Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 15 P134

SFEBES2008 Poster Presentations Diabetes, metabolism and cardiovascular (51 abstracts)

Endoplasmic reticulum stress and the innate immune signalling pathway in human abdominal adipose tissue: the effects of obesity

Christine Kusminski , Bruno Schisano , Alison Harte , Gyanendra Tripathi , Antonio Ceriello , Joseph P O’Hare , Sudhesh Kumar & Philip McTernan

University of Warwick, Coventry, UK.

Background and objectives: Obesity-associated inflammation is a key contributory factor in the pathogenesis of type 2 diabetes mellitus (T2DM). Murine studies have revealed potential links between obesity-induced activation of the innate immune response and endoplasmic reticular (ER) stress. Our aims were therefore to (1) examine whether human abdominal subcutaneous (AbSc) adipose tissue (AT) obtained from lean and obese patients, differs in the level of ER stress, through assessment of activating transcription factor-6 (ATF6), eukaryotic initiation factor-2α (eIF2α) and phosphorylated ER kinase-like ER-kinase (PERK) (2) concurrently, determine whether key components of the NF-κB pathway are upregulated in obesity.

Methods: AT was collected from patients undergoing elective liposuction surgery. Samples were divided into lean (n=20) and obese (n=20) sub-groups (lean: age, 45±3.3 years; BMI, 21.9±2.4 kg/m2; obese: 47±4.1 years; 29.6±4.2 kg/m2). Real-time PCR was utilised to examine ATF6, eIF2α and PERK expression. Western blot was performed to analyse components of the NF-κB pathway.

Results: ATF6, eIF2α and PERK mRNA levels were 7.3-fold, 9.1-fold and 8.2-fold higher in obese AbSc AT when compared with lean AbSc AT (ATF6: lean ΔCt: 10.22±0.96; obese ΔCt: 7.36±1.49; P<0.001; eIF2α: lean ΔCt: 10.84±1.36; obese ΔCt: 7.65±1.82; P<0.001; PERK: lean ΔCt: 10.36±0.43; obese ΔCt: 7.42±0.95; P<0.001). In parallel, expression of key components of the NF-κB pathways were markedly upregulated in obese AbSc AT in comparison with lean AbSc AT (MyD88: 1.94-fold ↑, P<0.001, n=6; TRAF-6: 1.13-fold ↑, P<0.05, n=6; NF-κB: 1.23-fold ↑, P<0.05, n=6).

Conclusions: Human AbSc AT exhibits an increased level of ER stress in obesity. In conjunction with this, key factors of the innate immune signalling pathway are upregulated in AbSc AT from obese subjects; suggesting interplay between the two mechanisms that contribute to T2DM. Collectively, these studies suggest a combined state of inflammation and ER stress in obesity in the pathogenesis of T2DM.

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