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Adipose-Derived Lipocalin-2 Causes Metabolic Dysfunction Only in Female Mice

ABSTRACT: Lipocalin-2 (LCN2) is a secreted protein involved in innate immunity and also has been associated with several cardiometabolic traits. We examined LCN2 expression in a panel of diverse inbred mouse strains and observed a striking sex difference. Adipose LCN2 was associated with obesity, insulin resistance, dyslipidemia, and hepatic steatosis in females but not males. We expressed LCN2 either in adipose or liver in a tissue specific manner on the background of a whole-body knockout mouse. Adipose LCN2 expression, acting in an autocrine/paracrine manner, promoted metabolic disturbances in females but not males, whereas liver LCN2 expression had no impact on the traits examined. The adipose expression was accompanied by adipose inflammation, fibrosis, and mitochondrial dysfunction, contributing in part to the metabolic disorders. We also show that LCN2 inversely regulates its receptor, LRP2 (or megalin), in a sex-specific manner. Our results demonstrate striking sex- and tissue- specific functions of LCN2.

ORGANISM(S): Mus musculus

PROVIDER: GSE121098 | GEO | 2018/10/11

REPOSITORIES: GEO

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Project description:Rearing conditions may elicit noticeable plastic responses in life-history traits of living organisms. For instance, diet composition has proven to influence prominent traits such as body size, fecundity, and lifespan. In contrast, the social environment may influence the survival rate at immature stages, food consumption, and fat storage. Nevertheless, the physiological mechanisms underlying such responses are largely unknown. In this study, we investigated changes in the proteome of the house cricket Acheta domesticus subjected to diets of different nutritional composition (i.e., protein to carbohydrates ratio) and two distinct social environments (i.e., solitary or in groups). We measured the relative abundances of 685 proteins identified in whole-body cricket samples using high-performance liquid chromatography coupled to tandem mass spectrometry. Differential expression of proteins induced by diet composition and social environment in female and male A. domesticus was assessed in a data-independent proteomics approach. Additionally, we performed a functional analysis of the differentially expressed proteins using comprehensive databases (KEGG and GO). We found that sex alone explained a significant portion (40.87%) of the relative protein abundance variation. Males had a higher representation of proteins involved in metabolic pathways and locomotion. In contrast, females exhibited a higher abundance of proteins related to genetic processes regulation and nutrient catabolism. Moreover, diet composition and social environment induced sex-specific changes in a smaller set of proteins with particular roles. Females had their protein profile affected by diet composition and social environment. The involved proteins were mainly related to several protein synthesis stages, carbohydrate metabolism, and muscle development. In contrast, males were only affected by diet composition, overexpressing proteins related to hormone production, carbohydrate metabolism, and apparently depositing excess protein in the cuticle when fed with a protein-rich diet. It was evident that diet had a more substantial influence on the proteome of the cricket A. domesticus than the social environment, showing that diet composition may exert profound physiological changes in insects in a sex-specific manner.

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Adipose-Derived Lipocalin-2 Causes Metabolic Dysfunction Only in Female Mice

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