the post-translational cleavage of POMC), CART and CRF are involved in the anorexigenic action of insulin in chicks. Furthermore, central administration of alpha-MSH or CART significantly suppressed food intake. In addition, alpha-MSH significantly upregulated CRF mRNA expression, suggesting that the anorexigenic action of alpha-MSH is mediated by CRF. Our findings demonstrate that insulin functions in chicks as an appetite-suppressive peptide in the central nervous system and suggest that this anorexigenic action is mediated by CART, alpha-MSH and CRF.
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PMID:Central administration of insulin suppresses food intake in chicks. 1769 22

Body mass--strictly speaking: the adipose tissue mass--is regulated in a feed-back system by the hypothalamus and brainstem, where adiposity signals (leptin, insulin, amylin) and intestinal peptides (ghrelin, PYY, PP, GLP-1, OXM, CCK) and the vagal nerve provide afferent information to the central controller on the size of white adipose tissue and the actual nutritional state, respectively. Two distinct groups of neurons in the arcuate nucleus accept and process the afferent information provided by leptin produced by white adipocytes in proportion to their mass. Leptin binding to the leptin-receptors on the surface of these neurons initiates intracellular signal transduction and activation of target genes, resulting in the synthesis and release of neuropeptides (POMC, CART) with anorectic effects. Secondary centers in the brain are also activated, and finally integrated effector mechanisms are generated in order to regulate the balance between energy intake and expenditure. The regulation of body weight is carried out by the central nervous system in a complex and redundant way, characterized by interconnections and overlaps with other neuroendocrine functions, such as growth, thyroid and adrenal function, memory, addictive and reward mechanisms. Targeting one or another component of this complicated system with drugs might result in interference with other systems and functions, so the occurrence of adverse events is probable. The worldwide epidemic of obesity--resulting mostly from the abundance of energy-dense foods and sedentary lifestyle coupled with a regulatory system unable to cope with this environment--has resulted in a continuous increase of research activities in both academic and industrial centers to develop new drugs and treatment strategies beyond lifestyle changes (diet, physical activity and behavioral therapy) to fight obesity more effectively.
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PMID:[The regulation of body mass and its relation to the development of obesity]. 1789 Jan 70

Appetite is regulated by a complex system of central and peripheral signals which interact in order to modulate the individual response to nutrient ingestion. Peripheral regulation includes satiety signals and adiposity signals, while central control is accomplished by several effectors, including the neuropeptidergic, monoaminergic and endocannabinoid systems. Satiety signals, including cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), originate from the gastrointestinal (GI) tract during a meal and, through the vagus nerve, reach the nucleus tractus solitarius (NTS) in the caudal brainstem. From NTS afferents fibers project to the arcuate nucleus (ARC), where satiety signals are integrated with adiposity signals, namely leptin and insulin, and with several hypothalamic and supra-hypothalamic inputs, thus creating a complex network of neural circuits which finally elaborate the individual response to a meal. As for the neuropeptidergic system, ARC neurons secrete orexigenic substances, such as neuropeptide Y (NPY) and agouti-related peptide (AGRP), and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Other brain areas involved in the control of food intake are located downstream the ARC: among these, the paraventricular nucleus (PVN), which produces anorexigenic peptides such as thyrotropin releasing hormone (TRH), corticotrophin releasing hormone (CRH) and oxytocin, the lateral hypothalamus (LHA) and perifornical area (PFA), secreting the orexigenic substances orexin-A (OXA) and melanin concentrating hormone (MCH). A great interest in endocannabinoids, important players in the regulation of food intake, has recently developed. In conclusion, the present work reviews the most recent insights into the complex and redundant molecular mechanisms regulating food intake, focusing on the most encouraging perspectives for the treatment of obesity.
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PMID:Neuroendocrine control of food intake. 1806 14

Intracerebroventricular (icv) administration of glucagon-like peptide-1 (GLP-1) inhibits food intake and induces c-fos expression in the hypothalamus. However, the effects of GLP-1 on hypothalamic neuronal activity or neuropeptide mRNA expression are unknown. In this study, we examined the effects of GLP-1 on fasting-induced changes in the expression of hypothalamic orexigenic and anorexigenic neuropeptide. Food intake was significantly inhibited after icv injection of GLP-1 in 48 h fasted rats. Hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNAs were significantly increased by fasting, whereas icv GLP-1 treatment significantly attenuated these fasting-induced increases. Both proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA levels were decreased by fasting, while GLP-1 treatment attenuated fasting-induced decreases in POMC and CART expression. We also determined the mRNA levels of AMP-activated kinase (AMPK) and found that fasting resulted in a significant stimulation of hypothalamic AMPKalpha2 mRNA. Fasting-induced increase in AMPKalpha2 mRNA was almost completely prevented by GLP-1 treatment. Analysis of phosphorylated AMPKalpha and acetyl CoA carboxylase showed similar results. Taken together, our observation suggests that the decreased food intake by GLP-1 is caused by preventing the fasting-induced increase in hypothalamic NPY and AgRP and the fasting-induced decrease in hypothalamic POMC and CART. Our results also suggest that the food intake lowering effect of GLP-1 is caused by reversing the fasting-induced increase in hypothalamic AMPK activity. Therefore we conclude that the anorectic effect of GLP-1 seems to be mediated by, at least in part, by the hypothalamus.
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PMID:Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. 1850 89

Pharmacological compounds enhancing serotonergic tone significantly decrease food intake and are among the most clinically efficacious treatments for obesity. However, the central mechanisms through which serotonergic compounds modulate feeding behavior have not been fully defined. The primary relay center receiving visceral gastrointestinal information in the central nervous system is the nucleus of the solitary tract (NTS) in the caudal brainstem. Here we investigated whether the classic anorectic serotonin receptor agonist m-chloro-phenylpiperazine (mCPP) enhances the activity of metabolically sensitive NTS neurons. Using c-fos immunoreactivity (FOS-IR) as a marker of neuronal activation in rats, we observed that mCPP significantly and dose-dependently activated a discrete population of caudal NTS neurons at the level of the area postrema (AP). In particular, this pattern of FOS-IR induction was consistent with the location of catecholamine-containing neurons. Dual-labeling performed with FOS-IR and the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) revealed that mCPP induced FOS-IR in 83.7% of TH-IR containing neurons in the NTS at the level of the AP. The degree of activation of TH neurons was strongly negatively correlated with food intake. Moreover, this activation was specific to catecholamine neurons, with negligible induction of cocaine- and amphetamine-regulated transcript (CART), cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), or neurotensin neurons. NTS catecholaminergic neurons relay visceral gastrointestinal signals to both the lateral hypothalamus (LHA) and paraventricular nucleus of the hypothalamus (PVH), where these signals are integrated into autonomic and hormonal responses regulating food intake. The data presented here identify a novel mechanism through which a serotonin receptor agonist acting in the caudal brainstem may regulate ingestive behavior.
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PMID:Distribution and neurochemical characterization of neurons within the nucleus of the solitary tract responsive to serotonin agonist-induced hypophagia. 1876 17


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