Sex-specific metabolic functions of adipose Lipocalin-2

Karthickeyan Chella Krishnan; Simon Sabir; Michaël Shum; Yonghong Meng; Rebeca Acín-Pérez; Jennifer M. Lang; Raquel R. Floyd; Laurent Vergnes; Marcus M. Seldin; Brie K. Fuqua; Dulshan W. Jayasekera; Sereena K. Nand; Diana C. Anum; Calvin Pan; Linsey Stiles; Miklós Péterfy; Karen Reue; Marc Liesa; Aldons J. Lusis

Molecular Metabolism (Dec 2019)

Sex-specific metabolic functions of adipose Lipocalin-2

Karthickeyan Chella Krishnan,
Simon Sabir,
Michaël Shum,
Yonghong Meng,
Rebeca Acín-Pérez,
Jennifer M. Lang,
Raquel R. Floyd,
Laurent Vergnes,
Marcus M. Seldin,
Brie K. Fuqua,
Dulshan W. Jayasekera,
Sereena K. Nand,
Diana C. Anum,
Calvin Pan,
Linsey Stiles,
Miklós Péterfy,
Karen Reue,
Marc Liesa,
Aldons J. Lusis

Affiliations

Karthickeyan Chella Krishnan: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA; Corresponding author. UCLA, Department of Medicine/Division of Cardiology, 650 Charles E. Young Drive South, Box 951679, Los Angeles, CA, 90095-1679, USA.
Simon Sabir: Department of Psychology, University of California, Los Angeles, CA, USA
Michaël Shum: Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA
Yonghong Meng: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
Rebeca Acín-Pérez: Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA
Jennifer M. Lang: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
Raquel R. Floyd: Department of Biology, University of California, Los Angeles, CA, USA
Laurent Vergnes: Department of Human Genetics, University of California, Los Angeles, CA, USA
Marcus M. Seldin: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
Brie K. Fuqua: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
Dulshan W. Jayasekera: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA
Sereena K. Nand: Department of Biology, University of California, Los Angeles, CA, USA
Diana C. Anum: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Calvin Pan: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA
Linsey Stiles: Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA
Miklós Péterfy: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA; Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA, USA
Karen Reue: Department of Human Genetics, University of California, Los Angeles, CA, USA
Marc Liesa: Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
Aldons J. Lusis: Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA; Corresponding author. UCLA, Department of Medicine/Division of Cardiology, 650 Charles E. Young Drive South, Box 951679, Los Angeles, CA, 90095-1679, USA.

Journal volume & issue: Vol. 30
pp. 30 – 47

Abstract

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Objective: Lipocalin-2 (LCN2) is a secreted protein involved in innate immunity and has also been associated with several cardiometabolic traits in both mouse and human studies. However, the causal relationship of LCN2 to these traits is unclear, and most studies have examined only males. Methods: Using adeno-associated viral vectors we expressed LCN2 in either adipose or liver in a tissue specific manner on the background of a whole-body Lcn2 knockout or wildtype mice. Metabolic phenotypes including body weight, body composition, plasma and liver lipids, glucose homeostasis, insulin resistance, mitochondrial phenotyping, and metabolic cage studies were monitored. Results: We studied the genetics of LCN2 expression and associated clinical traits in both males and females in a panel of 100 inbred strains of mice (HMDP). The natural variation in Lcn2 expression across the HMDP exhibits high heritability, and genetic mapping suggests that it is regulated in part by Lipin1 gene variation. The correlation analyses revealed striking tissue dependent sex differences in obesity, insulin resistance, hepatic steatosis, and dyslipidemia. To understand the causal relationships, we examined the effects of expression of LCN2 selectively in liver or adipose. On a Lcn2-null background, LCN2 expression in white adipose promoted metabolic disturbances in females but not males. It acted in an autocrine/paracrine manner, resulting in mitochondrial dysfunction and an upregulation of inflammatory and fibrotic genes. On the other hand, on a null background, expression of LCN2 in liver had no discernible impact on the traits examined despite increasing the levels of circulating LCN2 more than adipose LCN2 expression. The mechanisms underlying the sex-specific action of LCN2 are unclear, but our results indicate that adipose LCN2 negatively regulates its receptor, LRP2 (or megalin), and its repressor, ERα, in a female-specific manner and that the effects of LCN2 on metabolic traits are mediated in part by LRP2. Conclusions: Following up on our population-based studies, we demonstrate that LCN2 acts in a highly sex- and tissue-specific manner in mice. Our results have important implications for human studies, emphasizing the importance of sex and the tissue source of LCN2. Keywords: Sex differences, Diet-induced obesity, Insulin resistance, Adipose fibrosis, Adipose inflammation, Mitochondrial dysfunction

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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