Transient NADPH oxidase 2-dependent H2O2 production drives early palmitate-induced lipotoxicity in pancreatic islets

Autor(es)

Vilas-Boas, Eloisa Aparecida ^{[1, 2]} ; Nalbach, Lisa ^[3] ; Ampofo, Emmanuel ^[3] ; Lucena, Camila Ferraz ^[1] ; Naudet, Lea ^[2] ; Ortis, Fernanda ^[4] ; Carpinelli, Angelo Rafael ^[1] ; Morgan, Bruce ^[5] ; Roma, Leticia Prates ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo, SP - Brazil

^[2] Saarland Univ, Ctr Human & Mol Biol ZHMB, Dept Biophys, Homburg - Germany

^[3] Saarland Univ, Inst Clin & Expt Surg, Homburg - Germany

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, Sao Paulo, SP - Brazil

^[5] Saarland Univ, Ctr Human & Mol Biol ZHMB, Inst Biochem, Saarbrucken - Germany

• Tipo de documento: Artigo Científico
• Fonte: Free Radical Biology and Medicine; v. 162, JAN 2021.
• Citações Web of Science: 0

Resumo

Modern lifestyles, including lack of physical activity and poor nutritional habits, are driving the rapidly increasing prevalence of obesity and type 2 diabetes. Increased levels of free fatty acids (FFAs), particularly saturated FFAs, in obese individuals have been linked to pancreatic beta-cell failure. This process, termed lipotoxicity, involves activation of several stress responses, including ER stress and oxidative stress. However, the molecular underpinnings and causal relationships between the disparate stress responses remain unclear. Here we employed transgenic mice, expressing a genetically-encoded cytosolic H2O2 sensor, roGFP2-Orp1, to monitor dynamic changes in H2O2 levels in pancreatic islets in response to chronic palmitate exposure. We identified a transient increase in H2O2 levels from 4 to 8 h after palmitate addition, which was mirrored by a concomitant decrease in cellular NAD(P)H levels. Intriguingly, islets isolated from NOX2 knock-out mice displayed no H2O2 transient upon chronic palmitate treatment. Furthermore, NOX2 knockout rescued palmitate-dependent impairment of insulin secretion, calcium homeostasis and viability. Chemical inhibition of NOX activity protected islets from palmitate-induced impairment in insulin secretion, however had no detectable impact upon the induction of ER stress. In summary, our results reveal that transient NOX2-dependent H2O2 production is a likely cause of early palmitate-dependent lipotoxic effects. (AU)

• Processo FAPESP: 13/08769-1 - Papel da NAD(P)H oxidase nos mecanismos moleculares da fisiologia e patologia das células secretoras de insulina
• Beneficiário: Angelo Rafael Carpinelli
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/26339-5 - Envolvimento de isoformas da NADPH oxidase na disfunção de células secretoras de insulina expostas a citocinas pró-inflamatórias
• Beneficiário: Angelo Rafael Carpinelli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/51893-0 - Papel da NAD(P)H oxidase nos mecanismos moleculares da fisiologia das células beta pancreáticas
• Beneficiário: Angelo Rafael Carpinelli
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/04511-4 - Efeitos agudos e crônicos dos ácidos oleico e palmítico e do agonista GW9508 na secreção de insulina e no estresse oxidativo da linhagem BRIN-BD11
• Beneficiário: Eloisa Aparecida Vilas Boas
• Modalidade de apoio: Bolsas no Brasil - Mestrado