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Dlk1/FA1 Is a Novel Endocrine Regulator of Bone and Fat Mass and Its Serum Level Is Modulated by Growth Hormone

Department of Endocrinology (Clinic for Molecular Endocrinology Treatment Laboratory) (B.M.A., M.D., N.D., M.K.) and Orthopaedic Research Laboratory, Department of Orthopaedics (M.D.), Odense University Hospital, DK-5000 Odense, Denmark; Department of Immunology and Microbiology (C.H.J.), University of Southern Denmark, DK-5230 Odense, Denmark; The Medical Research Laboratories and Medical Department of Diabetes and Endocrinology (A.F.) and Medical Microbiology and Immunology (F.D.-H.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; Kennedy Institute (T.G.J.), National Eye Clinic, DK-2600 Glostrup, Denmark; and Novartis Institutes for BioMedical Research (J.A.G.), Pharma AG, CH-4002 Basel, Switzerland

Address all correspondence and requests for reprints to: Basem M. Abdallah, Ph.D., Department of Endocrinology and Metabolism, Odense University Hospital, Medical Biotechnology Center, University of South Denmark, DK-5000 Odense C, Denmark. E-mail: babdallah{at}health.sdu.dk.

Fat and bone metabolism are two linked processes regulated by several hormonal factors. Fetal antigen 1 (FA1) is the soluble form of dlk1 (delta-like 1), which is a member of the Notch-Delta family. We previously identified FA1 as a negative regulator of bone marrow mesenchymal stem cell differentiation. Here, we studied the effects of circulating FA1 on fat and bone mass in vivo by generating mice expressing high serum levels of FA1 (FA1 mice) using the hydrodynamic-based gene transfer procedure. We found that increased serum FA1 levels led to a significant reduction in total body weight, fat mass, and bone mass in a dose-dependent manner. Reduced bone mass in FA1 mice was associated with the inhibition of mineral apposition rate and bone formation rates by 58 and 72%, respectively. Because FA1 is colocalized with GH in the pituitary gland, we explored the possible modulation of serum FA1 by GH. Serum levels of IGF-I and IGF binding proteins did not change in FA1 mice, whereas increasing serum GH in normal mice using hydrodynamic-based gene transfer procedure dramatically reduced serum FA1 levels by 60%. Conversely, serum FA1 was increased 450% in hypophysectomized mice, and this high level was reduced by 40% during GH treatment. In conclusion, our data identify the FA1 as a novel endocrine factor regulating bone mass and fat mass in vivo, and its serum levels are regulated by GH. FA1 thus provides a novel class of developmental molecules that regulate physiological functions of the postnatal organisms.

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