BACKGROUND: The gut hormone, ghrelin, acts on neuropeptide Y neurons in the arcuate nucleus of the hypothalamus and stimulates food intake to control energy balance. However, recent evidence suggests that peripheral ghrelin regulates glucose metabolism. Here, we designed experiments to examine how central acyl ghrelin infusion affects peripheral glucose metabolism under pairfed or ad libitum feeding conditions.
METHOD: Three groups of mice received either ICV infusion of aCSF, ghrelin and allowed to eat ad libitum (Gh-lib) or ghrelin and pairfed to the average of the aCSF group (Gh-pf). Mini pumps delivered acyl ghrelin at a dose of 0.25 µg/hour at 0.5 µl/hour for 7 days.
RESULTS: There was no difference in daily fed blood glucose, insulin, glucagon, triglycerides or non-esterified fatty acids between the groups. Body weight gain and food intake was significantly higher in Gh-lib mice compared to aCSF and Gh-pf. However, both Gh-lib and Gh-pf groups exhibited heavier white adipose mass, independent of body weight and food intake. Gh-pf mice exhibited a state of negative energy balance, as hypothalamic NPY and AgRP mRNA expression was increased in Gh-pf mice relative to aCSF or Gh-lib. Gh-pf mice exhibited better glucose tolerance than aCSF or Gh-lib mice during a GTT, although both Gh-lib and Gh-pf increased insulin release during the GTT. Central acyl ghrelin infusion and pairfeeding also increased breakdown of liver glycogen and triglyceride, and regulated genes involved in hepatic lipid and glucose metabolism. Gh-pf mice had an increase in plasma blood glucose during a pyruvate tolerance test in relative to Gh-lib or aCSF mice. Our results suggest that under conditions of negative energy (Gh-pf mice) central acyl ghrelin engages a neural circuit that influences hepatic glucose function.
CONCLUSION: Metabolic status affects the ability of central acyl ghrelin to regulate peripheral glucose homeostasis.