Fat body phospholipid state dictates hunger driven feeding behavior

Abstract

Diet-induced obesity leads to dysfunctional feeding behavior. However, the precise molecular nodes underlying diet-induced feeding motivation dysregulation are poorly understood. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high sugar regime in Drosophila, we sought to address how diet-induced changes in adipocyte lipid composition regulate feeding behavior. We observed that subjecting adult Drosophila to a prolonged high-sugar diet degrades the hunger-driven feeding response. Lipidomics analysis reveals that longitudinal exposure to high-sugar diets significantly alters whole-body phospholipid profiles. By performing a systematic genetic screen for phospholipid enzymes in adult fly adipocytes, we identify Pect as a critical regulator of hunger-driven feeding. Pect is a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2. We show that disrupting Pect activity only in the Drosophila fat cells causes insulin resistance, dysregulated lipoprotein delivery to the brain, and a loss of hunger-driven feeding. Previously human studies have noted a correlation between PCYT2/Pect levels and clinical obesity. Now, our unbiased studies in Drosophila provide causative evidence for adipocyte Pect function in metabolic homeostasis. Altogether, we have uncovered that PE phospholipid homeostasis regulates hunger response.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures

Article and author information

Author details

  1. Kevin P Kelly

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mroj Alassaf

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6277-9417
  3. Camille E Sullivan

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ava E Brent

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zachary H Goldberg

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2972-9682
  6. Michelle E Poling

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Julien Dubrulle

    Cellular Imaging Core, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4186-7749
  8. Akhila Rajan

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    akhila@fredhutch.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1160-5796

Funding

National Institute of General Medical Sciences (GM124593)

  • Akhila Rajan

Directorate for Biological Sciences (2109398)

  • Kevin P Kelly

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

Reviewing Editor

  1. Tania Reis, University of Colorado Anschutz Medical Campus, United States

Publication history

  1. Preprint posted: December 17, 2021 (view preprint)
  2. Received: May 15, 2022
  3. Accepted: October 5, 2022
  4. Accepted Manuscript published: October 6, 2022 (version 1)
  5. Version of Record published: October 14, 2022 (version 2)

Copyright

© 2022, Kelly 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.

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  1. Kevin P Kelly
  2. Mroj Alassaf
  3. Camille E Sullivan
  4. Ava E Brent
  5. Zachary H Goldberg
  6. Michelle E Poling
  7. Julien Dubrulle
  8. Akhila Rajan
(2022)
Fat body phospholipid state dictates hunger driven feeding behavior
eLife 11:e80282.
https://doi.org/10.7554/eLife.80282

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