Urocortin Neuropeptide Levels Are Impaired in the PBMCs of Overweight Children

Sina Kavalakatt 1 2, Abdelkrim Khadir 1, Shihab Kochumon 3, Dhanya Madhu 1, Sriraman Devarajan 4, Maha Hammad 1, Nada Alam-Eldin 1, Samia Warsame 4, Hessa Al-Kandari 5, Maria AlMahdi 5, Rasheed Ahmad 3, Heikki A Koistinen 6 7 8, Jaakko Tuomilehto 8 9 10, Fahd Al-Mulla 4, Jehad Abubaker 1, Ali Tiss 1

Affiliations

18 January 2022

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doi: 10.3390/nu14030429

Abstract

The corticotropin-releasing hormone (CRH) and urocortins (UCNs) have been implicated in energy homeostasis and the cellular stress response. However, the expression of these neuropeptides in children remains unclear. Therefore, we determined the impact of obesity on their expression in 40 children who were normal weight, overweight, and had obesity. Peripheral blood mononuclear cells (PBMCs) and plasma were used to assess the expression of neuropeptides. THP1 cells were treated with 25 mM glucose and 200 µM palmitate, and gene expression was measured by real-time polymerase chain reaction (RT-PCR). Transcript levels of neuropeptides were decreased in PBMCs from children with increased body mass index as indicated by a significant decrease in UCN1, UCN3, and CRH mRNA in overweight and obese children. UCN3 mRNA expression was strongly correlated with UCN1, UCN2, and CRH. Exposure of THP1 cells to palmitate or a combination of high glucose and palmitate for 24 h increased CRH, UCN2, and UCN3 mRNA expression with concomitant increased levels of inflammatory and endoplasmic reticulum stress markers, suggesting a crosstalk between these neuropeptides and the cellular stress response. The differential impairment of the transcript levels of CRH and UCNs in PBMCs from overweight and obese children highlights their involvement in obesity-related metabolic and cellular stress.

Keywords: CRH; UCN3; children; obesity; urocortin.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1 Gene expression levels in PBMCs according to body weight. mRNA expression levels of UCN1, UCN2, UCN3, CRH, and spexin were measured by quantitative real-time PCR in PBMCs from normal weight (n = 8), overweight (n = 10), and obese children (n = 22). Data are normalized to internal GAPDH and presented as fold-changes compared with normal weight data. One-way ANOVA followed by Bonferroni´s post hoc test were used to determine the significance of difference in means between groups (* p < 0.05, ** p < 0.01). NW (•), OW (■), and OB (▲).

Figure 1 Gene expression levels in PBMCs according to body weight. mRNA expression levels of UCN1, UCN2, UCN3, CRH, and spexin were measured by quantitative real-time PCR in PBMCs from normal weight (n = 8), overweight (n = 10), and obese children (n = 22). Data are normalized to internal GAPDH and presented as fold-changes compared with normal weight data. One-way ANOVA followed by Bonferroni´s post hoc test were used to determine the significance of difference in means between groups (* p < 0.05, ** p < 0.01). NW (•), OW (■), and OB (▲).

Figure 2 Gene expression in THP1 cells treated for four hours. mRNA expression levels of UCN1, UCN2, UCN3, CRH, and spexin were measured by quantitative real-time PCR in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) or the combination for 4 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of the differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 2 Gene expression in THP1 cells treated for four hours. mRNA expression levels of UCN1, UCN2, UCN3, CRH, and spexin were measured by quantitative real-time PCR in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) or the combination for 4 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of the differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 3 Gene and protein expression levels in THP1 cells treated for twenty-four hours. mRNA (A) and protein (B) expression levels of UCN1, UCN2, UCN3, CRH, and Spexin were respectively measured by quantitative real-time PCR and Western blots in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and the combination for 24 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of the differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 3 Gene and protein expression levels in THP1 cells treated for twenty-four hours. mRNA (A) and protein (B) expression levels of UCN1, UCN2, UCN3, CRH, and Spexin were respectively measured by quantitative real-time PCR and Western blots in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and the combination for 24 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of the differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 3 Gene and protein expression levels in THP1 cells treated for twenty-four hours. mRNA (A) and protein (B) expression levels of UCN1, UCN2, UCN3, CRH, and Spexin were respectively measured by quantitative real-time PCR and Western blots in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and the combination for 24 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of the differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 3 Gene and protein expression levels in THP1 cells treated for twenty-four hours. mRNA (A) and protein (B) expression levels of UCN1, UCN2, UCN3, CRH, and Spexin were respectively measured by quantitative real-time PCR and Western blots in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and the combination for 24 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of the differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 4 Gene expression levels of inflammatory and ER stress markers in THP1 cells treated for four hours. Gene expression levels of inflammatory markers (TNFα, IL10, IL6, CCL2) and ER stress markers (ATF6, PERK, IRE1, PKR and CHOP) were measured by quantitative real-time PCR in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and the combination for 4 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with Control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 4 Gene expression levels of inflammatory and ER stress markers in THP1 cells treated for four hours. Gene expression levels of inflammatory markers (TNFα, IL10, IL6, CCL2) and ER stress markers (ATF6, PERK, IRE1, PKR and CHOP) were measured by quantitative real-time PCR in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and the combination for 4 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with Control data. One-way ANOVA with repeated measurements followed by Sidak´s post hoc test were used to determine the significance of differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 5 Gene expression levels of inflammatory and ER stress markers in THP1 cells treated for twenty-four hours. Gene expression levels of inflammatory markers (TNFα, IL10, IL6, CCL2) and ER stress markers (ATF6, PERK, IRE1, PKR and CHOP) were measured by quantitative real-time PCR in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and their combination for 24 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with Control data. One-way ANOVA with repeated measurements followed by Sidak’s post hoc test were used to determine the significance of differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 5 Gene expression levels of inflammatory and ER stress markers in THP1 cells treated for twenty-four hours. Gene expression levels of inflammatory markers (TNFα, IL10, IL6, CCL2) and ER stress markers (ATF6, PERK, IRE1, PKR and CHOP) were measured by quantitative real-time PCR in THP1 cells treated with high glucose (25 mM), palmitate (200 µM) and their combination for 24 h (n = 3 for each condition). Data are normalized to internal GAPDH and presented as fold-change compared with Control data. One-way ANOVA with repeated measurements followed by Sidak’s post hoc test were used to determine the significance of differences in means between the groups (* p < 0.05, ** p < 0.01, *** p < 0.001).

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