Abstract
Metabolic endotoxemia contributes to low-grade inflammation in obesity, which causes insulin resistance due to the activation of intracellular proinflammatory pathways, such as the c-Jun N-terminal Kinase (JNK) cascade in the hypothalamus and other tissues. However, it remains unclear whether the proinflammatory process precedes insulin resistance or it appears because of the development of obesity. Hypothalamic low-grade inflammation was induced by prolonged lipopolysaccharide (LPS) exposure to investigate if central insulin resistance is induced by an inflammatory stimulus regardless of obesity. Male Wistar rats were treated with single (1 LPS) or repeated injections (6 LPS) of LPS (100 μg/kg, IP) to evaluate the phosphorylation of the insulin receptor substrate-1 (IRS1), Protein kinase B (AKT), and JNK in the hypothalamus. Single LPS increased the expression of pIRS1, pAKT, and pJNK, whereas the repeated LPS treatment failed to recruit pIRS1 and pAKT. The 6 LPS treated rats showed increased total JNK and pJNK. The 6 LPS rats became unresponsive to the hypophagic effect induced by central insulin administration (12 μM/5 μL, ICV). Prolonged exposure to LPS (24 h) impaired the insulin-induced AKT phosphorylation and the translocation of the transcription factor forkhead box protein O1 (FoxO1) from the nucleus to the cytoplasm of the cultured hypothalamic GT1-7 cells. Central administration of the JNK inhibitor (20 μM/5 μL, ICV) restored the ability of insulin to phosphorylate IRS1 and AKT in 6 LPS rats. The present data suggest that an increased JNK activity in the hypothalamus underlies the development of insulin resistance during prolonged exposure to endotoxins. Our study reveals that weight gain is not mandatory for the development of hypothalamic insulin resistance and the blockade of proinflammatory pathways could be useful for restoring the insulin signaling during prolonged low-grade inflammation as seen in obesity.
Highlights
Chronic low-grade inflammation is associated with leptin and insulin resistance, which contributes to the establishment of obesity and its comorbidities, such as type 2 diabetes, cancer, and cardiovascular diseases [1]
To evaluate whether long-term endotoxemia stimulates insulin secretion and insulin signaling in the hypothalamus, rats were treated with repeated LPS injections in comparison with single LPS treatment
Since it was recently demonstrated that Jun N-terminal Kinase (JNK) inhibition was able to sensitize leptin’s anorectic effect by increasing leptin-induced STAT3 activation and SOCS3 downregulation in the hypothalamus of DIO animals [36], we propose that the activation of alternative pathways not investigated in our study might account for the restoration of the hypophagia
Summary
Chronic low-grade inflammation is associated with leptin and insulin resistance, which contributes to the establishment of obesity and its comorbidities, such as type 2 diabetes, cancer, and cardiovascular diseases [1]. Repeated exposure to LPS might be a useful approach to dissociate the impact of the low-grade inflammation that precedes the increased adiposity signals on the development of peripheral and hypothalamic resistance seen in obesity. The appetite-suppressive and weight-reducing effects of insulin have been shown in both rodents and primates [6,7] These effects are supported by the presence of the insulin receptor (IR) and the expression of intracellular components of the insulin signaling, the insulin receptor substrate 1 (IRS-1), and the phosphoinositide 3-kinase (PI3K) pathway-induced proteins in the hypothalamus [8,9,10,11]. The impact of low-grade inflammation induced by prolonged LPS exposure on central insulin signaling has not been addressed
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