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

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.

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Figure 1: MitoNEET causes massive adipose tissue expansion and improves hepatic insulin sensitivity.
Figure 2: MitoNEET promotes lipid uptake by stimulating adiponectin production and heightening β-3 adrenergic agonist sensitivity.
Figure 3: MitoNEET-induced alterations in fatty acid metabolism.
Figure 4: MitoNEET compromises mitochondrial dynamics and morphology by modulating mitochondrial iron content.
Figure 5: A lack of mitoNEET enhances mitochondrial oxidative capacity.
Figure 6: Proposed mechanism of mitoNEET action.

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Acknowledgements

We thank P.D. Neufer, G. Schatz and C.B. Newgard for helpful comments and suggestions. We also thank J. Song and J. Xia for technical assistance, in addition to the rest of the Scherer laboratory, R. Unger and D. Clegg for helpful discussions. We also thank P. Blanchard and Y. Deshaies for kindly providing LPL activity measurements, R. Hammer and the University of Texas Southwestern (UTSW) Transgenic Core Facility for the generation of mouse models, as well as the UTSW Metabolic Core Facility for help in the phenotypic characterization of the mice and G. Milne from Vanderbilt University Medical Center for the F2-isoprostane analysis. The authors were supported by US National Institutes of Health grants R01-DK55758, RC1-DK086629 and P01-DK088761 (P.E.S.), K99-DK094973 and an American Heart Association Beginning Grant in Aid 12BGIA8910006 (W.L.H.), R01-DK081842 (D.A.M.), T32-DK091317 (J.A.S.) and Department of Defense Fellowship USAMRMC-BC085909 (J.P.). C.M.K. was supported by a fellowship from the Juvenile Diabetes Foundation (JDRF 3-2008-130).

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C.M.K. conducted all experiments and wrote the manuscript, except the portions indicated below. W.L.H. helped with the 3H-triolein uptake and β-oxidation experiments and performed their analyses. K.S. generated TRE-mitoNEET mice. J.P. helped plan, perform injections and scan fat pads in control AAV and AAV-mitoNEET experiments. S.B.S. generated the AAV-mitoNEET construct. Y.L. performed the DiOC6 ΔΨm experiment using mitoNEET-transfected 3T3-L1 preadipocytes. G.R.A. and C.L. coordinated the generation of shRNA-MitoN knockdown mice. J.A.S. and D.A.M. measured heme iron and provided high-iron-diet–fed and Hfe−/− liver tissues. P.E.S. was involved in the experimental design, experiments, data analysis and data interpretation, in addition to writing the manuscript.

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Correspondence to Philipp E Scherer.

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Kusminski, C., Holland, W., Sun, K. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med 18, 1539–1549 (2012). https://doi.org/10.1038/nm.2899

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