MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity

Christine M. Kusminski, William L. Holland, Kai Sun, Jiyoung Park, Stephen B. Spurgin, Ying Lin, G. Roger Askew, Judith A. Simcox, Don A. McClain, Cai Li, Philipp E. Scherer

Research output: Contribution to journalArticle

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Abstract

We examined mouse models with altered adipocyte expression of mitoNEET, a protein residing in the mitochondrial outer membrane, to probe its impact on mitochondrial function and subsequent cellular responses. We found that overexpression of mitoNEET enhances lipid uptake and storage, leading to an expansion of the mass of adipose tissue. Despite the resulting massive obesity, benign aspects of adipose tissue expansion prevail, and insulin sensitivity is preserved. Mechanistically, we also found that mitoNEET inhibits mitochondrial iron transport into the matrix and, because iron is a rate-limiting component for electron transport, lowers the rate of β-oxidation. This effect is associated with a lower mitochondrial membrane potential and lower levels of reactive oxygen species-induced damage, along with increased production of adiponectin. Conversely, a reduction in mitoNEET expression enhances mitochondrial respiratory capacity through enhanced iron content in the matrix, ultimately corresponding to less weight gain on a high-fat diet. However, this reduction in mitoNEET expression also causes heightened oxidative stress and glucose intolerance. Thus, manipulation of mitochondrial function by varying mitoNEET expression markedly affects the dynamics of cellular and whole-body lipid homeostasis.

Original languageEnglish (US)
Pages (from-to)1539-1551
Number of pages13
JournalNature Medicine
Volume18
Issue number10
DOIs
StatePublished - Oct 2012

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Adipocytes
Insulin Resistance
Iron
Obesity
Insulin
Adipose Tissue
Tissue
Tissue Expansion
Membranes
Lipids
Oxidative stress
Glucose Intolerance
Mitochondrial Membrane Potential
Adiponectin
Mitochondrial Membranes
High Fat Diet
Nutrition
Electron Transport
Weight Gain
Reactive Oxygen Species

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. / Kusminski, Christine M.; Holland, William L.; Sun, Kai; Park, Jiyoung; Spurgin, Stephen B.; Lin, Ying; Askew, G. Roger; Simcox, Judith A.; McClain, Don A.; Li, Cai; Scherer, Philipp E.

In: Nature Medicine, Vol. 18, No. 10, 10.2012, p. 1539-1551.

Research output: Contribution to journalArticle

Kusminski, Christine M. ; Holland, William L. ; Sun, Kai ; Park, Jiyoung ; Spurgin, Stephen B. ; Lin, Ying ; Askew, G. Roger ; Simcox, Judith A. ; McClain, Don A. ; Li, Cai ; Scherer, Philipp E. / MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. In: Nature Medicine. 2012 ; Vol. 18, No. 10. pp. 1539-1551.
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