1. Cell Biology

Insulin sensitivity is preserved in mice made obese by feeding a high starch diet

  1. Amanda E Brandon  Is a corresponding author
  2. Lewin Small
  3. Tuong-Vi Nguyen
  4. Eurwin Suryana
  5. Henry Gong
  6. Christian Yassmin
  7. Sarah E Hancock
  8. Tamara Pulpitel
  9. Sophie Stonehouse
  10. Letisha Prescott
  11. Melkam A Kebede
  12. Belinda Yau
  13. Lake-Ee Quek
  14. Greg M Kowalski
  15. Clinton R Bruce
  16. Nigel Turner
  17. Gregory J Cooney
  1. University of Sydney, Australia
  2. Garvan Institute of Medical Research, Australia
  3. University of New South Wales, Australia
  4. Deakin University, Australia
https://doi.org/10.7554/eLife.79250
Share this article
Cite this article
  1. Amanda E Brandon
  2. Lewin Small
  3. Tuong-Vi Nguyen
  4. Eurwin Suryana
  5. Henry Gong
  6. Christian Yassmin
  7. Sarah E Hancock
  8. Tamara Pulpitel
  9. Sophie Stonehouse
  10. Letisha Prescott
  11. Melkam A Kebede
  12. Belinda Yau
  13. Lake-Ee Quek
  14. Greg M Kowalski
  15. Clinton R Bruce
  16. Nigel Turner
  17. Gregory J Cooney
(2022)
Insulin sensitivity is preserved in mice made obese by feeding a high starch diet
eLife 11:e79250.
https://doi.org/10.7554/eLife.79250
  2. Download BibTeX
  3. Download .RIS

Abstract

Obesity is generally associated with insulin resistance in liver and muscle and increased risk of developing type 2 diabetes, however there is a population of obese people that remain insulin sensitive. Similarly, recent work suggests that mice fed high carbohydrate diets can become obese without apparent glucose intolerance. To investigate this phenomenon further, we fed mice either a high fat (Hi-F) or high starch (Hi-ST) diet and measured adiposity, glucose tolerance, insulin sensitivity and tissue lipids compared to control mice fed a standard laboratory chow. Both Hi-ST and Hi-F mice accumulated a similar amount of fat and tissue triglyceride compared to chow-fed mice. However while Hi-F diet mice developed glucose intolerance as well as liver and muscle insulin resistance (assessed via euglycemic/hyperinsulinemic clamp), obese Hi-ST mice maintained glucose tolerance and insulin action similar to lean, chow-fed controls. This preservation of insulin action despite obesity in Hi-ST mice was associated with differences in de novo lipogenesis and levels of C22:0 ceramide in liver and C18:0 ceramide in muscle. This indicates that dietary manipulation can influence insulin action independently of the level of adiposity and that the presence of specific ceramide species correlate with these differences.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for Figures 1,2,3,4,5, and 6.

Article and author information

Author details

  1. Amanda E Brandon

    School of Medical Sciences, University of Sydney, Sydney, Australia
    For correspondence
    amanda.brandon@sydney.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4996-7189

  2. Lewin Small

    Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9767-9464

  3. Tuong-Vi Nguyen

    Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  4. Eurwin Suryana

    Diabetes and Metabolism Division, Garvan Institute of Medical Research, Syndey, Australia
    Competing interests
    The authors declare that no competing interests exist.

  5. Henry Gong

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  6. Christian Yassmin

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  7. Sarah E Hancock

    Department of Pharmacology, University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  8. Tamara Pulpitel

    School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  9. Sophie Stonehouse

    School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  10. Letisha Prescott

    School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  11. Melkam A Kebede

    School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9686-7378

  12. Belinda Yau

    School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  13. Lake-Ee Quek

    School of Mathematics and Statistics, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  14. Greg M Kowalski

    Institute for Physical Activity and Nutrition, Deakin University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.

  15. Clinton R Bruce

    Institute for Physical Activity and Nutrition, Deakin University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0515-3343

  16. Nigel Turner

    Department of Pharmacology, University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  17. Gregory J Cooney

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Health and Medical Research Council (Fellowship 1003313)

  • Gregory J Cooney

National Health and Medical Research Council (Program grant 535921)

  • Gregory J Cooney

Diabetes Australia Research Trust (Grant)

  • Gregory J Cooney

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

Ethics

Animal experimentation: All experimental procedures performed were approved by the Garvan Institute/St Vincent's Hospital Animal Ethics Committee and were in accordance with the National Health and Medical Research Council of Australia's guidelines on animal experimentation (protocol number 14_07).

Copyright

© 2022, Brandon 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

  • 3,464
    views
  • 381
    downloads
  • 12
    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. Amanda E Brandon
  2. Lewin Small
  3. Tuong-Vi Nguyen
  4. Eurwin Suryana
  5. Henry Gong
  6. Christian Yassmin
  7. Sarah E Hancock
  8. Tamara Pulpitel
  9. Sophie Stonehouse
  10. Letisha Prescott
  11. Melkam A Kebede
  12. Belinda Yau
  13. Lake-Ee Quek
  14. Greg M Kowalski
  15. Clinton R Bruce
  16. Nigel Turner
  17. Gregory J Cooney
(2022)
Insulin sensitivity is preserved in mice made obese by feeding a high starch diet
eLife 11:e79250.
https://doi.org/10.7554/eLife.79250

Share this article

https://doi.org/10.7554/eLife.79250

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    Changes in local mineral homeostasis facilitate the formation of benign and malignant testicular microcalcifications

    Ida Marie Boisen, Nadia Krarup Knudsen ... Martin Blomberg Jensen
    Research Article

    Testicular microcalcifications consist of hydroxyapatite and have been associated with an increased risk of testicular germ cell tumors (TGCTs) but are also found in benign cases such as loss-of-function variants in the phosphate transporter SLC34A2. Here, we show that fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and therefore cleaved into a C-terminal fragment which competitively antagonizes full-length FGF23. Here, Fgf23 knockout mice presented with marked calcifications in the epididymis, spermatogenic arrest, and focally germ cells expressing the osteoblast marker Osteocalcin (gene name: Bglap, protein name). Moreover, the frequent testicular microcalcifications in mice with no functional androgen receptor and lack of circulating gonadotropins are associated with lower Slc34a2 and higher Bglap/Slc34a1 (protein name: NPT2a) expression compared with wild-type mice. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2 and a subpopulation of germ cells express phosphate transporter NPT2a, Osteocalcin, and RUNX2 highlighting aberrant local phosphate handling and expression of bone-specific proteins. Mineral disturbance in vitro using calcium or phosphate treatment induced deposition of calcium phosphate in a spermatogonial cell line and this effect was fully rescued by the mineralization inhibitor pyrophosphate. In conclusion, testicular microcalcifications arise secondary to local alterations in mineral homeostasis, which in combination with impaired Sertoli cell function and reduced levels of mineralization inhibitors due to high alkaline phosphatase activity in GCNIS and TGCTs facilitate osteogenic-like differentiation of testicular cells and deposition of hydroxyapatite.

    1. Cell Biology
    2. Genetics and Genomics

    Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma

    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

    1. Cell Biology
    2. Immunology and Inflammation

    RAS–p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation

    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.