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Sex-specific metabolic functions of adipose Lipocalin-2.
Chella Krishnan, Karthickeyan; Sabir, Simon; Shum, Michaël; Meng, Yonghong; Acín-Pérez, Rebeca; Lang, Jennifer M; Floyd, Raquel R; Vergnes, Laurent; Seldin, Marcus M; Fuqua, Brie K; Jayasekera, Dulshan W; Nand, Sereena K; Anum, Diana C; Pan, Calvin; Stiles, Linsey; Péterfy, Miklós; Reue, Karen; Liesa, Marc; Lusis, Aldons J.
Afiliación
  • Chella Krishnan K; Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA. Electronic address: kchellakrishnan@mednet.ucla.edu.
  • Sabir S; Department of Psychology, University of California, Los Angeles, CA, USA.
  • Shum M; Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA.
  • Meng Y; Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
  • Acín-Pérez R; Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA.
  • Lang JM; Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
  • Floyd RR; Department of Biology, University of California, Los Angeles, CA, USA.
  • Vergnes L; Department of Human Genetics, University of California, Los Angeles, CA, USA.
  • Seldin MM; Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
  • Fuqua BK; Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
  • Jayasekera DW; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA.
  • Nand SK; Department of Biology, University of California, Los Angeles, CA, USA.
  • Anum DC; Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
  • Pan C; Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
  • Stiles L; Department of Medicine/Division of Endocrinology, University of California, Los Angeles, CA, USA.
  • Péterfy M; 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.
  • Reue K; Department of Human Genetics, University of California, Los Angeles, CA, USA.
  • Liesa M; 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.
  • Lusis AJ; 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 addre
Mol Metab ; 30: 30-47, 2019 12.
Article en En | MEDLINE | ID: mdl-31767179
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Tejido Adiposo / Lipocalina 2 Límite: Animals Idioma: En Revista: Mol Metab Año: 2019 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Tejido Adiposo / Lipocalina 2 Límite: Animals Idioma: En Revista: Mol Metab Año: 2019 Tipo del documento: Article