Endocrine Abstracts (2004) 7 P49

Increased C-jun N terminal kinase (JNK) activity may link insulin resistance and inflammation in human central obesity

AE Fowler, NF da Silva, C Burman, AL Harte, PG McTernan & S Kumar

Unit for Diabetes and Metabolism, University of Warwick, Coventry, UK.

Central obesity is strongly associated with insulin resistance and chronic sub-clinical inflammation, which is implicated in the development of type 2 diabetes (T2DM). However, the mechanisms underlying this link remain unclear. Recently JNK, a mitogen activated protein kinase (MAPK), has been implicated in obesity and insulin resistance by interfering with insulin action. Studies in rodent models show that phosphorylated JNK-1 is elevated in obesity, whilst the absence of JNK-1 results in decreased adiposity, improved insulin sensitivity and enhanced insulin receptor signalling capacity. We examined ex vivo human adipose tissue from patients undergoing elective surgery (subcutaneous n=20; omental, n=10; thigh, n=11; non-obese: Age 45plus/minus 3.3SD, BMI 21.9plus/minus 2.4; Obese: Age 47plus/minus 4.1, BMI 29.6plus/minus 4.2;). Our data showed JNK is expressed in subcutaneous (Sc) adipose tissue, Sc adipocytes and macrophages (control) with the two main forms of JNK located in ex vivo fat, JNK1 and JNK2 (43 kDa and 54 kDa, respectively). We examined the effect of fat depot and adiposity for total and phosphorylated protein expression of JNK1 by western blot and ELISA. Our findings indicated depot specific alteration of JNK1 with increased expression in abdominal subcutaneous (Sc) and omental (Om) depots compared with thigh (Sc: 2.6plus/minus 0.15 & Om: 3.1plus/minus 0.14; Vs thigh: 1.1plus/minus 0.1, p<0.01). Phosphorylated JNK-1 was specifically increased 2.6 fold from abdominal tissue compared with thigh (p=0.01). Increasing adiposity in Sc abdominal adipose tissue also significantly raised the expression of the phosphorylated JNK1 (Sc non-obese: 1.1plus/minus 0.3, Vs Sc obese: 3.2plus/minus 0.3; p<0.001). These studies show JNK1 activity is a) increased in central abdominal fat compared with thigh and b) upregulated in obesity. In summary, JNK-1 activity is increased in central abdominal fat and with increasing adiposity. JNK-1 may link human central obesity with insulin resistance and inflammation and thus play a role in the pathogenesis of T2DM and cardiovascular disease.

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