Abstract
Inflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes. AMPK activation inhibited IL-1β-stimulated CXCL10 secretion, associated with reduced interleukin-1 receptor associated kinase-4 (IRAK4) phosphorylation and downregulated MKK4/JNK and IKK/IκB/NFκB signalling. AMPK activation inhibited TNF-α-stimulated IKK/IκB/NFκB signalling but had no effect on JNK phosphorylation. The JAK/STAT3 pathway was also suppressed by AMPK after IL-6 stimulation and during adipogenesis. Adipose tissue from AMPKα1−/− mice exhibited increased JNK and STAT3 phosphorylation, supporting suppression of these distinct proinflammatory pathways by AMPK in vivo. The inhibition of multiple pro-inflammatory signalling pathways by AMPK may underlie the reported beneficial effects of AMPK activation in adipose tissue.
Highlights
Obesity is associated with chronic low-grade inflammation of white adipose tissue (WAT), in which there is upregulated secretion of the pro-inflammatory cytokines TNF-a, IL-1b and IL-6
IkB kinase (IKK) stimulates the phosphorylation of inhibitor of nuclear factor kappa B (NFkB) (IkBa), targeting IkB for proteasomal degradation and thereby releasing active NFkB dimers, with p65-p50 heterodimers being the principal form activated by the canonical NFkB pathway in response to TNF-a and IL-1b (Cohen, 2014; Brenner et al, 2015; Salt and Palmer, 2012)
Given the proposed antiinflammatory actions of AMPK and dearth of information concerning the role of AMPK in adipocyte pro-inflammatory signalling, we investigated the effect of AMPK activation on pro-inflammatory signalling in response to IL-1b, TNF-a and IL-6, the principal cytokines associated with adipose tissue inflammation, in cultured adipocytes using the selective AMPK activator A769662, which directly binds and activates AMPK heterotrimers containing the b1 non-catalytic subunit (Scott et al, 2008)
Summary
Obesity is associated with chronic low-grade inflammation of white adipose tissue (WAT), in which there is upregulated secretion of the pro-inflammatory cytokines TNF-a, IL-1b and IL-6. Plasma concentrations of these pro-inflammatory cytokines have been reported to be elevated in obese individuals (Lee et al, 2009). IRAK activation further stimulates formation of a signalosome including TNF receptor-associated factor-6 (TRAF6), TGFb-activated kinase-1 (TAK1) and IkB kinase (IKK) (Salt and Palmer, 2012). The p65-p50 heterodimers subsequently translocate into the nucleus to bind kB-
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