Abstract

Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice diverted pyruvate into circulating lactate. This switch disinhibited muscle fatty acid oxidation and drove Cori Cycling that contributed to increased energy expenditure. Loss of muscle MPC activity led to strikingly decreased adiposity with complete muscle mass and strength retention. Notably, despite decreasing muscle glucose oxidation, muscle MPC disruption increased muscle glucose uptake and whole-body insulin sensitivity. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a whole-body carbon flux control point. They highlight the potential utility of decreasing muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.

Data availability

All metabolomic results generated as part of this study are provided in Supplemental tables 2 and 3 related to Figure 5.

Article and author information

Author details

  1. Arpit Sharma

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lalita Oonthonpan

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ryan D Sheldon

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Adam J Rauckhorst

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zhiyong Zhu

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sean C Tompkins

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kevin Cho

    Department of Chemistry, Washington University in St Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Wojciech J Grzesik

    Fraternal Order of the Eagles Diabetes Research Center (FOEDRC), University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lawrence R Gray

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Diego A Scerbo

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Alvin D Pewa

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Emily M Cushing

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9495-802X
  13. Michael C Dyle

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. James E Cox

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Chris Adams

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Brandon S Davies

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Richard K Shields

    Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Andrew W Norris

    Department of Biochemistry, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Gary Patti

    FOEDRC Metabolomics Core Facility, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3748-6193
  20. Leonid V Zingman

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Eric B Taylor

    Department of Biochemistry, University of Iowa, Iowa City, United States
    For correspondence
    eric-taylor@uiowa.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4549-6567

Funding

National Institutes of Health (DK104998)

  • Eric B Taylor

National Institutes of Health (GM007337)

  • Sean C Tompkins

National Institutes of Health (HL007638)

  • Adam J Rauckhorst

National Institutes of Health (DK101183)

  • Lawrence R Gray

American Diabetes Association (1-18-PDF-060)

  • Adam J Rauckhorst

National Institutes of Health (DK112751)

  • Diego A Scerbo

National Institutes of Health (AR059190)

  • Eric B Taylor

National Institutes of Health (HD084645)

  • Richard K Shields

National Institutes of Health (HD082109)

  • Richard K Shields

National Institutes of Health (DK092412)

  • Leonid V Zingman

National Institutes of Health (ES028365)

  • Gary Patti

National Institutes of Health (HL130146)

  • Brandon S Davies

National Institutes of Health (HL007344)

  • Ryan D Sheldon

National Institutes of Health (DK116522)

  • Ryan D Sheldon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. David E James, The University of Sydney, Australia

Ethics

Animal experimentation: Animal work was performed in accordance with the University of Iowa Animal Use and Care Committee (IACUC). The University of Iowa IACUC is accredited by AALACi (#000833), is a Registered United States Department of Agriculture research facility (USDA No. 42-R-0004), and has PHS Approved Animal Welfare Assurance (#D16-00009).

Version history

  1. Received: February 7, 2019
  2. Accepted: July 15, 2019
  3. Accepted Manuscript published: July 15, 2019 (version 1)
  4. Accepted Manuscript updated: July 18, 2019 (version 2)
  5. Version of Record published: August 6, 2019 (version 3)

Copyright

© 2019, Sharma et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,660
    views
  • 872
    downloads
  • 54
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Arpit Sharma
  2. Lalita Oonthonpan
  3. Ryan D Sheldon
  4. Adam J Rauckhorst
  5. Zhiyong Zhu
  6. Sean C Tompkins
  7. Kevin Cho
  8. Wojciech J Grzesik
  9. Lawrence R Gray
  10. Diego A Scerbo
  11. Alvin D Pewa
  12. Emily M Cushing
  13. Michael C Dyle
  14. James E Cox
  15. Chris Adams
  16. Brandon S Davies
  17. Richard K Shields
  18. Andrew W Norris
  19. Gary Patti
  20. Leonid V Zingman
  21. Eric B Taylor
(2019)
Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness
eLife 8:e45873.
https://doi.org/10.7554/eLife.45873

Share this article

https://doi.org/10.7554/eLife.45873

Further reading

    1. Cell Biology
    2. Developmental Biology
    Corey D Holman, Alexander P Sakers ... Patrick Seale
    Research Article

    The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process in mice. We found that aging increases the expression of Cd9 and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation in vitro, suggesting that environmental factors suppress adipogenesis in vivo. Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with aging and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of de novo lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified Npr3, which encodes the natriuretic peptide clearance receptor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a resource for identifying cold and aging-regulated pathways in adipose tissue.

    1. Cell Biology
    Tongtong Ma, Ruimin Ren ... Heng Wang
    Research Article

    Current studies on cultured meat mainly focus on the muscle tissue reconstruction in vitro, but lack the formation of intramuscular fat, which is a crucial factor in determining taste, texture, and nutritional contents. Therefore, incorporating fat into cultured meat is of superior value. In this study, we employed the myogenic/lipogenic transdifferentiation of chicken fibroblasts in 3D to produce muscle mass and deposit fat into the same cells without the co-culture or mixture of different cells or fat substances. The immortalized chicken embryonic fibroblasts were implanted into the hydrogel scaffold, and the cell proliferation and myogenic transdifferentiation were conducted in 3D to produce the whole-cut meat mimics. Compared to 2D, cells grown in 3D matrix showed elevated myogenesis and collagen production. We further induced fat deposition in the transdifferentiated muscle cells and the triglyceride content could be manipulated to match and exceed the levels of chicken meat. The gene expression analysis indicated that both lineage-specific and multifunctional signalings could contribute to the generation of muscle/fat matrix. Overall, we were able to precisely modulate muscle, fat, and extracellular matrix contents according to balanced or specialized meat preferences. These findings provide new avenues for customized cultured meat production with desired intramuscular fat contents that can be tailored to meet the diverse demands of consumers.