The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chain n-3 PUFA.
The WHO estimate that >1 x 10(6) deaths in Europe annually can be attributed to diseases related to excess body weight, and with the rising global obesity levels this death rate is set to drastically increase. Obesity plays a central role in the metabolic syndrome, a state of insulin resistance that predisposes patients to the development of CVD and type 2 diabetes mellitus. Obesity is associated with low-grade chronic inflammation characterised by inflamed adipose tissue with increased macrophage infiltration. This inflammation is now widely believed to be the key link between obesity and development of insulin resistance. In recent years it has been established that activation of pro-inflammatory pathways can cross talk with insulin signalling pathways via a number of mechanisms including (a) down-regulation of insulin signalling pathway proteins (e.g. GLUT4 and insulin receptor substrate (IRS)-1), (b) serine phosphorylation of IRS-1 blocking its tyrosine phosphorylation in response to insulin and (c) induction of cytokine signalling molecules that sterically hinder insulin signalling by blocking coupling of the insulin receptor to IRS-1. Long-chain (LC) n-3 PUFA regulate gene expression (a) through transcription factors such as PPAR and NF-kappaB and (b) via eicosanoid production, reducing pro-inflammatory cytokine production from many different cells including the macrophage. LC n-3 PUFA may therefore offer a useful anti-inflammatory strategy to decrease obesity-induced insulin resistance, which will be examined in the present review.
Nutrigenomics Research Group, UCD Conway Institute, University College Dublin, Dublin 4, Republic of Ireland.
Elizabeth
E
Oliver
Fiona
F
McGillicuddy
Catherine
C
Phillips
Sinead
S
Toomey
Helen M
HM
Roche
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D015777:Eicosanoids / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008264:Macrophages / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000188:drug therapy / Q000276:immunology; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors
D015777:Eicosanoids; D015525:Fatty Acids, Omega-3; D007328:Insulin; D014157:Transcription Factors; D011972:Receptor, Insulin