Elevated FFAs cause ectopic lipid deposition in nonadipose tissue, and this lipotoxicity may induce a pro-inflammatory response, which in turn may negatively interfere with insulin signalling. Supporting this concept, the use of high dose salicylate has been proven to decrease plasma glucose in type 2 diabetic patients (236). The molecular basis of this observation relies on decreased activity of a serine kinase called IkB kinase p (IKKP) of the NFkB signalling pathway (237), and subsequent impaired phosphorylation of IRS-1 and PI3Kinase (238). The link between IKKp and FFAs in insulin resistance has been further supported by the report that, in rats, salicylate prevents the deleterious effects of lipid infusion on muscle glucose metabolism and insulin secretion (238). In a recent report Cai and colleagues showed that obesity- or high fat-induced hepatic lipid deposition is accompanied by increased NFkB activity in the liver (239). Studies of genetically modified mice with either silencing or activation of the NFkB pathway specifically in the liver demonstrated that inflammation owing to moderate hepatic NFkB overexpression may cause hepatic as well as systemic insulin resistance, whereas mice with reduced NFkB activity were resistant to the development of insulin resistance (239,240). Several hypotheses exist to explain how increased FFA delivery and ensuing intracellular acylCoA and DAGs may alter IKKp activity. One of them involves the activation of the protein kinase PKC 0 (169,241,242). The other one relies on fatty acid-induced alteration in another signalling pathway, named c-Jun amino-terminal kinase (JNK) pathway that can interfere with insulin action, and the activity of which is abnormally high in diabetes and obesity (210,243,244). To summarize, this pro-inflammatory state appears to be an integral component of insulin resistance (245), and may be in part a consequence of lipid accumulation in adipose and nonadipose tissue, through altered IKKp activity.
Adipose tissue is also able to secrete pro-inflammatory chemokines, the secretion of which is even more pronounced in insulin resistant states, with deleterious consequences on insulin action in adipocytes (246). A very recent report points to the possibility of an enhanced recruitment of monocytes to adipose tissue as a key factor for adipose tissue macrophage accumulation, an inflammatory state, and more generally systemic insulin resistance
(247). It remains to be determined whether lipid overaccumulation may initiate the inflammatory response leading to monocyte/macrophage homing.
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