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Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food

Published version
Peer-reviewed

Repository DOI


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Authors

Furigo, Isadora C 
Pantaleão, Lucas C 
Wong, LWP 
Fernandez-Twinn, Denise S 

Abstract

jats:pIn utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.</jats:p>

Description

Acknowledgements: We would like to thank Tom Ashmore, Claire Custance, and Laura Hunter for assistance with animal husbandry, the Genomics and Transcriptomics Core for assistance with RNA-sequencing, and Dr. Robin Antrobus for assistance with mass spectrometry. Illustrative figures were generated using BioRender. This research was conducted using the UK Biobank Resource under application 9905.


Funder: Centre for Health and Life Sciences (Coventry University)


Funder: Fundação de Amparo à Pesquisa do Estado da Bahia; funder-id: http://dx.doi.org/10.13039/501100006181; Grant(s): FAPESP: 20/01318-8

Keywords

Journal Title

PLOS Biology

Conference Name

Journal ISSN

1544-9173
1545-7885

Volume Title

22

Publisher

Public Library of Science (PLoS)
Sponsorship
Fundação de Amparo à Pesquisa do Estado da Bahia (19/06313-7)
British Society for Neuroendocrinology (Project Support Grant)
Wellcome Trust (106026/Z/14/Z)
Royal Society (DHF\R1\221051)
Fundação de Amparo à Pesquisa do Estado da Bahia (2014/17012-4)
Fundação de Amparo à Pesquisa do Estado da Bahia (2017/03525-8)
British Society for Neuroendocrinology (Summer Studentship)
British Heart Foundation (RG/17/12/33167)
Medical Research Council (MRC_MC_UU_00014/4)
British Heart Foundation (RG/18/7/33636)
Medical Research Council (MC_UU_00014/2)
Medical Research Council (MC_UU_12015/2)
Medical Research Council (MC_UU_00006/2)