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Liver-Derived IGF-I Regulates GH Secretion at the Pituitary Level in Mice

Research Centre for Endocrinology and Metabolism (K.W., K.S., V.W., O.I., C.O., J.-O.J.), Sahlgrenska University Hospital, Göteborg SE-413 45, Sweden; Department of Medicine (X.-D.P., S.P., L.F., R.K.), Section of Endocrinology and Metabolism, University of Illinois, Chicago, Illinois 60612; Department of Medicine (J.-L.L.), McGill University, Montréal QCH3A1A1, Canada; AstraZeneca R & D (M.U., H.W.), SE-43183 Mölndal, Sweden

Address all correspondence and requests for reprints to: John-Olov Jansson, Research Centre for Endocrinology and Metabolism, Gröna stråket 8, SE-413 45 Göteborg, Sweden. E-mail: john-olov.jansson{at}medic.gu.se

We have reported that liver-specific deletion of IGF-I in mice (LI-IGF-I-/-) results in decreased circulating IGF-I and increased GH levels. In the present study, we determined how elimination of hepatic IGF-I modifies the hypothalamic-pituitary GH axis to enhance GH secretion. The pituitary mRNA levels of GH releasing factor (GHRF) receptor and GH secretagogue (GHS) receptor were increased in LI-IGF-I-/- mice, and in line with this, their GH response to ip injections of GHRF and GHS was increased. Expression of mRNA for pituitary somatostatin receptors, hypothalamic GHRF, somatostatin, and neuropeptide Y was not altered in LI-IGF-I-/- mice, whereas hypothalamic IGF-I expression was increased. Changes in hepatic expression of major urinary protein and the PRL receptor in male LI-IGF-I-/- mice indicated an altered GH release pattern most consistent with enhanced GH trough levels. Liver weight was enhanced in LI-IGF-I-/- mice of both genders. In conclusion, loss of liver-derived IGF-I enhances GH release by increasing expression of pituitary GHRF and GHS receptors. The enhanced GH release in turn affects several liver parameters, in line with the existence of a pituitary-liver axis.

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