substance-p--phe(5)-trp(7-9)-leu(11)- and Obesity

Ghrelin is a peptide hormone secreted into circulation from the stomach. It has been postulated to act as a signal of hunger. Ghrelin administration acutely increases energy intake in lean and obese humans and chronically induces weight gain and adiposity in rodents. Circulating ghrelin levels are elevated by fasting and suppressed following a meal. Inhibiting ghrelin signaling therefore appears an attractive target for anti-obesity therapies. A number of different approaches to inhibiting the ghrelin system to treat obesity have been explored. Despite this, over a decade after its discovery, no ghrelin based anti-obesity therapies are close to reaching the market. This article discusses the role of ghrelin in appetite control in humans, examines different approaches to inhibiting the ghrelin system and assesses their potential as anti-obesity therapies.

Topics: Acyltransferases; Adipose Tissue; Adiposity; Animals; Antibodies, Neutralizing; Appetite; Appetite Regulation; Eating; Fasting; Ghrelin; Humans; Hunger; Mice; Obesity; Peptide Hormones; Peptide YY; Peptides; Rats; Receptors, Ghrelin; Satiety Response; Substance P; Weight Gain

New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.

Topics: Animals; Anti-Obesity Agents; Appetite Regulation; Drug Design; HEK293 Cells; High-Throughput Screening Assays; Humans; Mice; Niacinamide; Obesity; Rats; Receptors, Ghrelin; Structure-Activity Relationship

Obesity is a risk factor for poor outcomes after trauma, and circulating levels of ghrelin are decreased in obese patients. We hypothesized that ghrelin modifies microvascular permeability. The purposes of this study were to determine (1) the effect of ghrelin on microvascular permeability, (2) the effect of ghrelin on microvascular permeability during lipopolysaccharide (LPS)-induced inflammation, (3) the involvement of the growth hormone secretagogue receptor (GHS-R1a) cell receptor, and (4) the involvement of nuclear factor kappa B (NF-kappaB).. Hydraulic permeability (Lp), a measure of transendothelial fluid leak, was measured in rat mesenteric postcapillary venules. Lp was measured during continuous administration of (1) ghrelin (3 micromol/L), (2) ghrelin and systemic LPS (10 mg/kg), (3) the GHS-R1a receptor antagonist, (D-Arg1 D-Phe5 D-Trp7,9 Leu11)-substance P (9 micromol/L) plus ghrelin and LPS, and (4) an NF-kappaB inhibitor, parthenolide (10 micromol/L) plus ghrelin and LPS.. Ghrelin alone had no effect (p > 0.7). Compared with LPS alone, ghrelin plus LPS decreased Lp (Lp: ghrelin + LPS = 1.60 +/- 0.16 vs. LPS = 2.27 +/- 0.14, p < 0.006). The GHS-R1a ghrelin receptor antagonist blunted the effect of ghrelin by 86% during LPS-induced inflammation (Lp: ghrelin + LPS = 1.60 +/- 0.16 vs. ghrelin antagonist + ghrelin + LPS = 2.17 +/- 0.27, p < 0.018). NF-kappaB inhibition did not influence the initial increased microvascular leak effect of ghrelin (p > 0.8).. Although ghrelin has no effect on basal microvascular permeability, it has a biphasic effect with an overall decrease in microvascular permeability during LPS-induced inflammation through the GHS-R1a receptor, independent of NF-kappaB. Ghrelin is a key mediator of inflammation and may contribute to the increased morbidity and mortality in obese trauma patients.

Topics: Animals; Capillary Permeability; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Ghrelin; Lipopolysaccharides; Mesentery; NF-kappa B; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Sesquiterpenes; Signal Transduction; Substance P; Systemic Inflammatory Response Syndrome; Venules; Wounds and Injuries