Lipoxin A4 attenuates adipose inflammation.
Aging and adiposity are associated with chronic low-grade inflammation, which underlies the development of obesity-associated complications, including type 2 diabetes mellitus (T2DM). The mechanisms underlying adipose inflammation may include macrophage infiltration and activation, which, in turn, affect insulin sensitivity of adipocytes. There is a growing appreciation that specific lipid mediators (including lipoxins, resolvins, and protectins) can promote the resolution of inflammation. Here, we investigated the effect of lipoxin A4 (LXA4), the predominant endogenously generated lipoxin, on adipose tissue inflammation. Using adipose tissue explants from perigonadal depots of aging female C57BL/6J mice (Animalia, Chordata, Mus musculus) as a model of age-associated adipose inflammation, we report that LXA4 (1 nM) attenuates adipose inflammation, decreasing IL-6 and increasing IL-10 expression (P<0.05). The altered cytokine milieu correlated with increased GLUT-4 and IRS-1 expression, suggesting improved insulin sensitivity. Further investigations revealed the ability of LXA4 to rescue macrophage-induced desensitization to insulin-stimulated signaling and glucose uptake in cultured adipocytes, using vehicle-stimulated cells as controls. This was associated with preservation of Akt activation and reduced secretion of proinflammatory cytokines, including TNF-α. We therefore propose that LXA4 may represent a potentially useful and novel therapeutic strategy to subvert adipose inflammation and insulin resistance, key components of T2DM.
UCD Diabetes Research Centre, UCD Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
Emma
E
Börgeson
Fiona C
FC
McGillicuddy
Karen A
KA
Harford
Niamh
N
Corrigan
Debra F
DF
Higgins
Paola
P
Maderna
Helen M
HM
Roche
Catherine
C
Godson
D000273:Adipose Tissue / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D005260:Female; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D044045:Lipoxins / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; C526295:Irs1 protein, mouse; D044045:Lipoxins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D016753:Interleukin-10