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The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic B-Cell Survival and Insulin Secretion

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The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic B-Cell Survival and Insulin Secretion Diabetes Volume 66, November 2017 2849 The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic b-Cell Survival and Insulin Secretion Annalisa Natalicchio,1 Nicola Marrano,1 Giuseppina Biondi,1 Rosaria Spagnuolo,1 Rossella Labarbuta,1 Immacolata Porreca,2 Angelo Cignarelli,1 Marco Bugliani,3 Piero Marchetti,3 Sebastio Perrini,1 Luigi Laviola,1 and Francesco Giorgino1 Diabetes 2017;66:2849–2856 | https://doi.org/10.2337/db17-0002 This study explored the role of irisin as a new pancreatic correlate with markers of insulin resistance in subjects with- b-cell secretagogue and survival factor and its potential out diabetes, while they are reduced in overt type 2 diabetes role in the communication between skeletal muscle and (2,3). The biological functions of irisin include effects on pancreatic b-cells under lipotoxic conditions. Recombi- multiple tissues (1,4–7). Irisin also improves glucose toler- nant irisin stimulated insulin biosynthesis and glucose- ance and insulin sensitivity and increases energy expendi- stimulated insulin secretion (GSIS) in a PKA-dependent ture in both obese and diabetic mice (8). Irisin increases ISLET STUDIES – manner and prevented saturated fatty acid induced apo- proliferation of insulin-secreting INS-1E cells and protects b ptosis in human and rat pancreatic -cells, as well as in them from high glucose–induced apoptosis (9). human and murine pancreatic islets, via AKT/BCL2 signal- If chronically in excess, saturated free fatty acids (FFAs) ing. Treatment of myotubes with 0.5 mmol/L palmitate for can reduce insulin biosynthesis (10) and secretion (11) and 4 h, but not with oleate, promoted an increase in irisin promote b-cell apoptosis (12,13). Excessively high plasma release in the culture medium. Moreover, increased serum levels of FFAs, particularly long-chain saturated FFAs, also levels of irisin were observed in mice fed with a high-fat diet. Mouse serum rich in irisin and the conditioned medium foster insulin resistance (14). Palmitate can directly impair from myotubes exposed to palmitate for 4 h significantly insulin signaling in skeletal muscle cells (15) and alter the reduced apoptosis of murine pancreatic islets and insulin- expression of some myokines (16). secreting INS-1E cells, respectively, and this was abrogated Skeletal muscle, the major site of insulin-stimulated glucose fi in the presence of an irisin-neutralizing antibody. Finally, disposal (17), has recently been identi ed as a secretory organ in vivo administration of irisin improved GSIS and increased able to release myokines. It is thus plausible that this organ b-cell proliferation. In conclusion, irisin can promote might interact with the endocrine pancreas by releasing myo- b-cell survival and enhance GSIS and may thus participate kines that adjust insulin secretion to the actual insulin need in the communication between skeletal muscle and b-cells for appropriate peripheral glucose utilization (18,19). In this under conditions of excess saturated fatty acids. study, we have investigated the effects of irisin on pancreatic b-cells and the release of this myokine by skeletal muscle cells. Irisin is a newly discovered muscle-derived hormone, pro- RESEARCH DESIGN AND METHODS duced by cleavage of the membrane protein fibronectin type Animals III domain–containing protein 5 (FNDC5) and proposed to Animal experimentations were conducted after approval by bridge exercise with metabolic homeostasis (1). Irisin levels the Ethics Committee (CESA) of Istituto di Ricerche Genetiche 1Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, This article contains Supplementary Data online at http://diabetes Department of Emergency and Organ Transplantation, University of Bari Aldo .diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0002/-/DC1. Moro, Bari, Italy A.N. and N.M. contributed equally to the work. 2Istituto di Ricerche Genetiche “Gaetano Salvatore” (IRGS), Biogem, Ariano Irpino, © 2017 by the American Diabetes Association. Readers may use this article as Italy long as the work is properly cited, the use is educational and not for profit, and the 3Endocrinology and Metabolism of Transplantation, Azienda Ospedaliero Universi- work is not altered. More information is available at http://www.diabetesjournals taria Pisana, Pisa, Italy .org/content/license. Corresponding author: Francesco Giorgino, [email protected]. Received 1 January 2017 and accepted 12 July 2017. 2850 Irisin Effects on Pancreatic b-Cells Diabetes Volume 66, November 2017 Figure 1—Effects of irisin on palmitate-induced apoptosis in pancreatic b-cells. Rat (INS-1E) and human (1.1B4) b-cells and murine and human islets were treated or not with recombinant irisin (10–100 nmol/L) for 24 h and then incubated with or without 0.5 mmol/L palmitate for 24 h. A: Apoptosis was measured by assessing caspase-3 cleavage in INS-1E insulin-secreting cells (n = 11 independent experiments). Total caspase-3 is also shown. Densitometric analysis of the related bands was expressed as relative optical density, corrected using b-actin as a loading control and normalized against untreated control. B: Apoptosis was evaluated by measuring cytoplasmic oligonucleosomes with an ELISA assay (data expressed as percentage of untreated control) in INS-1E cells (n = 7 independent experiments), murine islets (n = 3 independent experiments), 1.1B4 human pancreatic cells (n = 9 independent experiments), and human islets (n = 3 independent experiments). C: Apoptosis was evaluated by a TUNEL assay. Left: Representative confocal images of murine islets (islets from n = 3 different isolations for each condition) treated as described above and subsequently immunostained for insulin (green) and apoptosis by TUNEL (red). Nuclear staining was performed with TO-PRO-3 (blue). Right: TUNEL-positive cells normalized for total cell number. D: AKT phosphorylation was measured by immunoblotting and quantified by densitometry (n = 6 independent experiments) in INS-1E cells treated with 100 nmol/L recombinant irisin for different times. Densitometric analysis of the related bands was expressed as relative optical density, corrected using total ΑΚΤ as a loading control and normalized against untreated control. E: BCL2 and BAX protein content was measured by immunoblotting and quantified by densitometry in INS-1E cells. The BCL2-to-BAX ratio was also calculated (n = 8 independent experiments). F and G: INS-1E cells were treated or not with diabetes.diabetesjournals.org Natalicchio and Associates 2851 “Gaetano Salvatore” (IRGS), Biogem, Italy (internal ID 0907) TMR red (Roche Biochemicals, Indianapolis, IN) and by in accordance with the Guide for the Care and Use of Lab- assessing caspase-3 cleavage. Proliferation was assessed with oratory Animals (National Institutes of Health publication the BrdU ELISA kit (colorimetric) (Abcam, Cambridge, U.K.). no. 85-23, revised 1985) and regulations of Italy and the EU. Irisin and Insulin Assays CD-1 and C57BL/6 mice were purchased from Charles River Irisin concentrations were measured using an irisin-competitive Laboratories (Calco, Lecco, Italy). The high-fat diet (HFD) (60% ELISA kit (AdipoGen SA, Liestal, Switzerland). Insulin levels of energy from fat) was from Mucedola (Settimo Milanese, were measured by specific ELISA (Mercodia AB, Sylveniusgatan, Milan, Italy) (formulation given in Supplementary Table 1). Uppsala, Sweden). Glucose-stimulated insulin secretion In Vivo Irisin Administration (GSIS) was performed as previously described (13). More Eighteen male 6-week-old C57BL/6 mice were randomized details are given in Supplementary Data. intothreegroups:6micewereimmediatelysacrificed; the remaining mice were intraperitoneally injected daily with irisin Statistical Analyses t (0.5 mg/gbodywt)orvehicle(PBS)for14days.Intraperi- Data were analyzed by the Student test or ANOVA, as 6 toneal glucose tolerance tests were carried out, and then appropriate, and are presented as mean SD. Statistical fi P , animals were sacrificed.Pancreas,serum,andplasmawere signi cance was set at value 0.05. collected. RESULTS Pancreatic Islets and Cell Culture Mouse and human islets were isolated and cultured as Irisin Prevents Palmitate-Induced b-Cell Apoptosis previously described (20,21). More details on cell lines and and Induces Insulin Secretion culture conditions are given in Supplementary Data. INS-1E cells treated with 0.5 mmol/L palmitate for 24 h Palmitate and oleate were obtained from Sigma-Aldrich showed increased caspase-3 cleavage, as expected. However, (St. Louis, MO) and prepared as previously reported (13). pretreatment with recombinant irisin for 24 h reduced this All controls were treated with the same volume of 10% response in a dose-dependent manner. A similar effect was fatty acid–free BSA solution without palmitate or oleate. observed in human pancreatic 1.1B4 cells and in murine A B fl Cells were preincubated with recombinant irisin and human pancreatic islets (Fig. 1 and ). Immuno uo- fi b (AdipoGen SA, Liestal, Switzerland) for the indicated rescence of murine islets con rmed that -cells showed doses and times. The chemical inhibitors AKT Inhibitor increased apoptosis in response to palmitate and that this C VIII (2.5 mmol/L) or H-89 (5 mmol/L) (Calbiochem; Merck was counteracted by irisin (Fig. 1 ). Since treatment of Millipore, Darmstadt, Germany)wereadded30minor INS-1E cells with irisin increased AKT phosphorylation (Fig. D 60 min before irisin. 1 ), which is known to upregulate B-cell lymphoma 2 (BCL2) expression
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