Disease relevance of Ghrl

• Furthermore, adult Ghrl-/- mice display a normal sensitivity to high-fat diet-induced obesity [1].
• These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control [2].
• Administration of ghrelin increased IA-2beta mRNA in mouse brain, pancreas, and insulinoma cell lines (MIN6 and betaTC3) [3].
• Collectively, these data suggest that estradiol inhibits the orexigenic action of ghrelin in females, that weight gain associated with OVX is ghrelin mediated, and that this endocrine interaction may account for an important sex differences in food intake and the regulation of body weight [4].
• In diabetic ghrelin(-/-) mice, hyperphagia was attenuated, and the maximal increase in food intake was 50% lower in mutant than in wild-type mice [5].

Psychiatry related information on Ghrl

• For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity [2].
• Ghrelin and leptin are suggested to regulate energy homeostasis as mutual antagonists on hypothalamic neurons that regulate feeding behavior [6].
• Reductions in plasma glucose and leptin as well as rapid increases in plasma ghrelin were apparent in the neonate 4 h following maternal deprivation and maximal at 8 h [7].
• A single dose of ghrelin also restored the decreased locomotor activity in rats induced by cisplatin to almost the same level of saline-treated rats [8].
• In contrast, support for endocrine actions of leptin in satiation and of ghrelin in hunger is incomplete, and areas urgently requiring further research are identified [9].

High impact information on Ghrl

• Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion [10].
• Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight [10].
• Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance [10].
• Ghrelin induces adiposity in rodents [10].
• Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats [10].

Chemical compound and disease context of Ghrl

• Furthermore, OVX increased food intake and body weight in wild-type mice, but not in Ghsr(-/-) mice, suggesting that OVX increases food intake by releasing ghrelin from a tonic inhibitory effect of estradiol [4].
• Role of endogenous ghrelin in the hyperphagia of mice with streptozotocin-induced diabetes [5].
• CONCLUSIONS/INTERPRETATION: Ghrelin hampers insulin's capacity to suppress endogenous glucose production, whereas it reinforces the action of insulin on glucose disposal, independently of food intake and body weight [11].
• Chronic repeated treatment with 12 nmol/kg/day ghrelin for 7 days increased body weight and adiposity assessed by the weight of adipose tissue, triglyceride content in WAT (p<0.05 for each versus control) [12].
• Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans [13].

Biological context of Ghrl

• Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons [2].
• Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity [2].
• Gastric ghrelin gene expression was assessed by northern blot analysis [14].
• CONCLUSIONS: Ghrelin appears to be closely related to excess weight gain, adiposity, and insulin resistance, particularly under a high fat diet and in the dynamic stage [14].
• Ghrelin is an orexigenic peptide involved in the regulation of energy homeostasis [5].

Anatomical context of Ghrl

• Ghrelin and the GHS receptor are expressed also in pancreatic islets [3].
• Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin [15].
• GHS-R mRNA in hypothalamus and ghrelin mRNA in gastric fundus were quantified by RT-PCR [16].
• We report that ghrelin mRNA expression in the gastric fundus was increased, but that ghrelin peptide content decreased after a 48-h fast [17].
• Ghrelin treatment increased food intake, body weight and whole body fat at both low and high doses of ghrelin in normal controls, while tumor-bearing mice showed improved intake and body composition at the high dose of ghrelin only [16].

Associations of Ghrl with chemical compounds

• Our data demonstrate the link among ghrelin, IA-2beta, and glucose-stimulated insulin secretion [3].
• Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats [4].
• The potential physiological relevance of coexpression of these two receptors and the direct effect of ghrelin on dopamine signaling was investigated in vitro [18].
• Ghrelin rearranged synapses in wild type animals to support suppressed POMC tone, whereas the estradiol triggered a robust increase in the number of excitatory, glutamate inputs of POMC neurons [19].
• This was in accordance with enhanced 2-deoxyglucose uptake in muscle in ghrelin-treated animals [11].
• Glucose tolerance tests showed glucose levels to be significantly lower in FABP4-ghrelin transgenic mice than in controls after glucose administration [20].

Physical interactions of Ghrl

• Ghrelin is a novel gut-brain peptide that binds to the growth hormone secretagogue receptor (GHS-R), thereby functioning in the regulation of growth hormone (GH) release and food intake [17].

Regulatory relationships of Ghrl

• However, lack of both gastrin and CCK attenuated fasting-induced ghrelin expression and secretion [21].
• Ghrelin is a novel brain-gut peptide that stimulates food intake and may secondarily increase body weight via a growth hormone secretagogue receptor (GHS-R) [16].
• Hence, chronically, ghrelin controls glucose homeostasis by regulating pancreatic Ucp2 expression and insulin sensitivity [6].
• These findings strongly suggest that inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of IA-2beta induced by ghrelin [3].
• Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fasting-induced changes in serum levels of leptin and insulin are identical in wild-type and null mice [15].
• Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting [22].

Other interactions of Ghrl

• Overnight (12 h) fasting resulted in a significant suppression of circulating glucose, insulin, IGF-I, and leptin levels and an increase in corticosterone, free fatty acids, and n-octanoyl ghrelin levels, and these directional changes were maintained at the 24- and 48-h time points [23].
• Our results suggest that enhanced NPY and reduced alpha-MSH expression are secondary to the release of ghrelin, which should be considered the underlying trigger of hyperphagia associated with uncontrolled diabetes [5].
• We further demonstrate that ablation of ghrelin reduces expression of Ucp2 mRNA in the pancreas, which contributes toward enhanced glucose-induced insulin secretion [6].
• We have identified several ghrelin-induced genes by PCR-select subtraction methods, among which is a beta-cell autoantigen for type 1 diabetes, IA-2beta [3].
• However, the expression of IA-2, another structurally related beta-cell autoantigen, was not induced by ghrelin [3].

Analytical, diagnostic and therapeutic context of Ghrl

• Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses [24].
• These results suggest that ghrelin may protect the kidneys from ischemia/reperfusion injury and that this effect is related to an improvement of endothelial function through an IGF-1-mediated pathway [25].
• 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) [26].
• METHODS: : Food intake, oxygen consumption, gastric emptying, and hypothalamic neuropeptide Y (NPY) messenger RNA expression were measured after intra-third cerebroventricular or intraperitoneal injections of ghrelin in mice [27].
• RESULTS: : Ghrelin exhibited gastroprokinetic activity with structural resemblance to motilin and potent orexigenic activity through action on the hypothalamic neuropeptide Y (NPY) and Y(1) receptor, which was lost after vagotomy [27].

References