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

• Published in: The Journal of clinical investigation Vol. 134; no. 23; pp. 1 - 16
• Main Authors: LaPoint, Andrew, Singer, Jason M., Ferguson, Daniel, Shew, Trevor M., Renkemeyer, M. Katie, Palacios, Hector H., Field, Rachael L., Yerrathota, Sireesha, Kumari, Roshan, Shankaran, Mahalakshmi, Smith, Gordon I., Yoshino, Jun, He, Mai, Patti, Gary J., Hellerstein, Marc K., Klein, Samuel, Brestoff, Jonathan R., Morris, E. Matthew, Finck, Brian N., Lutkewitte, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.12.2024
• Subjects: Adipocytes; Adipocytes - metabolism; Adipose tissue; Adipose Tissue - metabolism; Adipose tissues; Animals; Body fat; Diet; Diglycerides; Fat cells; Fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Female; Gene expression; Genotype & phenotype; Glucose; Glycerol; Health aspects; High fat diet; Humans; Insulin Resistance; Lipids; Lipogenesis; Liver; Liver - metabolism; Male; Metabolism; Mice; Mice, Knockout; Musculoskeletal system; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Phenotypes; Phenotyping; Phosphatidate Phosphatase - genetics; Phosphatidate Phosphatase - metabolism; Phosphatidic acid; Physiological aspects; Plasma; Proteins; Skeletal muscle; Steatosis; Transcriptomics; United States; Obesity; Diabetes; Metabolism; Hepatology; Insulin signaling
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI169722

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, 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 with lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multiomic 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.