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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.)

Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark

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de Almeida-Faria, Juliana [1, 2, 3] ; Duque-Guimaraes, Daniella E. [1, 2] ; Ong, Thomas P. [4, 1, 2] ; Pantaleao, Lucas C. [1, 2] ; Carpenter, Asha A. [1, 2] ; Loche, Elena [1, 2] ; Kusinski, Laura C. [1, 2] ; Ashmore, Thomas J. [1, 2] ; Antrobus, Robin [5] ; Bushell, Martin [6] ; Fernandez-Twinn, Denise S. [1, 2] ; Ozanne, Susan E. [1, 2]
Total Authors: 12
[1] Univ Cambridge, Metab Res Labs, Cambridge - England
[2] Addenbrookes Hosp, Wellcome Trust MRC Inst Metab Sci, MRC Metab Dis Unit, Cambridge - England
[3] Univ Estadual Campinas, Fac Med Sci, Obes & Comorbid Res Ctr, Sao Paulo - Brazil
[4] Univ Sao Paulo, Food Res Ctr, Fac Pharmaceut Sci, Dept Food & Expt Nutr, Sao Paulo - Brazil
[5] Univ Cambridge, Cambridge Inst Med Res, Hills Rd, Cambridge - England
[6] Beatson Inst, Canc Res UK CRUK, Glasgow, Lanark - Scotland
Total Affiliations: 6
Document type: Journal article
Source: Diabetologia; v. 64, n. 4 JAN 2021.
Web of Science Citations: 0

Aims/hypothesis Levels of the microRNA (miRNA) miR-126-3p are programmed cell-autonomously in visceral adipose tissue of adult offspring born to obese female C57BL/6J mice. The spectrum of miR-126-3p targets and thus the consequences of its dysregulation for adipocyte metabolism are unknown. Therefore, the aim of the current study was to identify novel targets of miR-126-3p in vitro and then establish the outcomes of their dysregulation on adipocyte metabolism in vivo using a well-established maternal obesity mouse model. Methods miR-126-3p overexpression in 3T3-L1 pre-adipocytes followed by pulsed stable isotope labelling by amino acids in culture (pSILAC) was performed to identify novel targets of the miRNA. Well-established bioinformatics algorithms and luciferase assays were then employed to confirm those that were direct targets of miR-126-3p. Selected knockdown experiments were performed in vitro to define the consequences of target dysregulation. Quantitative real-time PCR, immunoblotting, histology, euglycaemic-hyperinsulinaemic clamps and glucose tolerance tests were performed to determine the phenotypic and functional outcomes of maternal programmed miR-126-3p levels in offspring adipose tissue. Results The proteomic approach confirmed the identity of known targets of miR-126-3p (including IRS-1) and identified Lunapark, an endoplasmic reticulum (ER) protein, as a novel one. We confirmed by luciferase assay that Lunapark was a direct target of miR-126-3p. Overexpression of miR-126-3p in vitro led to a reduction in Lunapark protein levels and increased Perk (also known as Eif2ak3) mRNA levels and small interference-RNA mediated knockdown of Lunapark led to increased Xbp1, spliced Xbp1, Chop (also known as Ddit3) and Perk mRNA levels and an ER stress transcriptional response in 3T3-L1 pre-adipocytes. Consistent with the results found in vitro, increased miR-126-3p expression in adipose tissue from adult mouse offspring born to obese dams was accompanied by decreased Lunapark and IRS-1 protein levels and increased markers of ER stress. At the whole-body level the animals displayed glucose intolerance. Conclusions/interpretation Concurrently targeting IRS-1 and Lunapark, a nutritionally programmed increase in miR-126-3p causes adipose tissue insulin resistance and an ER stress response, both of which may contribute to impaired glucose tolerance. These findings provide a novel mechanism by which obesity during pregnancy leads to increased risk of type 2 diabetes in the offspring and therefore identify miR-126-3p as a potential therapeutic target. (AU)

FAPESP's process: 17/03525-8 - The role of maternal obesity on modulation of offspring hypothalamic miRNAs and metabolic consequences associated
Grantee:Juliana de Almeida Faria
Support type: Scholarships abroad - Research Internship - Post-doctor
FAPESP's process: 14/17012-4 - Uma intervenção Farmacológica para prevenir os efeitos da obesidade materna sobre a resistência à insulina no tecido adiposo da prole
Grantee:Juliana de Almeida Faria
Support type: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 14/20380-5 - Involvement of microRNAs on the accelerated ageing process caused by obesity
Grantee:Daniella Esteves Duque Guimarães
Support type: Scholarships abroad - Research Internship - Post-doctor
FAPESP's process: 13/07914-8 - FoRC - Food Research Center
Grantee:Bernadette Dora Gombossy de Melo Franco
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC