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.
01 - 05 Apr 2006
European Society of Endocrinology