title: Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid-induced apoptosis.
abstract: As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators β-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for β-cell function associated with T2D and obesity in humans is macrophage migration inhibitory factor (MIF). Therefore, the aim of this study was to explore MIF expression in vivo during development of obesity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 mice and whether MIF inhibition could affect β-cell apoptosis and dysfunction induced by palmitic acid (PA) in vitro. Indeed, increase in systemic and locally produced MIF correlated well with the weight gain, triglyceride upregulation, glucose intolerance and insulin resistance, which developed in HFD-fed mice. In in vitro settings PA dose-dependently induced MIF secretion before apoptosis development in islets. Further, mif gene deletion, mRNA silencing or protein inhibition rescued β-cells from PA-induced apoptosis as measured by MTT assay and histone-DNA enzyme linked immuno sorbent assay. Protection from induced apoptosis was mediated by altered activation of caspase pathway and correlated with changes in the level of Bcl-2 family members. Further, MIF inhibition conveyed a significant resistance to PA-induced downregulation of insulin and PDX-1 expression and ATP content. However, β-cell function was not entirely preserved in the absence of MIF judging by low glucose oxidation and depolarized mitochondrial membrane. In conclusion, the observed considerable preservation of β-cells from nutrient-induced apoptosis might implicate MIF as a potential therapeutic target in the later stage of obesity-associated T2D.
authors: Department of Immunology, Institute for Biological Research Sinisa Stankovic, University of Belgrade, Belgrade, Serbia.
authors: Tamara
authors: T
authors: Saksida
authors: Stanislava
authors: S
authors: Stosic-Grujicic
authors: Gordana
authors: G
authors: Timotijevic
authors: Stellan
authors: S
authors: Sandler
authors: Ivana
authors: I
authors: Stojanovic
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019308:Palmitic Acid / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D001786:Blood Glucose; D007328:Insulin; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D014280:Triglycerides; D051028:bcl-2-Associated X Protein; D019308:Palmitic Acid; D053453:Caspase 9