Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue

Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high-fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, whereas the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2−/− mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2−/− mice than in WT mice. In Lcn2−/− mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of peroxisome proliferator-activated receptor-γ protein was significantly down-regulated, whereas the gene expression of extracellular matrix proteins was up-regulated selectively in epididymal adipocytes of Lcn2−/− mice. Consistent with these observations, collagen deposition was selectively higher in the epididymal, but not in the inguinal adipose depot of Lcn2−/− mice. Administration of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did not alter the responsiveness of adipose tissue to Rosi effects on the extracellular matrix expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2−/− mice, which may be associated with a more pronounced effect of Rosi treatment in reducing TGF-β in Lcn2−/− adipose tissue. Consistent with these in vivo observations, Lcn2 deficiency reduces the adipocyte differentiation capacity of stromal-vascular cells isolated from HFD-fed mice in these cells. Herein Rosi treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2−/− inguinal and epididymal stromal-vascular cells. Thus, combined, our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling.

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Lipocalin 2 Deficiency Alters Estradiol Production and Estrogen Receptor Signaling in Female Mice

Endocrinology ◽

10.1210/en.2011-1642 ◽

2012 ◽

Vol 153 (3) ◽

pp. 1183-1193 ◽

Cited By ~ 30

Author(s):

Hong Guo ◽

Yuanyuan Zhang ◽

David A. Brockman ◽

Wendy Hahn ◽

David A. Bernlohr ◽

...

Keyword(s):

Estrogen Receptor ◽

Adipose Tissue ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipocalin 2 ◽

Wild Type ◽

Female Mice ◽

Estrogen Receptor Signaling ◽

Age Related

We have previously characterized lipocalin 2 (Lcn2) as a new adipokine having a critical role in energy and lipid metabolism in male mice. Previous studies by others have suggested that Lcn2 is a putative target gene of estrogens. In this study, we reported the effect of Lcn2 deficiency on estradiol biosynthesis and estrogen receptor signaling in female Lcn2-deficient (Lcn2−/−) mice. We found that Lcn2 expression in white adipose tissue is gender, depot, and age dependent. In female mice, Lcn2 is predominantly expressed in inguinal adipose tissue but at relatively very low levels in perigonadal depot and ovary. After 22 wk of high-fat diet (HFD) feeding or at old age, Lcn2−/− female mice had significantly reduced levels of serum 17β-estradiol and down-regulated expression of estrogen receptor α in multiple metabolic tissues. Consistently, the expression of estrogen-regulated genes involved in cholesterol homeostasis, such as liver X receptor β and low-density lipoprotein receptor was also down-regulated in the adipose tissue of Lcn2−/− mice. These changes were in line with the development of atherogenic dyslipidemia in response to HFD feeding; female Lcn2−/− mice had significantly elevated levels of total cholesterol and low-density lipoprotein cholesterol, whereas reduced high-density lipoprotein cholesterol levels compared with wild-type female mice. Interestingly, when compared with wild-type controls, HFD-fed female Lcn2−/− mice had significantly reduced expression levels of aromatase, a key enzyme regulating estradiol biosynthesis, in adipose tissue. Moreover, Lcn2 deficiency markedly blunted age-related increase in adipose aromatase expression but had no significant impact on age-related reduction in ovarian aromatase expression. Our findings suggest that Lcn2 has a tissue-specific role in adipose estradiol biosynthesis, which may link Lcn2 to obesity- and age-related estradiol production and metabolic complications in females.

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Adipokines levels in HIV infected patients: lipocalin-2 and fatty acid binding protein-4 as possible markers of HIV and antiretroviral therapy-related adipose tissue inflammation

BMC Infectious Diseases ◽

10.1186/s12879-017-2925-4 ◽

2018 ◽

Vol 18 (1) ◽

Cited By ~ 5

Author(s):

Mario Luca Morieri ◽

Viola Guardigni ◽

Juana Maria Sanz ◽

Edoardo Dalla Nora ◽

Cecilia Soavi ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Antiretroviral Therapy ◽

Fatty Acid Binding Protein ◽

Binding Protein ◽

Adipose Tissue Inflammation ◽

Lipocalin 2 ◽

Fatty Acid Binding ◽

Tissue Inflammation ◽

Acid Binding Protein

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Lipocalin 2 regulates retinoic acid-induced activation of beige adipocytes

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0017 ◽

2018 ◽

Vol 61 (3) ◽

pp. 115-126 ◽

Cited By ~ 2

Author(s):

Jessica A Deis ◽

Hong Guo ◽

Yingjie Wu ◽

Chengyu Liu ◽

David A Bernlohr ◽

...

Keyword(s):

Adipose Tissue ◽

Retinoic Acid ◽

Uncoupling Protein ◽

Oxidative Capacity ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Lipocalin 2 ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Beige Adipocytes

Lipocalin-2 (LCN2) has been previously characterized as an adipokine regulating thermogenic activation of brown adipose tissue and retinoic acid (RA)-induced thermogenesis in mice. The objective of this study was to explore the role and mechanism for LCN2 in the recruitment and retinoic acid-induced activation of brown-like or ‘beige’ adipocytes. We found LCN2 deficiency reduces key markers of thermogenesis including uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in inguinal white adipose tissue (iWAT) and inguinal adipocytes derived from Lcn2 −/− mice. Lcn2 −/− inguinal adipocytes have attenuated insulin-induced upregulation of thermogenic gene expression and p38 mitogen-activated protein kinase (p38MAPK) signaling pathway activation. This is accompanied by a lower basal and maximal oxidative capacity in Lcn2 −/− inguinal adipocytes, indicating mitochondrial dysfunction. Recombinant Lcn2 was able to restore insulin-induced p38MAPK phosphorylation in both WT and Lcn2 −/− inguinal adipocytes. Rosiglitazone treatment during differentiation of Lcn2 −/− adipocytes is able to recruit beige adipocytes at a normal level, however, further activation of beige adipocytes by insulin and RA is impaired in the absence of LCN2. Further, the synergistic effect of insulin and RA on UCP1 and PGC-1α expression is markedly reduced in Lcn2 −/− inguinal adipocytes. Most intriguingly, LCN2 and the retinoic acid receptor-alpha (RAR-α) are concurrently translocated to the plasma membrane of adipocytes in response to insulin, and this insulin-induced RAR-α translocation is absent in adipocytes deficient in LCN2. Our data suggest a novel LCN2-mediated pathway by which RA and insulin synergistically regulates activation of beige adipocytes via a non-genomic pathway of RA action.

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Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2016.03.011 ◽

2016 ◽

Vol 427 ◽

pp. 124-132 ◽

Cited By ~ 17

Author(s):

Prasad G. Kamble ◽

Maria J. Pereira ◽

Cherno O. Sidibeh ◽

Sam Amini ◽

Magnus Sundbom ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Human Adipose Tissue ◽

Lipocalin 2

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Acinetobacter baumanniiLipopolysaccharide Influences Adipokine Expression in 3T3-L1 Adipocytes

Mediators of Inflammation ◽

10.1155/2017/9039302 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Yuka Unno ◽

Yoshinori Sato ◽

Satoshi Nishida ◽

Akiyo Nakano ◽

Ryuichi Nakano ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Potential Role ◽

Molecular Level ◽

Opportunistic Pathogen ◽

Lipocalin 2 ◽

Increased Risk ◽

Adipocyte Cell

Acinetobacter baumanniiis one of the most important nosocomial opportunistic pathogen worldwide. In addition, obesity has been associated with an increased risk of nosocomial infection, suggesting that there may be an association betweenA. baumanniiand white adipose tissue. However, the effects ofA. baumanniion adipocytes have not been well studied at the molecular level. Here, we investigated the potential role ofA. baumannii-derived lipopolysaccharides (LPS) as signaling molecules that affect adipocyte functionality. We tested the effect of increasing concentrations ofA. baumannii-derived LPS (10, 100, or 1000 ng/mL) on the 3T3-L1 adipocyte cell line. Exposure to LPS was found to increase the expression of several adipokines (e.g., MIP-2, MCP-1, TNF-α, IL-6, lipocalin-2, and FABP4) in 3T3-L1 adipocytes and significantly reduced the expression of leptin and adiponectin. The effects ofA. baumannii-derived LPS on MIP-2 expression were similar in comparison with that of LPS prepared fromPseudomonas aeruginosaandEscherichia coliin our cell culture-based system. This study suggests thatA. baumannii-derived LPS functions as a signaling molecule that impacts the inflammatory function of white adipose tissue on the level of gene expression.

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