Research ArticleHepatologyMetabolism Open Access | 10.1172/JCI169722

Andrew LaPoint,1 Jason M. Singer,1 Daniel Ferguson,1 Trevor M. Shew,1 M. Katie Renkemeyer,1 Hector H. Palacios,1 Rachael L. Field,2 Sireesha Yerrathota,3 Roshan Kumari,3 Mahalakshmi Shankaran,4 Gordon I. Smith,1 Jun Yoshino,5,6 Mai He,2 Gary J. Patti,1,7 Marc K. Hellerstein,4 Samuel Klein,1 Jonathan R. Brestoff,2 E. Matthew Morris,8,9,10 Brian N. Finck,1 and Andrew J. Lutkewitte3,9

1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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1Department of Medicine and

2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, USA.

4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA.

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

6Center for Integrated Kidney Research and Advance (IKRA), Shimane University, Izumo, Shimane, Japan.

7Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA.

8Department of Cell Biology and Physiology and

9KU Diabetes Institute and Kansas Center for Metabolism and Obesity, University of Kansas Medical Center, Kansas City, Kansas, USA.

10Center for Children’s Healthy Lifestyles and Nutrition, Kansas City, Missouri, USA.

Address correspondence to: Andrew J. Lutkewitte, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. Phone: 913.945.8518; Email: alutkewitte@kumc.edu.

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

Published October 15, 2024 - More info

Published in Volume 134, Issue 23 on December 2, 2024
J Clin Invest. 2024;134(23):e169722. https://doi.org/10.1172/JCI169722.
© 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
Received: February 14, 2023; Accepted: October 11, 2024 View PDF 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.

Graphical Abstract Introduction

Adipose tissue plays essential roles in maintaining metabolic homeostasis by serving as a fat reservoir (lipogenesis) and a secretory organ that releases hormones and other biological factors that signal to distal organs. Although increased adipose tissue mass (obesity) is associated with an increased risk for hepatic steatosis, systemic insulin resistance, and cardiometabolic diseases, a subset of people with obesity do not develop these abnormalities and have metabolically healthy obesity (MHO), as opposed to metabolically unhealthy obesity (MUO) (1–3). These studies suggest that dysfunctional adipose tissue (defined here by adipose tissue insulin resistance, inflammation, and fibrosis), not adipose tissue mass, is linked to metabolic disease development. For example, whole-body insulin resistance is associated with decreased adipose tissue lipogenic gene expression in people with MUO compared with people with MHO (3–6). Alternatively, enhanced lipogenic capacity (i.e., lipid storage capacity) in adipose tissue prevents systemic insulin resistance in mouse models of obesity and is associated with increased insulin sensitivity in people (3, 7, 8). Furthermore, adipose tissue inflammation and fibrosis are also associated with insulin resistance and hepatic steatosis in people with obesity (9).

Adipocytes store lipids as triglycerides (TAGs) by the sequential acylation of glycerol-3-phosphate. The penultimate step of TAG synthesis, which is the conversion of phosphatidic acid to diacylglycerol (DAG), is carried out by phosphatidic acid phosphohydrolase (PAP) enzymes known as lipins (10, 11). There are 3 lipin family proteins (lipins 1, 2, and 3) that are differentially expressed in various tissues (12, 13). Lpin1, which encodes lipin 1, was first identified as the gene deleted in fatty liver dystrophic (fld) mice (12), which exhibit severe lipodystrophy associated with systemic metabolic abnormalities (14, 15). Lpin1 is highly expressed in adipocytes and is essential for TAG synthesis in mice through its action as a PAP enzyme. Lipin 1 is also required to initiate adipogenic gene expression programs, likely via the effects of phosphatidic acid on signaling cascades and direct transcriptional regulation of gene expression in the nucleus (16–20). Conditional mice with adipocyte-specific expression of a truncated form of lipin 1, which lacked intrinsic PAP activity but retained activity as a transcriptional regulator, exhibited a lean phenotype (21, 22). These mice also exhibited insulin resistance despite being lean (22), whereas lipin 1–overexpressing mice had increased adiposity yet were insulin sensitive (23). Prior work has also identified correlations between high adipose tissue LPIN1 expression and insulin sensitivity in people (24–26). These studies suggest that high expression of lipin 1 in adipocytes may preserve adipose tissue function and protect from the development of fatty liver, insulin resistance, and other metabolic abnormalities.

Despite these striking effects of modulating of adipocyte lipin 1 activity on metabolic health, the mechanisms by which lipin 1 regulates systemic metabolism, specifically through adipose-liver crosstalk, are poorly understood. Moreover, prior studies of lipin 1 loss-of-function models were complicated by the expression of the truncated lipin 1 protein that retained activity as a transcriptional regulator (21). Herein, we used mice with a floxed Lpin1 allele that was designed to completely delete the lipin 1 protein (27, 28), thereby generating mice with total loss of lipin 1 in adipocytes, and characterized their metabolic phenotype using rigorous metabolic phenotyping and multiomic approaches. In addition, we evaluated LPIN1 gene expression in subcutaneous adipose tissue obtained from people who were metabolically healthy and lean (MHL) and people with MHO and MUO.

Results

Adipose tissue LPIN1 gene expression is decreased in people with MUO and correlates with insulin sensitivity and hepatic de novo lipogenesis. We compared LPIN1 gene expression in subcutaneous abdominal adipose tissue from people who were metabolically healthy and lean (MHL), metabolically healthy with obesity (MHO), and metabolically unhealthy with obesity (MUO), stratified based on body mass index (BMI), glucose tolerance, hemoglobin A1c, and intrahepatic triglyceride (IHTG) content assessed by MRI (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI169722DS1) (11). Gene expression of LPIN1 was highest in the MHL group and progressively decreased from MHL to the MHO and MUO groups (Figure 1A). In addition, LPIN1 expression directly correlated with skeletal muscle insulin sensitivity, defined as the glucose disposal rate (Rd) per kilogram fat-free mass divided by plasma insulin during a hyperinsulinemic-euglycemic clamp procedure (1), and hepatic insulin sensitivity (assessed as the hepatic insulin sensitivity index), which is the reciprocal of the product of basal endogenous glucose production rate and basal plasma insulin concentration (Figure 1C) (2, 3). In contrast, LPIN1 expression was inversely associated with rates of hepatic de novo lipogenesis (DNL) (Figure 1, B–D). These data demonstrate that adipose tissue LPIN1 expression is associated with a healthy metabolic profile in people.

Figure 1

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

Adipocyte-specific Lpin1-knockout mice have reduced fat mass. To test the consequences of adipocyte Lpin1 loss on systemic metabolism, we generated mice with adipocyte-specific Lpin1 deletion (Adn-Lpin1–/–) by using Lpin1-floxed mice crossed with mice expressing adiponectin promoter–driven Cre recombinase. Prior work to delete Lpin1 in adipocytes used a distinct line of floxed mice that resulted in expression of a truncated, partially functional protein (4, 5). However, in the present study we used mice with a floxed allele shown to induce the complete loss of lipin 1 protein in skeletal muscle and heart (6, 7). Loss of lipin 1 protein and Lpin1 gene expression was restricted to adipose tissue (Supplemental Figure 1A