Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice.
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.
Longo
Kenneth A
KA
Elixir Pharmaceuticals, Inc., 12 Emily St., Cambridge, MA 02139, United States. klongo@elixirpharm.com
Charoenthongtrakul
Soratree
S
Giuliana
Derek J
DJ
Govek
Elizabeth K
EK
McDonagh
Thomas
T
Qi
Yong
Y
DiStefano
Peter S
PS
Geddes
Brad J
BJ
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
D001786:Blood Glucose; D002784:Cholesterol; D004041:Dietary Fats; D006442:Glycated Hemoglobin; D007328:Insulin; D054440:Receptors, Ghrelin; D014280:Triglycerides