Abstract

Simple SummaryObesity is associated with the development of metabolic disorders and alterations in immune responses. Notably, obesity-induced inflammation promotes the chronic activation of T-cells, which may result in the aberrant expression of their regulatory markers. Programmed cell death -1 (PD-1) and Fas (CD95) are some of the important modulators of T-cell function. Although it is apparent that their expression is dysregulated in obesity, it remains unclear whether the eventual T-cell dysfunction is due to the upregulation or downregulation of these markers. Therefore, this study aimed to assess the expression of PD-1 and Fas in T-cells in metabolic disorders.This study was conducted to assess the expression of Fas (CD95) and programmed cell death-1 (PD-1) on circulating T-cells in obesity using a diet-induced obesity mouse model. Furthermore, we aimed to determine if there are any associations between metabolic disorders and the expression of T-cell regulatory markers. A total of 12 male C57BL/6 mice were randomized into either a high-fat diet (HFD) or low-fat diet (LFD) group for 8 weeks (n = 6/group). Changes in body weights were monitored on a weekly basis. The lipid, glucose, and hematological profiles, as well as Fas and PD1 expression on the T-cell immunophenotype, were measured after 8 weeks of feeding. The HFD-fed group had a higher percentage weight gain (29.17%) in comparison with the LFD-fed group (21.74%) after the 8-week period. In addition, the HFD group had increased fasting glucose and glucose excursion following a 2-h postprandial period. The levels of total cholesterol were elevated in the HFD group when compared with the LFD group (p < 0.05). Notably, the absolute white cell count (p = 0.0096), neutrophil count (p = 0.0022, lymphocytes (p = 0.0155), and monocyte count (p = 0.0015) were elevated in the HFD group when compared with the LFD-fed group. However, the platelets (0.0680), red cell counts (0.3575), and their indices (p > 0.05) were comparable between the two groups. Interestingly, HFD feeding was associated with elevated expression of Fas on T-cells (p < 0.0001), which positively correlated with body weights (r = 0.93, p = 0.0333). No associations were found between Fas expression and dyslipidemia or fasting blood glucose levels (p > 0.05). The multivariant regression analysis showed that the association between the levels of Fas on T-cells and body weights (coefficient: −1.00, t-value: 19.27, p = 0.0330) was independent of fasting blood glucose, total cholesterol, and lymphocyte count. Lastly, the expression of PD-1 on T-cells was comparable between the two diet groups (p = 0.1822). In all, immune activation, dyslipidemia, and poor glucose control in the early stages of obesity may drive the pathogenesis of metabolic T-cell disorders. Importantly, T-cell dysfunction in obesity is partially mediated by an upregulation of Fas which is independent of dyslipidemia and hyperglycemia.

Highlights

  • The prevalence of obesity has rapidly increased over the years [1], with more than two-thirds of individuals with obesity at high risk of developing metabolic syndrome and cardiovascular disease (CVD) [2,3]

  • When we assessed the lipid profiles, only the total cholesterol levels were elevated in the high-fat diet diet (HFD)-fed group, whereas low-density lipoprotein (LDL) cholesterol and HDL cholesterol remained comparable between the two diet groups

  • Our results showed that HFD-fed mice gained weight and had a significantly elevated WCC, which was indicative of a pro-inflammatory state in obesity

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Summary

Introduction

The prevalence of obesity has rapidly increased over the years [1], with more than two-thirds of individuals with obesity at high risk of developing metabolic syndrome and cardiovascular disease (CVD) [2,3]. The exacerbated levels of interleukin (IL)-6 and leptin in obesity result in the downstream activation of STAT3 signaling [8,9], which is closely associated with insulin resistance [10] The manifestation of the latter has been attributed to the blockage of insulin signaling transduction induced by an upregulation of suppressor of cytokine signaling 3 expression in obesity [11]. We previously described the involvement of T-cells in obesity-induced immune activation, insulin resistance, and impaired glucose control [7] The former is strongly associated with T-cell dysfunction [12], mediated by increased expression of regulatory markers such as Fas (CD95) and programmed cell death-1 (PD-1) [13,14]

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