Abstract
BackgroundInsulin resistance is associated with a proinflammatory state that promotes the development of complications such as type 2 diabetes mellitus (T2DM) and atherosclerosis. The metabolic stimuli that initiate and propagate proinflammatory cytokine production and the cellular origin of proinflammatory cytokines in insulin resistance have not been fully elucidated. Circulating proinflammatory monocytes show signs of enhanced inflammation in obese, insulin resistant subjects and are thus a potential source of proinflammatory cytokine production. The specific, circulating metabolic factors that might stimulate monocyte inflammation in insulin resistant subjects are poorly characterized. We have examined whether saturated nonesterified fatty acids (NEFA) and insulin, which increase in concentration with developing insulin resistance, can trigger the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in human monocytes.MethodsMessenger RNA and protein levels of the proinflammatory cytokines IL-6 and TNF-α were measured by quantitative real-time PCR (qRT-PCR) and Luminex bioassays. Student's t-test was used with a significance level of p < 0.05 to determine significance between treatment groups.ResultsEsterification of palmitate with coenzyme A (CoA) was necessary, while β-oxidation and ceramide biosynthesis were not required, for the induction of IL-6 and TNF-α in THP-1 monocytes. Monocytes incubated with insulin and palmitate together produced more IL-6 mRNA and protein, and more TNF-α protein, compared to monocytes incubated with palmitate alone. Incubation of monocytes with insulin alone did not affect the production of IL-6 or TNF-α. Both PI3K-Akt and MEK/ERK signalling pathways are important for cytokine induction by palmitate. MEK/ERK signalling is necessary for synergistic induction of IL-6 by palmitate and insulin.ConclusionsHigh levels of saturated NEFA, such as palmitate, when combined with hyperinsulinemia, may activate human monocytes to produce proinflammatory cytokines and support the development and propagation of the subacute, chronic inflammatory state that is characteristic of insulin resistance. Results with inhibitors of β-oxidation and ceramide biosynthesis pathways suggest that increased fatty acid flux through the glycerolipid biosynthesis pathway may be involved in promoting proinflammatory cytokine production in monocytes.
Highlights
Insulin resistance is associated with a proinflammatory state that promotes the development of complications such as type 2 diabetes mellitus (T2DM) and atherosclerosis
Saturated long-chain nonesterified fatty acids (NEFA) stimulate IL-6 and tumor necrosis factor (TNF)-a production in THP-1 cells THP-1 monocytic cells have been used extensively as a model of primary human monocytes, have been shown to closely mimic primary human monocytes in their production of TNF-a in response to lipopolysaccharide [20] and have been utilized in diabetes-related studies, such as studies to investigate the production of IL-6 by monocytes in hyperglycemic conditions [21]
Normal circulating NEFA concentrations are less than 700 μM in the post-absorptive state [22], we chose to use 500 μM as an initial concentration of NEFA to determine the effect of long-chain saturated NEFA on inflammatory cytokine production in THP-1 monocytes
Summary
Insulin resistance is associated with a proinflammatory state that promotes the development of complications such as type 2 diabetes mellitus (T2DM) and atherosclerosis. Circulating proinflammatory monocytes show signs of enhanced inflammation in obese, insulin resistant subjects and are a potential source of proinflammatory cytokine production. Insulin resistance is characterized by a myriad of metabolic abnormalities, including hyperinsulinemia, hypertriglyceridemia, and an increased concentration of NEFA in blood [1]. These dysmetabolic features, sometimes referred to as the metabolic syndrome, are believed to contribute to the development of severe complications of insulin resistance, such as T2DM and atherosclerotic heart disease [2]. It is possible that the bulk of the systemic proinflammatory cytokines in the obese, insulin resistant state are derived from non-adipose cellular and tissue sources
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