Abstract
Inflammation critically contributes to the development of various metabolic diseases. However, the effects of inhibiting inflammatory signaling on hepatic steatosis and insulin resistance, as well as the underlying mechanisms remain obscure. In the current study, male C57BL/6J mice were fed a chow diet or high-fat diet (HFD) for 8 weeks. HFD-fed mice were respectively treated with p65 siRNA, non-silence control siRNA or vehicle every 4th day for the last 4 weeks. Vehicle-treated (HF) and non-silence siRNA-treated (HFNS) mice displayed overt inflammation, hepatic steatosis and insulin resistance compared with chow-diet-fed (NC) mice. Upon treatment with NF-κB p65 siRNA, HFD-fed (HFPS) mice were protected from hepatic steatosis and insulin resistance. Furthermore, Atg7 and Beclin1 expressions and p-AMPK were increased while p-mTOR was decreased in livers of HFPS mice in relative to HF and HFNS mice. These results suggest a crosslink between NF-κB signaling pathway and liver AMPK/mTOR/autophagy axis in the context of hepatic steatosis and insulin resistance.
Highlights
Insulin resistance is a hallmark of Type-2 diabetes and evidence demonstrates chronic lowgrade inflammation as a contributor to the initiation and perpetuation of insulin resistance [1, 2]
It was observed that HF mice displayed enhanced nuclear factor-kappa B (NF-κB) activation, parallel to HFNS mice’s level, in the hepatic and adipose tissue by 52% and 41%, respectively (Fig 1A)
MRNA expression analyses of M1 macrophages immune activators including CD68, F4/80 and CD11c were increased by approximately 50%, 180% and 80%, sequentially, in
Summary
Insulin resistance is a hallmark of Type-2 diabetes and evidence demonstrates chronic lowgrade inflammation as a contributor to the initiation and perpetuation of insulin resistance [1, 2]. Plenty of proinflammatory factors are involved in such low-grade inflammation [3]. The mechanisms responsible for these inflammation-induced deleterious changes provide considerable therapeutic targets for drug discovery. Nowadays several studies have provided clues that nuclear factor kappa B (NF-κB) may be a principal regulator of pathways downstream of calorie excess that produce detrimental effects on glucose homeostasis and insulin sensitivity[4,5,6] and, insulin resistance is partially promoted by a shift of macrophage polarization from alterative M2 activation state to classic M1 activation state, during which process, PLOS ONE | DOI:10.1371/journal.pone.0149677. Nowadays several studies have provided clues that nuclear factor kappa B (NF-κB) may be a principal regulator of pathways downstream of calorie excess that produce detrimental effects on glucose homeostasis and insulin sensitivity[4,5,6] and, insulin resistance is partially promoted by a shift of macrophage polarization from alterative M2 activation state to classic M1 activation state, during which process, PLOS ONE | DOI:10.1371/journal.pone.0149677 March 1, 2016
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