Ghrelin does not orchestrate the metabolic changes seen in fasting but has significant effects on lipid mobilisation and substrate utilisation

Objective: Short-term fasting is associated with increased GH pulsatility and mobilisation of fats, but underlying mechanisms are unclear. We studied ghrelin's role during fasting and the effects of exogenous ghrelin on lipid mobilisation. Design: Randomised placebo-controlled study. Methods: In this study, ten controls (body mass index (BMI) 23.3 +/- 3.2), ten morbidly obese subjects (BMI 50.1 +/- 10.6) and six post-gastrectomy subjects (BMI 25.2 +/- 1.0) were fasted for 36 h undergoing regular blood sampling. On a separate occasion, subjects were infused with either i.v. ghrelin (5 pmol/kg per min) or saline over 270 min. Results: Obese and post-gastrectomy subjects had lower ghrelin compared with controls (ANOVA, P=0.02) during the fast. Controls and gastrectomy subjects showed a similar increase in GH pulsatility, circulating non-esterified fatty acids (NEFA) and 3 beta-hydroxybutyrate (3 HB). Obese subjects had an impaired GH response (P<0.001), reduced excursions of 3 HB (P=0.01) but no change in NEFA excursions (P=0.09) compared with controls. Ghrelin infusion increased GH, NEFA and ketone bodies (ANOVA, P<0.0001) in all the three groups, but GH response was impaired in the obese subjects (P=0.001). Ghrelin also induced a significant (ANOVA, P=0.004) biphasic NEFA response to meals in all the subjects. Conclusions: Despite low circulating ghrelin, gastrectomy subjects maintain a normal metabolic response to fasting, implying that ghrelin plays a minimal role. In contrast, infused ghrelin has significant effects on lipid mobilisation and induces a marked biphasic NEFA response to meals. Hence, ghrelin may play a significant role in meal-related substrate utilisation and metabolic flexibility.