Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health

Joji Kusuyama; Ana Barbara Alves-Wagner; Royce H Conlin; Nathan S Makarewicz; Brent G Albertson; Noah B Prince; Shio Kobayashi; Chisayo Kozuka; Magnus Møller; Mette Bjerre; Jens Fuglsang; Emily Miele; Roeland J W Middelbeek; Yang Xiudong; Yang Xia; Léa Garneau; Jayonta Bhattacharjee; Céline Aguer; Mary Elizabeth Patti; Michael F Hirshman; Niels Jessen; Toshihisa Hatta; Per Glud Ovesen; Kristi B Adamo; Eva Nozik-Grayck; Laurie J Goodyear

doi:10.1016/j.cmet.2021.03.004

Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health

Cell Metab. 2021 May 4;33(5):939-956.e8. doi: 10.1016/j.cmet.2021.03.004. Epub 2021 Mar 25.

Authors

Joji Kusuyama¹, Ana Barbara Alves-Wagner², Royce H Conlin², Nathan S Makarewicz², Brent G Albertson², Noah B Prince², Shio Kobayashi³, Chisayo Kozuka⁴, Magnus Møller⁵, Mette Bjerre⁶, Jens Fuglsang⁵, Emily Miele², Roeland J W Middelbeek², Yang Xiudong⁷, Yang Xia⁷, Léa Garneau⁸, Jayonta Bhattacharjee⁹, Céline Aguer¹⁰, Mary Elizabeth Patti², Michael F Hirshman², Niels Jessen¹¹, Toshihisa Hatta¹², Per Glud Ovesen⁵, Kristi B Adamo⁹, Eva Nozik-Grayck¹³, Laurie J Goodyear¹⁴

Affiliations

¹ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Miyagi, Japan. Electronic address: joji.kusuyama.c1@tohoku.ac.jp.
² Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
³ Section of Immunobiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
⁴ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; YCI Laboratory for Metabolic Epigenetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
⁵ Department of Gynecology and Obstetrics, Aarhus University Hospital and Clinical Institute, Aarhus University, Aarhus, Denmark.
⁶ Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁷ Graduate School of Biomedical Sciences, University of Texas at Houston, Houston, TX, USA.
⁸ Institut du Savoir Montfort, recherche, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
⁹ School of Human Kinetics, Faculty of Health Science University of Ottawa, Ottawa, Canada.
¹⁰ Institut du Savoir Montfort, recherche, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada; School of Human Kinetics, Faculty of Health Science University of Ottawa, Ottawa, Canada; Interdisciplinary School of Health Sciences, Faculty of Health Science University of Ottawa, Ottawa, Canada.
¹¹ Steno Diabetes Center Aarhus, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
¹² Department of Anatomy, Kanazawa Medical University, Ishikawa, Japan.
¹³ Cardiovascular Pulmonary Research Laboratories and Pediatric Critical Care, Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
¹⁴ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. Electronic address: laurie.goodyear@joslin.harvard.edu.

Abstract

Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.

Keywords: AMPK; DNA methylation; TET; glucose metabolism; maternal exercise; placenta; pregnancy; superoxide dismutase 3; vitamin D.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Cells, Cultured
DNA Demethylation
Diet, High-Fat
Exercise*
Female
Hepatocytes / cytology
Hepatocytes / metabolism
Humans
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mixed Function Oxygenases / genetics
Mixed Function Oxygenases / metabolism
Placenta / metabolism*
Pregnancy
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Receptors, Calcitriol / metabolism
Signal Transduction
Superoxide Dismutase / genetics
Superoxide Dismutase / metabolism*

Substances

Proto-Oncogene Proteins
Receptors, Calcitriol
Mixed Function Oxygenases
TET1 protein, human
SOD3 protein, human
Superoxide Dismutase
AMP-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding