Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice

Andrew LaPoint; Jason M. Singer; Daniel Ferguson; Trevor M. Shew; M. Katie Renkemeyer; Hector H. Palacios; Rachael L. Field; Sireeesha Yerrathota; Roshan Kumari; Mahalakshmi Shankaran; Gordon I. Smith; Jun Yoshino; Mai He; Gary J. Patti; Marc K. Hellerstein; Samuel Klein; E. Matthew Morris; Jonathan R. Brestoff; Brian N. Finck; Andrew Lutkewitte

doi:10.1172/JCI169722

¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

Find articles by He, M. in: JCI | PubMed | Google Scholar

¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

Find articles by Patti, G. in: JCI | PubMed | Google Scholar

¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

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¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

Find articles by Morris, E. in: JCI | PubMed | Google Scholar

¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

Find articles by Brestoff, J. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

Find articles by Finck, B. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

²Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

³Department of Medicine, Division of Endocrinology, Diabetes, and Clinical P, University of Kansas Medical Center, Kansas City, United States of America

⁴Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁵Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

⁶Division of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, United States of America

⁷Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, United States of America

Find articles by Lutkewitte, A. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI169722.
Copyright © 2024, LaPoint et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 15, 2024 - Version history

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1^–/– mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.

Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice

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Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice

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