Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice

Regul Pept. 2008 Oct 9;150(1-3):55-61. doi: 10.1016/j.regpep.2008.03.011. Epub 2008 Mar 30.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Calorimetry, Indirect / methods
  • Cholesterol / metabolism
  • Dietary Fats / administration & dosage
  • Dietary Fats / metabolism*
  • Dietary Fats / pharmacology
  • Energy Metabolism / physiology*
  • Fasting
  • Glucose Tolerance Test
  • Glycated Hemoglobin A / analysis
  • Glycated Hemoglobin A / metabolism
  • Insulin / blood
  • Insulin Resistance / physiology*
  • Mice
  • Mice, Knockout
  • Receptors, Ghrelin / genetics*
  • Triglycerides / metabolism


  • Blood Glucose
  • Dietary Fats
  • Glycated Hemoglobin A
  • Insulin
  • Receptors, Ghrelin
  • Triglycerides
  • Cholesterol