Abstract

The activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) has been associated to anti-inflammatory response in macrophages. High-fat diet (HFD) consumption during pregnancy and lactation impairs the cholinergic anti-inflammatory pathway in liver and white adipose tissue of offspring. In order to evaluate the relationship between damage in the cholinergic anti-inflammatory pathway and insulin resistance (IR) development, the liver of offspring of obese dams was investigated. Additionally, the capacity of α7nAChR activation to reduce IR induced by saturated fatty acid was investigated in hepatoma cell line. Initially, female mice were subjected to either standard chow (SC) or HFD during pregnancy and lactation period. After weaning, only male offspring from HFD dams (HFD-O) and SC dams (SC-O) were fed with the SC diet. Hepatic α7nAChR expression was downregulated, and hepatic TNF-α, IL-1β, and pIKK level, but not pJNK, were elevated in the HFD-O compared to SC-O mice. Besides, hepatic expression of TNF-α in response to lipopolysaccharide (LPS) was higher in HFD-O than SC-O mice. Insulin-stimulated phosphorylation of the AKT was lower in HFD-O compared to SC-O. Additionally, insulin-stimulated phosphorylation of the AKT in KOα7Alb-Cre mice fed HFD was lower than WT mice fed HFD. In hepatoma cell line, palmitate increased IL-6 and TNF-α expressions and pJNK level. These effects were accompanied by reduced capacity of insulin to stimulate AKT phosphorylation. PNU or nicotine reduced cytokine expression and JNK activation, but improved insulin resistance induced by palmitate. Our results suggest that maternal obesity impairs hepatic α7nAChR expression and AKT phosphorylation in the offspring. In vitro studies suggest that α7nAChR activation has potential to reduce deleterious effect of saturated fatty acids on insulin signalling.

Highlights

  • The activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) has been associated to anti-inflammatory response in macrophages

  • During pregnancy the body weight gain was similar for both groups (Fig. S1b) but during the suckling period (Fig. S1c) body weight gain was higher in offspring from high-fat diet (HFD)-fed dams (HFD-O) than in offspring from standard chow (SC)-fed dams (SC-O)

  • Saturated fatty acids and LPS can activate TLR4 receptor and stimulate inflammatory cytokines expression, leading to activation of serine kinases (JNK and IKK) that are responsible for inhibiting insulin signalling[7,8,16]

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Summary

Introduction

The activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) has been associated to anti-inflammatory response in macrophages. Palmitate increased IL-6 and TNF-α expressions and pJNK level These effects were accompanied by reduced capacity of insulin to stimulate AKT phosphorylation. Cholinergic anti-inflammatory pathway activation reduces inflammatory cytokines expression through the activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) by acetylcholine[1,2] This mechanism was first described to occur in macrophages, and it comprises an afferent arm that senses inflammation and an efferent arm that inhibits innate immune responses[1,3]. Characteristics of obesity-induced inflammation include elevated production of proinflammatory molecules by adipose tissue and activation of a network of inflammatory signalling pathways These are important factors for the development of insulin resistance[7,8]. We showed that high-fat diet (HFD) during pregnancy and lactation impairs the cholinergic anti-inflammatory pathway in liver and white adipose tissue and exacerbates cytokine production in response to LPS11. To establish the correlation among liver α7nAChR activation, inhibition of inflammatory pathways and improvement in the insulin signalling, we used mouse hepatoma cell line treated with saturated fatty acid (SFA) in the presence or absence of pharmacological agonists of α7nAChR

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