Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

Abstract

Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor b1 (Tgfb1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFb1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitinepalmitoyl transferase 1b (Cpt1b), peroxisome proliferatoractivated receptor d (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfb1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.

A single early postnatal estradiol injection affects morphology and gene expression of the ovary and parametrial adipose tissue in adult female rats

“…We have recently reported that a single early postnatal injection of testosterone or estradiol benzoate, but not of dihydrotestosterone, resulted in insulin resistance and increased mesenteric adipose tissue mass and adipocyte size in adult female rats, suggesting that postnatal estrogen receptor activation exerts stronger programming effects on metabolic indices than androgen receptor activation [9]. Furthermore, we have extended these findings by showing that estradiol exposure affected gene expression in skeletal muscle; expression of inflammation markers was increased while expression of genes involved in glucose and lipid metabolism was decreased [11]. This suggests that estradiol may exert an early programming effect on insulin sensitivity in adult organism partly by inducing low-grade chronic inflammation.…”

“…The dose of 0.35 mg estradiol benzoate used in this study has previously been applied by us [11]. We have earlier also evaluated imprinting effects of a single dose of 0.5 mg estradiol benzoate [9].…”

“…Sex hormone programming in animals has been shown to affect adipose tissue, insulin sensitivity, and ovarian morphology and function [8][9][10][11]. We have recently reported that a single early postnatal injection of testosterone or estradiol benzoate, but not of dihydrotestosterone, resulted in insulin resistance and increased mesenteric adipose tissue mass and adipocyte size in adult female rats, suggesting that postnatal estrogen receptor activation exerts stronger programming effects on metabolic indices than androgen receptor activation [9].…”

Differences in neonatal exposure to estradiol or testosterone on ovarian function and hormonal levels

“…It is important to acknowledge that the gene expression of steroidogenic enzymes (i.e., CYP17a1) does not necessarily reflect enzyme activity due to post transcriptional mechanisms. From another point of view, increased Cyp17a1 expression may also be influenced by other factors of the rat models induced by androgen or estrogen once treatment with sex steroids in early life was demonstrated to induce insulin resistance during rat adulthood (Alexanderson et al, 2007(Alexanderson et al, , 2009Mahamed et al, 2011), and insulin resistance may intensify androgenic potential in theca cells (Qu et al, 2009). In this sense, this was one limitation of our study because the link between insulin resistance and hyperandrogenism and ovarian morphological modifications were not explored in detail.…”

17Beta-estradiol affects the response of complement components and survival of rainbow trout (Oncorhynchus mykiss) challenged by bacterial infection

“…Farkas et al (2008) found that neuroendocrine neurons of the rodent hypothalamus had significantly elevated complement C5a receptor transcriptions after estrogenic pretreatment and hypothesized that the C5a receptors are involved in the estrogen-induced calcium response of the hypothalamus, which links immune and neuroendocrine functions [35]. Recently, Alexanderson et al (2009) clearly demonstrated a connection between early estrogen exposure and adult inflammatory response in circulation and skeletal muscles including a tissue-dependent increase of complement C3 expression [36]. Thus, there is compelling evidence for a tight regulation of the mammalian complement system by estrogens.…”