Obesity, insulin resistance and high cholesterol levels are hallmarks of the metabolic syndrome. The molecular players involved in the onset of the metabolic syndrome are mostly unknown. In this context the three pseudokinases of the tribbles family have emerged as potential candidates. Among them, TRB3 has been described as a negative regulator of Akt, a key player in insulin signal transduction. However, the biological functions of TRB family members remain largely unknown. Therefore, the aim of this study was to learn more about the metabolic role of the three tribbles orthologs.
Analysis of tribbles mRNA expression in wt C57Bl/6J, db/db and ob/ob mice under fasting and refed conditions revealed that in both diabetic animal models the expression of TRB1 is significantly upregulated in adipose tissue. The expression of TRB3 is upregulated due to fasting conditions only in wt and db/db and the expression of TRB2 was not altered under any condition. Furthermore, in adipose tissue of C57Bl/6J mice treated with either dexamethasone for three weeks or with LPS for eight hours an upregulation of TRB1 and a downregulation of TRB3 could be observed compared to control animals, pointing to a role of TRB1 in the control of adipose tissue metabolism. To test for the cell autonomy of these effects, 3T3-L1 adipocytes were treated with different stimuli and analyzed for TRB expression patterns. Whereas, TRB1 expression was found to be upregulated due to insulin, dexamethasone, and LPS, TRB3 expression was downregulated.
The opposite regulation of TRB1 and TRB3 might be indicative of a role for these pseudokinases in the control of adipose tissue biology. Therefore, future experiments will address TRB-dependent signalling pathways in these cells and investigate their impact on the obesity phenotype.
03 - 07 May 2008
European Society of Endocrinology