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

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

Further reading

    1. Cell Biology
    Affiong Ika Oqua, Kin Chao ... Alejandra Tomas
    Research Article

    G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active vs inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.

    1. Cell Biology
    2. Immunology and 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.