Disease relevance of Ghsr

• However, recent studies by Wortley et al. and Zigman et al. demonstrate that Ghrl-/- and Ghsr-/- mice are resistant to diet-induced obesity when fed a high-fat diet during the early post-weaning period [1].
• Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism [2].
• Ghrelin receptor agonists offer a treatment option for syndromes like anorexia nervosa, cancer cachexia, or AIDS wasting [3].
• We devised a method to selectively ablate these neurons in neonatal mice and then tested adult mice for their feeding responses to fasting, mild hypoglycemia, 2-deoxy-d-glucose and a ghrelin receptor agonist [4].

Psychiatry related information on Ghsr

• GHSR deletion also affected locomotor activity and levels of glycemia [5].

High impact information on Ghsr

• Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow [5].
• Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates [2].
• Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin [2].
• 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 [6].
• Neurons expressing the GHS-R exhibit green fluorescence and are clearly evident in the hypothalamus, hippocampus, cortex, and midbrain [7].

Biological context of Ghsr

• These metabolic effects are unlikely to be mediated by the GHS receptor [8].
• Our results indicate that MCG 101-bearing mice became ghrelin resistant despite upregulation of hypothalamic GHS-R expression, which confirms similar indirect observations in cancer patients [9].
• We found that [Trp3, Arg5]-ghrelin(1-5) (GSWFR), a novel pentapeptide composed of all L-amino acids, had affinity for the GHS receptor (IC50 = 10 microM) [10].
• Our results demonstrate that ghrelin inhibits adipogenesis by stimulation of cell proliferation via the mediation of a ghrelin receptor, likely a novel unidentified subtype [11].
• Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves [12].

Anatomical context of Ghsr

• When the arcuate nucleus (ARC) of the hypothalamus, a ghrelin receptor-rich region of the brain, was chemically ablated with monosodium glutamate (MSG), fasted mice failed to enter torpor (minimum T(b) = 31.6 +/- 0.6 degrees C) [13].
• GHS-R mRNA in hypothalamus and ghrelin mRNA in gastric fundus were quantified by RT-PCR [9].
• Ghrelin and the GHS receptor are expressed also in pancreatic islets [14].
• We observed ghrelin receptor expression in 3T3-L1 preadipocytes and adipocytes [15].
• Addition of ghrelin to culture media inhibited the development of two-cell embryos to the hatched blastocysts, and the inhibitory effects of ghrelin were abolished by an antagonist for the GHS-R [16].

Associations of Ghsr with chemical compounds

• Using immunohistochemistry in combination with green fluorescent protein fluorescence, we identified neurons that coexpress the dopamine receptor subtype 1 (D1R) and GHS-R [7].
• Because such adiposity was thought to be mediated by hypothalamic NPY neurons, we investigated by which mechanism a synthetic ghrelin receptor agonist, GHRP-2, would generate a positive energy balance in NPY-deficient [Npy(-/-) mice] and wild-type controls [3].
• The effect of atropine, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated [12].
• Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors [17].

Physical interactions of Ghsr

• 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 [18].

Regulatory relationships of Ghsr

• 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) [9].
• Repeated administration of GHS-R antagonist decreased body weight gain and improved glycaemic control in ob/ob obese mice [19].

Other interactions of Ghsr

• In addition, treating primary pituitary cell cultures from lean mice with insulin reduced GH release as well as GH, GHRH receptor, and ghrelin receptor mRNA levels compared with vehicle-treated controls, where the magnitude of suppression of pituitary mRNA levels was similar to that observed in the DIO mouse [20].
• Repeated administration of GHS-R antagonist was continued for six days in ob/ob obese mice [19].
• These observations demonstrate that NPY is not required for basal regulation of the GH axis, but is required for fasting-induced suppression of GHRH and SRIH expression, as well as fasting-induced augmentation of pituitary GHS-R mRNA [21].
• These changes were associated with increases in pituitary expression of GHRH-R and GHS-R and a concomitant suppression of sst2 [21].
• The results showed that ArKO/OVX mice have a low expression of pituitary GH, GHRH-R, GHS-R and Pit-1, and significantly reduced GH levels [22].

Analytical, diagnostic and therapeutic context of Ghsr

• To identify neurons that express the ghrelin receptor [GH secretagogue receptor (GHS-R)], we generated GHS-R-IRES-tauGFP mice by gene targeting [7].
• Immunohistochemical staining and Western blot analyses were used to identify GHS-R expression in the brain as well as its relationship to NPY expression in hypothalamic neurons [9].

References