Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice
Andrew LaPoint, … , Brian N. Finck, Andrew J. Lutkewitte
Andrew LaPoint, … , Brian N. Finck, Andrew J. Lutkewitte
Published October 15, 2024
Citation Information: J Clin Invest. 2024;134(23):e169722. https://doi.org/10.1172/JCI169722.
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Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice

Abstract

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.

Authors

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

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Figure 1

Abdominal adipose tissue LPIN1 gene expression is decreased in people with metabolically unhealthy obesity and LPIN1 expression correlates with metabolic health.

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Abdominal adipose tissue LPIN1 gene expression is decreased in people wi...
(A) Gene expression of LPIN1 from subcutaneous abdominal adipose tissue (SAAT) determined by RNA sequencing in metabolically healthy lean (MHL; n = 14), metabolically healthy obese (MHO; n = 22), and metabolically unhealthy obese (MUO; n = 25) groups. Data are expressed as means ± SEM. One-way ANOVA was used to compare LPIN1 expression among MHL, MHO, and MUO groups with Fisher’s least significant difference post hoc procedure used to identify significant mean differences. #P < 0.05 vs. MHL and †P < 0.05 vs. MUO. (B–D) Relationship between SAAT LPIN1 expression and skeletal muscle insulin sensitivity (glucose rate of disappearance relative to plasma insulin concentration during the hyperinsulinemic-euglycemic clamp procedure [glucose Rd/I]), hepatic insulin sensitivity index (HISI), and contribution from hepatic de novo lipogenesis (DNL) to plasma triglyceride-palmitate. Logarithmic regression analysis was used to determine the line best fit to the data.