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Knockdown of ANT2 reduces adipocyte hypoxia and improves insulin resistance in obesity

Nature Metabolism volume 1, pages 86–97 (2019)Cite this article

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Abstract

Decreased adipose tissue oxygen tension and increased expression of the transcription factor hypoxia-inducible factor–1α (HIF-1α) can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte oxygen demand, mediated by activity of the mitochondrial protein adenine nucleotide translocase 2 (ANT2), is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 (also known as Scl25a5) improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This effect of adipocyte ANT2 knockout led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both preventative and therapeutic settings. Our results suggest that ANT2 may be a target for the development of insulin-sensitizing drugs and that ANT2 inhibition might have clinical utility.

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Fig. 1: Adipocyte-specific ANT2 knockout mice exhibit normal body weight with increased adipose tissue mass.
Fig. 2: Intracellular oxygen tension and HIF-1α expression are decreased in eWAT of ANT2 AKO mice.
Fig. 3: ANT2 AKO mice are protected from HFD-induced adipose tissue inflammation, glucose intolerance and insulin resistance.
Fig. 4: HFD-induced ATM accumulation and M1-like polarization is reduced in ANT2 AKO mice with improved adipose tissue fibrosis.
Fig. 5: Inducible ANT2 AKO reverses established glucose and insulin intolerance.
Fig. 6: HFD-induced adipocyte apoptosis is decreased in ANT2 AKO mice.

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All data that support the findings of this study are included in the paper or its supplementary information.

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Acknowledgements

We thank D. Wallace (University of Pennsylvania) for providing Ant2 floxed mice. This study was supported by the US National Institute of Diabetes and Digestive and Kidney Diseases (DK063491 and DK101395), a University of California San Diego/University of California Los Angeles Diabetes Research Center P&F grant, the Basic Science Research Program and the Bio-Synergy Research Project through National Research Foundation of Korea (NRF-2017R1C1B2011125 and NRF-2017M3A9C4065956), the POSCO TJ Park Foundation, and a grant from the Merck, Inc., Janssen Pharmceuticals, Inc., and Pershing Square Foundation. M.R. was supported by a postdoctoral fellowship from the American Heart Association (16POST29990015).

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA

    Jong Bae Seo, Matthew Riopel, Jin Young Huh, Gautam K. Bandyopadhyay, Samuel Klein, Yun Sok Lee & Jerrold M. Olefsky

  2. Department of Engineering, University of California San Diego, La Jolla, CA, USA

    Pedro Cabrales

  3. Department of Pharmacology, University of California San Diego, La Jolla, CA, USA

    Aleksander Yu Andreyev & Anne N. Murphy

  4. Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA

    Scott C. Beeman, Gordon I. Smith & Samuel Klein

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Contributions

Y.S.L. and J.B.S. designed and performed the majority of the experiments. M.R. performed glucose clamp experiments. P.C. measured adipose tissue interstitial oxygen tension and hemodynamics. A.N.M. and A.Y.A supported measuring mitochondrial activity and oxygen consumption. J.Y.H. performed flow cytometry analysis of adipose tissue immune cells. S.C.B., G.I.S. and S.K. performed clinical studies in MNL, MAO and MNO subjects and measured human adipose tissue oxygen tension. Y.S.L. and J.M.O. conceived and supervised the project. J.B.S., Y.S.L. and J.M.O. wrote the manuscript and all authors commented on the paper.

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Correspondence to Yun Sok Lee or Jerrold M. Olefsky.

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Seo, J.B., Riopel, M., Cabrales, P. et al. Knockdown of ANT2 reduces adipocyte hypoxia and improves insulin resistance in obesity. Nat Metab 1, 86–97 (2019). https://doi.org/10.1038/s42255-018-0003-x

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