Lipocalin-2 is an anorexigenic signal in primates

Πετροπούλου, Περιστέρα-Ιωάννα; Mosialou, Ioanna; Shikhel, Steven; Hao, Lihong; Panitsas, Konstantinos; Bisikirska, Brygida; Luo, Na; Bahna, Fabiana; Kim, Jongho; Carberry, Patrick; Zanderigo, Francesca; Simpson, Norman R.; Bakalian, Mihran J.; Kassir, Suham; Shapiro, Lawrence; Underwood, Mark D.; May, Christina; Sai, Kiran Kumar Soligapuram; Jorgensen, Matthew J.; Confavreux, Cyrille; Shapses, Sue; Laferrère, Blandine; Mintz, Akiva; Mann, J. John; Rubin, Mishaela R.; Kousteni, Stavroula

doi:10.7554/elife.58949

Cited by 31 publications

(39 citation statements)

References 29 publications

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“…In our study, 56% of the cell cycle-associated lncRNAs were assigned to S phase, whereas 19% were assigned to G1. All of our candidate lncRNAs were identified in the study by Hao et al 65 where SNHG26 , EPB41L4A-AS1 , and EMSLR showed reduced expression levels in S phase, which is in line with our results. We do note the differences between these studies in the number of identified lncRNAs and in their phase-specific expression characteristics.…”

Section: Discussionsupporting

confidence: 89%

“…The data included three time points in the subsequent S-phase and their analyses identified 1145 lncRNAs with temporal expression changes. Hao et al 65 used deep RNA-seq of U2OS cells synchronized to different phases of the cell cycle and identified more than 2000 lncRNAs that had phase-specific expression. Cells were synchronized to different stages by nocodazole (M) followed by mitotic shake-off (G1), and by double thymidine block (G1/S) and subsequent isolation at 4 h (S) and 8 h (G2) following release.…”

Section: Discussionmentioning

confidence: 99%

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Joint changes in RNA, RNA polymerase II, and promoter activity through the cell cycle identify non-coding RNAs involved in proliferation

Hegre

Samdal

Klima

et al. 2021

Sci Rep

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Proper regulation of the cell cycle is necessary for normal growth and development of all organisms. Conversely, altered cell cycle regulation often underlies proliferative diseases such as cancer. Long non-coding RNAs (lncRNAs) are recognized as important regulators of gene expression and are often found dysregulated in diseases, including cancers. However, identifying lncRNAs with cell cycle functions is challenging due to their often low and cell-type specific expression. We present a highly effective method that analyses changes in promoter activity, transcription, and RNA levels for identifying genes enriched for cell cycle functions. Specifically, by combining RNA sequencing with ChIP sequencing through the cell cycle of synchronized human keratinocytes, we identified 1009 genes with cell cycle-dependent expression and correlated changes in RNA polymerase II occupancy or promoter activity as measured by histone 3 lysine 4 trimethylation (H3K4me3). These genes were highly enriched for genes with known cell cycle functions and included 57 lncRNAs. We selected four of these lncRNAs—SNHG26, EMSLR, ZFAS1, and EPB41L4A-AS1—for further experimental validation and found that knockdown of each of the four lncRNAs affected cell cycle phase distributions and reduced proliferation in multiple cell lines. These results show that many genes with cell cycle functions have concomitant cell-cycle dependent changes in promoter activity, transcription, and RNA levels and support that our multi-omics method is well suited for identifying lncRNAs involved in the cell cycle.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Joint changes in RNA, RNA polymerase II, and promoter activity through the cell cycle identify non-coding RNAs involved in proliferation

Hegre

Samdal

Klima

et al. 2021

Sci Rep

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“…Targeting instead the pathway downstream of these factors may a better therapeutic strategy. Specifically, directly stimulating MC4R by injecting the satiety hormone, LIPOCALIN-2 (38), which anorexigenic effect is conserved between rodents, non-human primates and humans (42), could block the effect of Flx on feeding and therefore limit weight gain in patients. Additional studies analyzing LCN2 pharmacology and safety profile are, however, needed to establish its value as a co-drug and in particular to assess its effect on blood pressure and heart rate, as other MC4R agonists have been clinically abandoned due to unacceptable increases in these parameters (43).…”

Section: Discussionmentioning

confidence: 99%

Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure

Ortuño¹,

Schneeberger²,

Ilanges³

et al. 2021

Journal of Clinical Investigation

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Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, longterm use of selective serotonin reuptake inhibitors (SSRIs) antidepressants correlates with body weight gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased body weight by enhancing food intake in healthy mice at two different time points and through two distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through the Htr1a receptor. Upon longer treatment Flx blunted Htr2c expression/signaling, decreased the phosphorylation of Creb and Stat3 and dampened the production of POMC/-MSH in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (MC4R) by co-treating mice with Flx and lipocalin-2, an anorexigenic hormone signaling through this receptor, normalized feeding and body weight. Flx and other SSRIs also inhibit CREB/STAT3 phosphorylation in a human neuronal cell line suggesting that these non-canonical effects could also occur in long-term users of SSRIs. By defining the molecular basis of the long-term SSRIsassociated weight gain this study proposes a therapeutic strategy to counter it.

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“…An 8-week rosiglitazone treatment decreases the plasma levels of CRP as well as LCN2. Petropoulou et al showed that circulating LCN2 increases after a meal in lean individuals, but not in obese subjects, and this increase correlates with a reduced hunger feeling [ 84 ], suggesting an anorexigenic effect of LCN2 in lean humans. This was supported by human LCN2 administration in monkeys, which displayed an acute 21% reduced food intake without short-time side effects.…”

Section: Lcn2mentioning

confidence: 99%

Adipose-Derived Lipid-Binding Proteins: The Good, the Bad and the Metabolic Diseases

Frances

Tavernier

Viguerie

2021

IJMS

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Adipose tissue releases a large range of bioactive factors called adipokines, many of which are involved in inflammation, glucose homeostasis and lipid metabolism. Under pathological conditions such as obesity, most of the adipokines are upregulated and considered as deleterious, due to their pro-inflammatory, pro-atherosclerotic or pro-diabetic properties, while only a few are downregulated and would be designated as beneficial adipokines, thanks to their counteracting properties against the onset of comorbidities. This review focuses on six adipose-derived lipid-binding proteins that have emerged as key factors in the development of obesity and diabetes: Retinol binding protein 4 (RBP4), Fatty acid binding protein 4 (FABP4), Apolipoprotein D (APOD), Lipocalin-2 (LCN2), Lipocalin-14 (LCN14) and Apolipoprotein M (APOM). These proteins share structural homology and capacity to bind small hydrophobic molecules but display opposite effects on glucose and lipid metabolism. RBP4 and FABP4 are positively associated with metabolic syndrome, while APOD and LCN2 are ubiquitously expressed proteins with deleterious or beneficial effects, depending on their anatomical site of expression. LCN14 and APOM have been recently identified as adipokines associated with healthy metabolism. Recent findings on these lipid-binding proteins exhibiting detrimental or protective roles in human and murine metabolism and their involvement in metabolic diseases are also discussed.

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Lipocalin-2 is an anorexigenic signal in primates

Cited by 31 publications

References 29 publications

Joint changes in RNA, RNA polymerase II, and promoter activity through the cell cycle identify non-coding RNAs involved in proliferation

Joint changes in RNA, RNA polymerase II, and promoter activity through the cell cycle identify non-coding RNAs involved in proliferation

Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure

Adipose-Derived Lipid-Binding Proteins: The Good, the Bad and the Metabolic Diseases

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