title: Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice.
abstract: 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.
authors.affiliation: Elixir Pharmaceuticals, Inc., 12 Emily St., Cambridge, MA 02139, United States. klongo@elixirpharm.com
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Longo
authors.forename: Soratree
authors.initials: S
authors.lastname: Charoenthongtrakul
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Giuliana
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Govek
authors.forename: Thomas
authors.initials: T
authors.lastname: McDonagh
authors.forename: Yong
authors.initials: Y
authors.lastname: Qi
authors.forename: Peter S
authors.initials: PS
authors.lastname: DiStefano
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Geddes
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002153:Calorimetry, Indirect / Q000379:methods; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D005215:Fasting; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D054440:Receptors, Ghrelin / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002784:Cholesterol; D004041:Dietary Fats; D006442:Glycated Hemoglobin; D007328:Insulin; D054440:Receptors, Ghrelin; D014280:Triglycerides