Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.
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PMID:Genetic linkage and association of the growth hormone secretagogue receptor (ghrelin receptor) gene in human obesity. 1561 37

Obesity is a multi-gene syndrome, expression of which is modulated not only by environmental factors but above all by a number of modified genes interacting with each other. Among candidate genes related to obesity phenotype is ghrelin gene. Ghrelin plays a significant role in feeding regulation and is the strongest stimulator of growth hormone secretion. Ghrelin acts by GHS1a receptor (growth hormone secretagogue receptor). Mutations in preproghrelin and ghrelin gene or ghrelin receptor gene could be responsible for low ghrelin levels observed in obese individuals. Among identificated mutations, two Arg51 Gln and Leu72Met are most often described and change amino-acid sequence of ghrelin (Arg51Gln) and preproghrelin (Leu72Met). Although no direct relationship between Arg51Gln mutation and obesity phenotype was found, it had been shown that carriers of Arg51Gln mutation had significantly decreased plasma ghrelin levels. Furthermore 51Gln allele carriers had higher prevalence of type 2 diabetes mellitus and hypertension than non-carriers. Met 72 carrier status is associated with higher serum IGF-1 levels and seems to be a protective factor against fat accumulation and cardiovascular complications of obesity. No evidence of relationship between ghrelin receptor gene polymorphisms and body mass regulation was found, however, until now there is no study on relationships between these polymorphisms and metabolic complications of obesity. The presence of genetic variants in ghrelin or GHS receptor gene could be responsible for impaired GH secretion in visceral type obesity and development of metabolic syndrome in some of obese subjects. On the other hand, some mutations in preproghrelin gene could be protective against metabolic syndrome.
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PMID:[Preproghrelin gene, ghrelin receptor and metabolic syndrome]. 1622 41

Over the past decade, hypothalamic circuits have been described that impact energy homeostasis in rodents and humans. Our drug development efforts for the treatment of obesity and the metabolic syndrome have largely focused on selected genetic and/or pharmacologically validated pathways. The translation of these pathways into therapeutics for the treatment of obesity will find its first clinical successes over the coming decade. Initial efforts have focused on gaining a better understanding of the relevance of rodent pharmacological and genetic observations for the development of therapeutics for the treatment of human obesity. We pursue pathways defined by the expression of the ghrelin receptor, melanin-concentrating hormone receptors, melanocortin receptors, cannabinoid receptors and neuropeptide Y1 and Y5 receptors. In this review, we will discuss drug development efforts for the treatment of obesity, focused on selective melanocortin 4 receptor agonists and neuropeptide Y1 and Y5 receptor antagonists. These drug development efforts required an in-depth understanding of cell-based observations which drive the development of compound structure-activity relationships. These include understanding of receptor function in selected cell-based backgrounds and early evaluation and validation of ex vivo observations in appropriate in vivo models. In order to develop selective and safe anti-obesity drugs, diverse approaches are needed to increase the likelihood of clinical success, including: (i) developing a detailed understanding of the predictive value of rodent pathways for treatment of human disease; (ii) knowledge of the exact location of targeted receptor subtypes for the clinical indication under study in order to derive a suitable compound profile; (iii) predictive measures of in vivo and/or ex vivo receptor occupancy required to bring about a desired physiological effect; (iv) predictive parameters that outline that the drug-derived effects are safe and mechanism-based; and (v) the refinement of selected compound classes, aimed at their clinical use.
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PMID:Design and synthesis of (ant)-agonists that alter appetite and adiposity. 1687 70

Ghrelin is an orexigenic peptide hormone secreted by the stomach. In patients with metabolic syndrome and low ghrelin levels, intra-arterial ghrelin administration acutely improves their endothelial dysfunction. Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase (eNOS) in vascular endothelium, resulting in increased production of nitric oxide (NO) using signaling pathways shared in common with the insulin receptor. Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells (BAEC) in primary culture (assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time- and dose-dependent manner. Production of NO in response to ghrelin (100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with NG-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys3)-GHRP-6 (selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering (si) RNA (but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser473) and eNOS (Akt phosphorylation site Ser1179) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. Ghrelin also stimulated phosphorylation of mitogen-activated protein (MAP) kinase in BAEC. However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI 3-kinase, Akt, and eNOS. Our findings may be relevant to developing novel therapeutic strategies to treat diabetes and related diseases characterized by reciprocal relationships between endothelial dysfunction and insulin resistance.
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PMID:Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. 1710 60

Polycystic ovary syndrome (PCOS) is commonly associated with insulin resistance, obesity, dyslipidemia and hypertension. Adiponectin, an adipocyte-specific protein with important roles in glucose and lipid homeostasis, possesses antidiabetic and insulin-sensitizing properties. Ghrelin, a protein ligand for the growth hormone secretagog receptor, has been shown to stimulate food intake and to influence energy balance, insulin signaling and glucose metabolism. We aimed to evaluate the relationships between metabolic alterations and adiponectin and ghrelin levels in lean PCOS women, compared with lean and obese women. The study was carried out on 20 non-obese PCOS women aged 20 - 48 years and age-matched groups of 45 healthy lean and 37 obese women. Hormonal and biochemical parameters, adiponectin and ghrelin concentrations and anthropometric data were determined. In PCOS subjects, we found increased homeostasis model assessment - insulin resistance index (HOMA-IR) with non-significant differences in adiponectin and ghrelin concentrations compared with healthy women, although the PCOS group showed a tendency to lower adiponectin levels. However, ghrelin levels in PCOS women were significantly higher than in obese women. Moreover, we observed a negative correlation between adiponectin and testosterone, cholesterol, triglycerides, glucose and diastolic blood pressure in PCOS. In conclusion, it can be suggested that higher values of HOMA-IR with lower adiponectin levels may indicate future development of metabolic syndrome or other metabolic disturbances in lean PCOS women.
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PMID:The relationship between metabolic status and levels of adiponectin and ghrelin in lean women with polycystic ovary syndrome. 1761 56

Metabolic syndrome accelerates the atherosclerotic process, and the earliest event of which is endothelial dysfunction. Ghrelin, a newly discovered gastric peptide, improves endothelial function and inhibits proatherogenic changes. In particular, low ghrelin concentration has been associated with several features of metabolic syndrome, including obesity, insulin resistance, and high blood pressure. However, the molecular mechanisms underlying ghrelin vascular actions remain largely unclear. Here, we showed that ghrelin activated endothelial nitric oxide (NO) synthase (eNOS) in cultured endothelial cells (ECs) and in intact vessels. Specifically, ghrelin rapidly induced phosphorylation of eNOS on an activation site and production of NO in human umbilical vein ECs and bovine aortic ECs. The eNOS phosphorylation was also observed in mouse aortas ex vivo perfused with ghrelin and in aortic tissues isolated from mice injected with ghrelin. Mechanistically, ghrelin stimulated AMP-activated protein kinase (AMPK) and Akt activation in cultured ECs and intact vessels. Inhibiting AMPK and Akt with their pharmacological inhibitors, small interference RNA and adenoviruses carried dominant-negative mutants, markedly attenuated ghrelin-induced eNOS activation, and NO production. Furthermore, ghrelin receptor/Gq protein/calcium-dependent pathway mediates activation of AMPK, Akt, and eNOS, and calmodulin-dependent kinase kinase is a potential convergent point to regulate Akt and AMPK activation in ghrelin signaling. Importantly, eNOS activation is critical for ghrelin inhibition of vascular inflammation. Together, both in vitro and in vivo data demonstrate a new role of ghrelin signaling for eNOS activation, and highlight the therapeutic potential for ghrelin to correct endothelial dysfunction associated with atherosclerotic vascular diseases and metabolic syndrome.
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PMID:Molecular mechanisms of ghrelin-mediated endothelial nitric oxide synthase activation. 1845 Sep 53

Stimulation of the ghrelin receptor (GhrR) by ghrelin results in a variety of metabolic changes including increased food intake, fat storage and insulin resistance. Loss of ghrelin signaling is protective against diet-induced obesity, suggesting that ghrelin plays a significant homeostatic role in conditions of metabolic stress. We examined glycemic control in GhrR -/- mice fed a high-fat diet, and used indirect calorimetry to assess fuel substrate usage and energy expenditure. GhrR -/- mice fed a high-fat diet had several measures of greater insulin sensitivity, including: lower fasted blood glucose and plasma insulin, lower %Hb(A1c), lower insulin levels during glucose tolerance tests, and improved performance in hyperinsulinemic-euglycemic and hyperglycemic clamp studies. GhrR -/- mice fed a high-fat diet did not develop hepatic steatosis and had lower total cholesterol, relative to controls. Furthermore, GhrR -/- mice demonstrated a lower intestinal triglyceride secretion rate of dietary lipid. GhrR -/- mice have higher respiratory quotients (RQ), indicating a preference for carbohydrate as fuel. The range of RQ values was wider in GhrR -/- mice, indicating greater metabolic flexibility and insulin sensitivity in these animals. We therefore propose that loss of ghrelin signaling promotes insulin sensitivity and metabolic flexibility, and protects against several fatty diet-induced features of metabolic syndrome due to convergent changes in the intake, absorption and utilization of energy.
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PMID:Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice. 1845 14

Ghrelin is a gut-brain peptide that has somatotropic, food intake increasing and adipogenic effects. Ghrelin is involved in modulating insulin and glucose metabolism in rodents according to recent studies. In humans acylated ghrelin reduces insulin sensitivity while unacylated ghrelin has opposite effects. In general, ghrelin seems to have diabetogenic effects. Obese, in particular abdominally obese, subjects have low ghrelin levels and decreased total ghrelin levels have been associated with metabolic syndrome and Type 2 diabetes. Most of the human studies in Type 1 diabetes have reported low ghrelin levels probably as a compensatory mechanism against hyperglycaemia. The data on obestatin in the regulation of energy balance is extremely contradictory. Interestingly, ghrelin receptor antagonists may improve glucose tolerance in rats without inducing weight gain by increasing insulin secretion. Antagonism of ghrelin function to treat diabetes is thus a fascinating idea. This review concentrates on recent findings on the orexigenic peptide ghrelin and its derivatives in metabolic disorders with emphasis put on human studies.
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PMID:Ghrelin and metabolic disorders. 1927 67

The ghrelin-ghrelin receptor system is one of the most important mechanisms regulating energy balance and metabolism. Among other actions, central and peripheral administration of ghrelin increases food intake and adiposity. During the last years, many efforts have been made in the investigation of the cellular and molecular mechanisms modulating the effects of ghrelin. One particularity of this peptide hormone is its acylation at serine-3 with an eight-carbon fatty acid (octanoate), which confers its biological activity. Recent reports have demonstrated that the ghrelin O-acyltransferase (GOAT) is the enzyme that catalyzes ghrelin octanoylation. Therefore, all questions concerning the posttranslational acylation of ghrelin are of great interest for the complete understanding of this system. In this review, we summarize the discovery and characterization of GOAT, and remark the importance of GOAT as a novel and potential target that regulates the biological actions of ghrelin, revealing several therapeutical possibilities for the treatment of the metabolic syndrome.
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PMID:GOAT: the master switch for the ghrelin system? 2042 34

Ghrelin influences a variety of metabolic functions through a direct action at its receptor, the GhrR (GhrR-1a). Ghrelin knockout (KO) and GhrR KO mice are resistant to the negative effects of high-fat diet (HFD) feeding. We have generated several classes of small-molecule GhrR antagonists and evaluated whether pharmacologic blockade of ghrelin signaling can recapitulate the phenotype of ghrelin/GhrR KO mice. Antagonist treatment blocked ghrelin-induced and spontaneous food intake; however, the effects on spontaneous feeding were absent in GhrR KO mice, suggesting target-specific effects of the antagonists. Oral administration of antagonists to HFD-fed mice improved insulin sensitivity in both glucose tolerance and glycemic clamp tests. The insulin sensitivity observed was characterized by improved glucose disposal with dramatically decreased insulin secretion. It is noteworthy that these results mimic those obtained in similar tests of HFD-fed GhrR KO mice. HFD-fed mice treated for 56 days with antagonist experienced a transient decrease in food intake but a sustained body weight decrease resulting from decreased white adipose, but not lean tissue. They also had improved glucose disposal and a striking reduction in the amount of insulin needed to achieve this. These mice had reduced hepatic steatosis, improved liver function, and no evidence of systemic toxicity relative to controls. Furthermore, GhrR KO mice placed on low- or high-fat diets had lifespans similar to the wild type, emphasizing the long-term safety of ghrelin receptor blockade. We have therefore demonstrated that chronic pharmacologic blockade of the GhrR is an effective and safe strategy for treating metabolic syndrome.
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PMID:Pharmacologic inhibition of ghrelin receptor signaling is insulin sparing and promotes insulin sensitivity. 2177 75


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