OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance

Renata Oliveira Pereira, Satya M. Tadinada, Frederick M. Zasadny, Karen Jesus Oliveira, Karla Maria Pereira Pires, Angela Olvera, Jennifer Jeffers, Rhonda Souvenir, Rose McGlauflin, Alec Seei, Trevor Funari, Hiromi Sesaki, Matthew J. Potthoff, Christopher M. Adams, Ethan J. Anderson, E. Dale Abel

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Mitochondrial dynamics is a conserved process by which mitochondria undergo repeated cycles of fusion and fission, leading to exchange of mitochondrial genetic content, ions, metabolites, and proteins. Here, we examine the role of the mitochondrial fusion protein optic atrophy 1 (OPA1) in differentiated skeletal muscle by reducing OPA1 gene expression in an inducible manner. OPA1 deficiency in young mice results in non-lethal progressive mitochondrial dysfunction and loss of muscle mass. Mutant mice are resistant to age-and diet-induced weight gain and insulin resistance, by mechanisms that involve activation of ER stress and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle, resulting in increased metabolic rates and improved whole-body insulin sensitivity. OPA1-elicited mitochondrial dysfunction activates an integrated stress response that locally induces muscle atrophy, but via secretion of FGF21 acts distally to modulate whole-body metabolism.

Original languageEnglish (US)
Pages (from-to)2126-2145
Number of pages20
JournalEMBO Journal
Volume36
Issue number14
DOIs
StatePublished - Jul 2017

Keywords

  • ER stress
  • FGF21
  • Mitochondrial dysfunction
  • OPA1
  • Skeletal muscle

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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