Obestatin Promotes Survival of Pancreatic β-Cells and Human Islets and Induces Expression of Genes Involved in the Regulation of β-Cell Mass and Function

Obestatin Promotes Survival of Pancreatic β-Cells and Human Islets and Induces Expression of Genes Involved in the Regulation of β-Cell Mass and Function Riccarda Granata 1 2 , Fabio Settanni 1 2 , Davide Gallo 1 2 , Letizia Trovato 1 2 , Luigi Biancone 2 , Vincenzo Cantaluppi 2 , Rita Nano 3 , Marta Annunziata 1 2 , Pietro Campiglia 4 , Elisa Arnoletti 5 , Corrado Ghè 5 , Marco Volante 6 , Mauro Papotti 6 , Giampiero Muccioli 5 and Ezio Ghigo 2 1 Laboratory of Molecular and Cellular Endocrinology, Department of Internal Medicine, University of Turin, Turin, Italy 2 Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy 3 Department of Medicine, Transplant Unit, Scientific Institute San Raffaele, Vita-Salute University, Milan, Italy 4 Department of Pharmaceutical Sciences, University of Salerno, Fisciano (Salerno), Italy 5 Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, Turin, Italy 6 Department of Clinical and Biological Sciences and San Luigi Hospital, University of Turin, Turin, Italy Address correspondence and reprint requests to Riccarda Granata, PhD, Laboratory of Molecular and Cellular Endocrinology, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti, 14-10126 Turin, Italy. E-mail: riccarda.granata{at}unito.it Abstract OBJECTIVE— Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of β-cells and human pancreatic islets and the underlying signaling pathways. RESEARCH DESIGN AND METHODS— β-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression. RESULTS— Obestatin showed specific binding on HIT-T15 and INS-1E β-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-γ/tumor necrosis factor-α/interleukin-1β treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys 3 ]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in β-cells and human islets. β-Cells and islet cells released obestatin, and addition of anti-obestatin antibody reduced their viability. Obestatin increase