title: Diluted serum from calorie-restricted animals promotes mitochondrial β-cell adaptations and protect against glucolipotoxicity.
abstract: β-cells quickly adjust insulin secretion to oscillations in nutrients carried by the blood, acting as fuel sensors. However, most studies of β-cell responses to nutrients do not discriminate between fuel levels and signaling components present in the circulation. Here we studied the effect of serum from calorie-restricted rats versus serum from rats fed ad libitum, diluted tenfold in the medium, which did not contribute significantly to the pool of nutrients, on β-cell mitochondrial function and dynamics under regular and high-nutrient culture conditions. Insulin secreting beta-cell derived line (INS1) cells incubated with serum from calorie-restricted rats (CR serum) showed higher levels of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and active nitric oxide synthase. The expression of mitofusin-2 (Mfn-2) and optic atrophy 1 (OPA-1), proteins involved in mitochondrial fusion, was increased, while the levels of the mitochondrial fission mediator dynamin related protein 1 (DRP-1) were reduced. Consistent with changes in mitochondrial dynamics protein levels, CR serum treatment increased mitochondrial fusion rates, as well as their length and connectivity. These changes in mitochondrial morphology were associated with prolonged glucose-stimulated insulin secretion and mitochondrial respiration. When combining CR serum and high levels of glucose and palmitate (20 and 0.4 mm, respectively), an in vitro model of type II diabetes, we observed that signaling promoted by CR serum was enough to overcome glucolipotoxicity, as indicated by CR-mediated prevention of mitochondrial fusion arrest and reduced respiratory function in INS1 cells under glucolipotoxicity. Overall, our results provide evidence that non-nutrient factors in serum have a major impact on β-cell mitochondrial adaptations to changes in metabolism.
authors.affiliation: Department of Medicine, Boston University School of Medicine, MA, USA.|Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.|Departamento de Bioquímica, Universidade de São Paulo, Brazil.
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Cerqueira
authors.affiliation: Departamento de Bioquímica, Universidade de São Paulo, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Chausse
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.
authors.forename: Boris M
authors.initials: BM
authors.lastname: Baranovski
authors.affiliation: Department of Medicine, Boston University School of Medicine, MA, USA.|UCLA Section of Endocrinology, Department of Medicine, David Geffen School of Medicine, UCLA, CA, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
authors.affiliation: Department of Medicine, Boston University School of Medicine, MA, USA.|Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.|UCLA Section of Endocrinology, Department of Medicine, David Geffen School of Medicine, UCLA, CA, USA.
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.affiliation: Departamento de Bioquímica, Universidade de São Paulo, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D002460:Cell Line; D019069:Cell Respiration; D002469:Cell Separation; D034281:Dynamins / Q000378:metabolism; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020558:GTP Phosphohydrolases; C498811:Opa1 protein, rat; C519851:Dnm1l protein, rat; D034281:Dynamins; D005947:Glucose
keywords: caloric restriction; diabetes; mitochondrial dynamics; mitochondrial efficiency; mitochondrial morphology