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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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]
Total Authors: 9
Affiliation:
[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
Total Affiliations: 5
Document type: Journal article
Source: Free Radical Biology and Medicine; v. 162, JAN 2021.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 13/08769-1 - The role of NAD(P)H oxidase in the physiological and pathological molecular mechanisms of insulin secreting cells
Grantee:Angelo Rafael Carpinelli
Support type: Research Projects - Thematic Grants
FAPESP's process: 17/26339-5 - Involvement of NADPH oxidase isoforms in the dysfunction of insulin secreting cells exposed to pro-inflammatory cytokines
Grantee:Angelo Rafael Carpinelli
Support type: Regular Research Grants
FAPESP's process: 09/51893-0 - The role of NAD(P)H oxidase in the molecular mechanisms of pancreatic beta cell physiology
Grantee:Angelo Rafael Carpinelli
Support type: Research Projects - Thematic Grants
FAPESP's process: 11/04511-4 - Acute and chronic effects of oleic and palmitic acids and the agonist GW9508 on insulin secretion and oxidative stress of the lineage BRIND-BD11
Grantee:Eloisa Aparecida Vilas Boas
Support type: Scholarships in Brazil - Master