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Fasting Unmasks a Strong Inverse Association between Ghrelin and Cortisol in Serum: Studies in Obese and Normal-Weight Subjects

Medical Research Laboratories (U.E., T.K.H., H.Ø., J.O.L.J., J.F.), Clinical Institute and Medical Department M, Aarhus University Hospital, DK-8000 Aarhus C, Denmark; Diabetes Research Centre (K.H., H.B.-N.), Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark; Department of Assay and Cell Technology (J.T.C.), Research and Development, Novo Nordisk A/S, DK-2880 Bagsværd, Denmark; and Biochemistry and Metabolism (B.S.H.), Novo Nordisk A/S, DK-2760 Måløv, Denmark

Address all correspondence and requests for reprints to: Jan Frystyk, M.D., Ph.D., D.M.Sc., Medical Research Laboratories, Aarhus University Hospital, Aarhus Sygehus, Building #3, Nørrebrogade 44, DK-8000 Aarhus C, Denmark. E-mail: jan{at}frystyk.dk.

Administration of ghrelin, the endogenous ligand for the GH secretagogue receptor, stimulates not only GH secretion but also appetite and food intake in humans. Endogenous ghrelin levels display a distinct circadian rhythm, which is reciprocal to that of insulin and presumed to be meal dependent and not associated with GH secretion. We tested the hypothesis that food deprivation could impact circadian serum ghrelin levels and unmask meal-independent regulatory mechanisms.

Thirty-three young adults, subdivided according to gender and level of obesity, were studied with blood sampling every 3 h from 12–84 h of fasting. Serum ghrelin levels showed a marked diurnal rhythm with a nadir in the morning (0800 h), peak levels in the afternoon, and a gradual decline during the night. This pattern was preserved during the entire fasting period and was independent of gender and obesity. Mean 24-h ghrelin levels exhibited a small but significant decline during the fast (P < 0.001). As expected, GH secretion increased with fasting in lean subjects, and a gradual decline in insulin concentrations was observed in all subjects. Neither GH nor insulin showed any significant relationship to ghrelin. In contrast, serum cortisol exhibited a strong inverse temporal association with ghrelin (r = –0.79; P < 0.0001).

In conclusion, our study yields no evidence that ghrelin stimulates GH release during fasting. As a novel finding, ghrelin appears to be related to cortisol. However, further studies are needed to elucidate the physiological mechanisms behind this relationship.

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