Dietary control of peripheral adipose storage capacity through membrane lipid remodelling

Marcus J Tol^#^{1

2}, Yuta Shimanaka^#^{1

2}, Alexander H Bedard^{1

2}, Jennifer Sapia³, Liujuan Cui^{1

2}, Mariana Colaço-Gaspar⁴, Peter Hofer⁴, Alessandra Ferrari^{1

2}, Kevin Qian^{1

2}, John P Kennelly^{1

2}, Stephen D Lee^{1

2}, Yajing Gao^{1

2}, Xu Xiao^{1

2}, Jie Gao⁵, Julia J Mack^{6

7}, Thomas A Weston^{7

8}, Kevin J Williams², Baolong Su², Calvin Pan^{7

8

9}, Aldons J Lusis^{7

8

9}, Daniel P Pike¹⁰, Alex Reed¹¹, Natalia Milosevich¹¹, Benjamin F Cravatt¹¹, Makoto Arita^{12

13}, Stephen G Young^{7

8}, David A Ford¹⁰, Rudolf Zechner^{4

14

15}, Stefano Vanni^{3

16}, Peter Tontonoz^{17

18}

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, CA, USA.
³ Department of Biology, University of Fribourg, Fribourg, Switzerland.
⁴ Institute of Molecular Biosciences, University of Graz, Graz, Austria.
⁵ Department of Neuroscience, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
⁶ Molecular Biology Institute, University of California, Los Angeles, CA, USA.
⁷ Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA, USA.
⁸ Department of Human Genetics, University of California, Los Angeles, CA, USA.
⁹ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA.
¹⁰ Edward A. Doisy Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, USA.
¹¹ Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
¹² Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
¹³ Laboratory of Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁴ BioTechMed-Graz, Graz, Austria.
¹⁵ Biohealth Field of Excellence, University of Graz, Graz, Austria.
¹⁶ Swiss National Center for Competence in Research (NCCR) Bio-inspired Materials, University of Fribourg, Fribourg, Switzerland.
¹⁷ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA. PTontonoz@mednet.ucla.edu.
¹⁸ Department of Biological Chemistry, University of California, Los Angeles, CA, USA. PTontonoz@mednet.ucla.edu.

^# Contributed equally.

PMID: 40579620
DOI: 10.1038/s42255-025-01320-y

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling

Marcus J Tol et al. Nat Metab. 2025 Jul.

. 2025 Jul;7(7):1424-1442.

doi: 10.1038/s42255-025-01320-y. Epub 2025 Jun 27.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, CA, USA.
³ Department of Biology, University of Fribourg, Fribourg, Switzerland.
⁴ Institute of Molecular Biosciences, University of Graz, Graz, Austria.
⁵ Department of Neuroscience, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
⁶ Molecular Biology Institute, University of California, Los Angeles, CA, USA.
⁷ Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA, USA.
⁸ Department of Human Genetics, University of California, Los Angeles, CA, USA.
⁹ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA.
¹⁰ Edward A. Doisy Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, USA.
¹¹ Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
¹² Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
¹³ Laboratory of Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁴ BioTechMed-Graz, Graz, Austria.
¹⁵ Biohealth Field of Excellence, University of Graz, Graz, Austria.
¹⁶ Swiss National Center for Competence in Research (NCCR) Bio-inspired Materials, University of Fribourg, Fribourg, Switzerland.
¹⁷ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA. PTontonoz@mednet.ucla.edu.
¹⁸ Department of Biological Chemistry, University of California, Los Angeles, CA, USA. PTontonoz@mednet.ucla.edu.

^# Contributed equally.

PMID: 40579620
DOI: 10.1038/s42255-025-01320-y

Abstract

Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3^-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Update of

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
Tol MJ, Shimanaka Y, Bedard AH, Sapia J, Cui L, Colaço-Gaspar M, Hofer P, Ferrari A, Qian K, Kennelly JP, Lee SD, Gao Y, Xiao X, Gao J, Mack JJ, Weston TA, Pan C, Lusis AJ, Williams KJ, Su B, Pike DP, Reed A, Milosevich N, Cravatt BF, Arita M, Young SG, Ford DA, Zechner R, Vanni S, Tontonoz P. Tol MJ, et al. bioRxiv [Preprint]. 2024 Oct 29:2024.10.25.620374. doi: 10.1101/2024.10.25.620374. bioRxiv. 2024. Update in: Nat Metab. 2025 Jul;7(7):1424-1442. doi: 10.1038/s42255-025-01320-y. PMID: 39554041 Free PMC article. Updated. Preprint.

References

1. Sakers, A., De Siqueira, M. K., Seale, P. & Villanueva, C. J. Adipose-tissue plasticity in health and disease. Cell 185, 419–446 (2022). - PubMed - PMC
1. Wang, Q. A., Tao, C., Gupta, R. K. & Scherer, P. E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19, 1338–1344 (2013). - PubMed - PMC
1. Kim, S. M. et al. Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 20, 1049–1058 (2014). - PubMed - PMC
1. Spalding, K. L. et al. Dynamics of fat cell turnover in humans. Nature 453, 783–787 (2008). - PubMed
1. Kubota, N. et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell 4, 597–609 (1999). - PubMed

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Dietary control of peripheral adipose storage capacity through membrane lipid remodelling

Affiliations

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous