New mechanistic insights on the metabolic-disruptor role of chlorpyrifos in apoE mice: a focus on insulin- and leptin-signalling pathways

Abstract

Recently, we have provided evidence, suggesting that mice expressing the human apolipoprotein E3 (apoE3) are more prone to develop an obesity-like phenotype and a diabetic profile when subchronically fed a chlorpyrifos (CPF)-supplemented diet. The aim of the current study was to examine the underlying mechanisms through which CPF alters both insulin- and leptin-signalling pathways in an APOE-dependent manner. Both adult apoE3- and E4-targeted replacement and C57BL/6 mice were exposed to CPF at 0 or 2 mg/kg body weight/day through the diet for 8 consecutive weeks. We determined the expression of JAK2, p-JAK2, STAT3, p-STAT3, SOCS3, IRS-1, p-IRS-1, AKT, p-AKT, GSK3β, p-GSK3β, and apoE in the liver, as well as hepatic mRNA levels of pon1, pon2, and pon3. CPF markedly disrupted both leptin and insulin homeostasis, particularly in apoE3 mice. Indeed, only CPF-fed apoE3 mice exhibited an increased phosphorylation ratio of STAT3, as well as increased total SOCS3 protein levels. Similarly, the exposure to CPF drastically reduced the phosphorylation ratio of both AKT and GSK3β, especially in apoE3 mice. Overall, CPF reduced the expression of the three pon genes, principally in C57BL/6 and apoE3 mice. These results provide notable mechanistic insights on the metabolic effects of the pesticide CPF, and attest the increased vulnerability of apoE3 carriers to its metabolic-disruptor role.

Sex and Exposure to Postnatal Chlorpyrifos Influence the Epigenetics of Feeding-Related Genes in a Transgenic APOE Mouse Model: Long-Term Implications on Body Weight after a High-Fat Diet

“…The present investigation was designed to study how APOE genotype, sex, and postnatal exposure to the pesticide CPF regulates the methylation of genes involved in feeding control, and how these epigenetic modifications can condition the subject's outcomes in an obesogenic environment with a HFD. In recent studies, we have reported the capacity of CPF to alter insulin and leptin signaling pathways [17], and to increase body weight in a genotype-dependent manner [8,9]. Even though the underlying mechanisms have not been yet completely elucidated, we hypothesize that epigenetic modifications may be involved.…”

“…Gene expression analysis of Lepr in the hypothalamus has found a tendency towards an interaction between genotype and treatment, which highlights the potential influence of CPF on leptin signaling. Previous studies with males have reported that the APOE genotype determines the response to CPF in terms of the hepatic protein expression of the SOCS3 and the ratio between phospho-STATS3 and total STATS3, both involved in the leptin signaling pathway [17]. Indeed, CPF-treated apoE3-TR males presented higher levels than apoE4-TR males [17].…”

“…Previous studies with males have reported that the APOE genotype determines the response to CPF in terms of the hepatic protein expression of the SOCS3 and the ratio between phospho-STATS3 and total STATS3, both involved in the leptin signaling pathway [17]. Indeed, CPF-treated apoE3-TR males presented higher levels than apoE4-TR males [17]. Interestingly, in the present investigation the results of gene expression negatively correlated with the data of methylation analysis, suggesting that higher methylation inhibits gene expression and vice-versa.…”

“…The different isoforms of the APOE gene also have different responses to toxic insults, including exposure to CPF [15,16]. The greater vulnerability of mice carrying the human form of the APOE3 gene to developing an obese-like phenotype [8,9] is explained by the capacity of CPF to disrupt the homeostasis of insulin and leptin signaling pathways, so the incidence in this genotype is greater [17].…”

Relationship between Prenatal or Postnatal Exposure to Pesticides and Obesity: A Systematic Review

“…These mechanisms may lead to metabolic disruption, such as insulin resistance and changes in body weight, as observed in adult mice exposed to CPF [ 112 ]. In this regard, chlorpyrifos seems to have an influence over the leptin and insulin signaling pathway [ 113 ] and on the adipogenic process facilitating lipid storage [ 110 ]. Some studies have shown that the gut microbiota could play an essential role in these effects [ 114 , 115 ].…”