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

doi:10.1016/j.molmet.2019.09.009

Sex-specific metabolic functions of adipose Lipocalin-2

Mol Metab. 2019 Dec:30:30-47. doi: 10.1016/j.molmet.2019.09.009. Epub 2019 Sep 27.

Authors

Karthickeyan Chella Krishnan¹, Simon Sabir², Michaël Shum³, Yonghong Meng⁴, Rebeca Acín-Pérez³, Jennifer M Lang⁴, Raquel R Floyd⁵, Laurent Vergnes⁶, Marcus M Seldin⁴, Brie K Fuqua⁴, Dulshan W Jayasekera⁷, Sereena K Nand⁵, Diana C Anum⁸, Calvin Pan⁴, Linsey Stiles³, Miklós Péterfy⁹, Karen Reue⁶, Marc Liesa¹⁰, Aldons J Lusis¹¹

Affiliations

¹ Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA. Electronic address: kchellakrishnan@mednet.ucla.edu.
² Department of Psychology, University of California, Los Angeles, CA, USA.
³ Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA.
⁴ Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
⁵ Department of Biology, University of California, Los Angeles, CA, USA.
⁶ Department of Human Genetics, University of California, Los Angeles, CA, USA.
⁷ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA.
⁸ Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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. Electronic address: JLusis@mednet.ucla.edu.

Abstract

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: Adipose fibrosis; Adipose inflammation; Diet-induced obesity; Insulin resistance; Mitochondrial dysfunction; Sex differences.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism*
Adiposity
Animals
Body Composition
Body Weight
Female
Glucose / analysis
Homeostasis
Insulin Resistance
Lipids / analysis
Lipocalin-2 / genetics
Lipocalin-2 / metabolism*
Lipocalin-2 / physiology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Obesity / metabolism
Sex Factors

Substances

Lipids
Lipocalin-2
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding