title: Pharmacologic inhibition of ghrelin receptor signaling is insulin sparing and promotes insulin sensitivity.
abstract: 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.
authors.affiliation: Elixir Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Longo
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Govek
authors.forename: Anna
authors.initials: A
authors.lastname: Nolan
authors.forename: Thomas
authors.initials: T
authors.lastname: McDonagh
authors.forename: Soratree
authors.initials: S
authors.lastname: Charoenthongtrakul
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Giuliana
authors.forename: Kristen
authors.initials: K
authors.lastname: Morgan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hixon
authors.forename: Chaoseng
authors.initials: C
authors.lastname: Zhou
authors.forename: Bruce
authors.initials: B
authors.lastname: Kelder
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Saunders
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Navia
authors.forename: Rory
authors.initials: R
authors.lastname: Curtis
authors.forename: Peter S
authors.initials: PS
authors.lastname: DiStefano
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Geddes
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004041:Dietary Fats / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D054439:Ghrelin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015309:Glucose Clamp Technique; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D004041:Dietary Fats; D054439:Ghrelin; D007328:Insulin; D054440:Receptors, Ghrelin