Obestatin regulates adipocyte function and protects against diet-induced insulin resistance and inflammation

Riccarda Granata, Davide Gallo, Raul M. Luque, Alessandra Baragli, Francesca Scarlatti, Cristina Grande, Iacopo Gesmundo, Jose Córdoba-Chacón, Loredana Bergandi, Fabio Settanni, Gabriele Togliatto, Marco Volante, Stefano Garetto, Marta Annunziata, Belén Chanclón, Eleonora Gargantini, Stefano Rocchietto, Lina Matera, Giacomo Datta, Mario MorinoMaria Felice Brizzi, Huy Ong, Giovanni Camussi, Justo P. Castaño, Mauro Papotti, Ezio Ghigo

Research output: Contribution to journalArticle

Abstract

The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mouse 3T3-L1 and in human subcutaneous (hSC) and omental (hOM) adipocytes. In vivo, the influence of obestatin on glucose metabolism was assessed in mice fed an HFD for 8 wk. 3T3-L1, hSC, and hOM preadipocytes and adipocytes secreted obestatin and showed specific binding for the hormone. Obestatin prevented apoptosis in 3T3-L1 preadipocytes by increasing phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. In both mice and human adipocytes, obestatin inhibited isoproterenol-induced lipolysis, promoted AMP-activated protein kinase phosphorylation, induced adiponectin, and reduced leptin secretion. Obestatin also enhanced glucose uptake in either the absence or presence of insulin, promoted GLUT4 translocation, and increased Akt phosphorylation and sirtuin 1 (SIRT1) protein expression. Inhibition of SIRT1 by small interfering RNA reduced obestatin-induced glucose uptake. In HFD-fed mice, obestatin reduced insulin resistance, increased insulin secretion from pancreatic islets, and reduced adipocyte apoptosis and inflammation in metabolic tissues. These results provide evidence of a novel role for obestatin in adipocyte function and glucose metabolism and suggest potential therapeutic perspectives in insulin resistance and metabolic dysfunctions.

Original languageEnglish
Pages (from-to)3393-3411
Number of pages19
JournalFASEB Journal
Volume26
Issue number8
DOIs
Publication statusPublished - Aug 2012

Keywords

  • Glucose uptake
  • High-fat diet
  • Lipolysis
  • PI3K/Akt and AMP-activated protein kinase
  • Sirtuin 1

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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  • Cite this

    Granata, R., Gallo, D., Luque, R. M., Baragli, A., Scarlatti, F., Grande, C., Gesmundo, I., Córdoba-Chacón, J., Bergandi, L., Settanni, F., Togliatto, G., Volante, M., Garetto, S., Annunziata, M., Chanclón, B., Gargantini, E., Rocchietto, S., Matera, L., Datta, G., ... Ghigo, E. (2012). Obestatin regulates adipocyte function and protects against diet-induced insulin resistance and inflammation. FASEB Journal, 26(8), 3393-3411. https://doi.org/10.1096/fj.11-201343