Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome

Abstract

Metabolic syndrome is a proatherosclerotic condition clustering cardiovascular risk factors, including glucose and lipid profile alterations. The pathophysiological mechanisms favoring atherosclerotic inflammation in the metabolic syndrome remain elusive. Here, we investigated the potential role of the antilipolytic drug acipimox on neutrophil- and monocyte-mediated inflammation in the metabolic syndrome. Acipimox (500 mg) was orally administered to metabolic syndrome patients (n = 11) or healthy controls (n = 8). Serum and plasma was collected before acipimox administration (time 0) as well as 2-5 h afterward to assess metabolic and hematologic parameters. In vitro, the effects of the incubation with metabolic syndrome serum were assessed on human neutrophil and monocyte migration toward the proatherosclerotic chemokine CCL3. Two to five hours after acipimox administration, a significant reduction in circulating levels of insulin and nonesterified fatty acid (NEFA) was shown in metabolic syndrome patients. At time 0 and 2 h after acipimox administration, metabolic syndrome serum increased neutrophil migration to CCL3 compared with healthy controls. No effect was shown in human monocytes. At these time points, serum-induced neutrophil migration positively correlated with serum levels of insulin and NEFA. Metabolic syndrome serum or recombinant insulin did not upregulate CCR5 expression on neutrophil surface membrane, but it increased intracellular JNK1/2 phosphorylation. Insulin immunodepletion blocked serum-induced neutrophil migration and associated JNK1/2 phosphorylation. Although mRNA expression of acipimox receptor (GPR109) was shown in human neutrophils, 5-500 μM acipimox did not affect insulin-induced neutrophil migration. In conclusion, results suggest that acipimox inhibited neutrophil proatherosclerotic functions in the metabolic syndrome through the reduction in circulating levels of insulin

Update on the Pathophysiological Role of Intracellular Signaling Pathways in Atherosclerotic Plaques and Ischemic Myocardium

“…Furthermore, this article confirmed the inhibition of JNK2 as a promising therapeutic approach to reduce atherosclerosis at different stages [27]. The potential pro-atherosclerotic and pro-inflammatory activities driven by JNK phosphorylation were also confirmed in vitro in human inflammatory [28] and vascular cells [29], suggesting a relevance for controlling this pathway in hyperinsulinemic states associated with atherosclerotic diseases. The JNK-dependent downstream signalization was further investigated in vivo in mice and in vitro in endothelial cells.…”

High Prevalence of Anti‐Apolipoprotein/A‐1 Autoantibodies in Maintenance Hemodialysis and Association With Dialysis Vintage

“…CRP, C-reactive protein; IL-6, Interleukin-6; IL-8, Interleukin-8; MCP-1, monocyte chemoattractant protein-1; MMP-9, metalloproteinase-9; TNF-a, tumor necrosis factor-a. (12,13,17,20,21)…”

Caloric restriction

“…The other approaches aim to stimulate or inhibit the three main pathways that are affected by CR. These approaches include (a) drugs that affect the IGF-1/insulin signaling pathway, principally the anti-diabetic biguanides (Anisimov, 2003;Anisimov et al, 2003;Anisimov, 2001) (b) anti-lipolytic drugs such as Acipimox Montecucco et al, 2011), (c) drugs that affect the sirtuin pathway such as resveratrol (Chen et al, 2008) (d) drugs that affect mTOR signaling such as rapamycin (Tsang et al, 2007). This is not an exclusive list as several other approaches have been adopted including the use of agonists of lipid activated nuclear receptors (Corton et al, 2004) or suggested but not yet investigated such as the use of ghrelin .…”

“…Acipimox (5-methylpyrazine-2-carboxylic acid-4-oxide), a nicotinic acid derivative has been shown to reduce insulin, and improve insulin resistance and oral glucose tolerance in cases of Metabolic Syndrome (Montecucco et al, 2011). The aforementioned improvements have particular significance in delaying the aging process, and once-a-week life-long administration of the Acipimox induced significant anti-aging effects similar to those of CR, without adversely effecting food intake or body weight .…”