Endocrine Abstracts (2006) 11 P315

Depot specific activation of inflammatory signalling molecules JNK and NFκB in human abdominal subcutaneous and omental adipose tissue

NF da Silva, AE Fowler, AL Harte, AR Baker, CM Kusminski, SJ Creely, P O’Hare, S Kumar & PG McTernan

Unit for Diabetes and Metabolism, Warwick Medical School, Division of Clinical Sciences, University of Warwick, Coventry,West Midlands, United Kingdom.

Central obesity is strongly associated with sub-clinical inflammation, insulin resistance (IR) and type 2 diabetes mellitus (T2DM), but the intracellular mechanisms involved in its pathogenesis remain unclear. Recent Murine studies have implicated C-jun N terminal kinase (JNK) as an important molecule linking insulin action and inflammation, therefore we investigated JNK in human abdominal adipose tissue (AT). JNK expression/activity was assessed in abdominal subcutaneous (AbdSc n=20), omental (Om n=10) and thigh (n=12) depots (age: 47.8±(mean±SD)5.0yrs; BMI: 25.0±0.6 kg/m2), as well as the effect of adiposity and T2DM. The effect of differential JNK activity on the intracellular signalling pathway involving I-kappaB kinase (IKK)β and IKKγ, IκBα and NFκB was also investigated. Finally the effect of TNF-α and its antagonist as a JNK modulator in human AbdSc adipocytes was examined. Our ex vivo studies demonstrated total JNK protein expression was increased in the Om versus AbdSc (Om: 5.79±(mean±SEM)0.87 ng/mL; AbdSc: 2.98±0.43 ng/mL; P<0.05), independent of macrophage content. Phosphospecific JNK1 was increased 5.8 fold in the AbdSc depot versus Om AT (AbdSc JNK1/2, P<0.01vsOM), whilst JNK1/2 expression was unaltered with adiposity or diabetes. From this, we determined that Om AT exhibited the lowest JNK activity compared with AbdSc (P<0.01). We also showed that other intracellular pathways may operate in omental fat to stimulate an inflammatory response by increased expression of the IKKβ (P<0.001), IKKγ and both phosphorylated IκBα (IκBα-P) and IκBα in Om compared with AbdSc AT (P<0.01). Finally JNK activity was unaffected in AbdSc adipocytes treated with TNF-α. In conclusion, this is the first study to demonstrate depot specific JNK expression and functional activity in human abdominal AT. Furthermore, JNK may be a potential mediator of inflammation and IR in AbdSc AT, whilst other intracellular signaling pathways may play a more central role in activation of inflammation and IR in omental AT.

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