Abstract
Adipocyte differentiation is regulated by a complex array of extracellular signals, intracellular mediators and transcription factors. Here we describe suppression of adipocyte differentiation by TRBs, mammalian orthologs of Drosophila Tribbles. Whereas all the three TRBs were expressed in 3T3-L1 preadipocytes, TRB2 and TRB3, but not TRB1, were immediately down-regulated by differentiation stimuli. Forced expression of TRB2 and TRB3 inhibited adipocyte differentiation at an early stage. Akt activation is a key event in adipogenesis and was severely inhibited by TRB3 in 3T3-L1 cells. However, the inhibition by TRB2 was mild compared with severe inhibition by TRB3, though TRB2 suppressed adipogenesis as strongly as TRB3. Interestingly, TRB2 but not TRB3 reduced the level of C/EBPbeta, a transcription factor required for an early stage of adipogenesis, through a proteasome-dependent mechanism. Furthermore, knockdown of endogenous TRB2 by siRNA allowed 3T3-L1 cells to differentiate without full differentiation stimuli. These results suggest that inhibition of Akt activation in combination with degradation of C/EBPbeta is the basis for the strong inhibitory effect of TRB2 on adipogenesis.
Highlights
In the past decade, genetic studies using knock-out mice have identified several key transcription factors that regulate adipocyte development
Mouse Tribbles Orthologs Are Differentially Regulated during Adipogenesis—It has been shown that insulin and IGF are key molecules in early adipogenesis [14]
To investigate a possible involvement of TRB3 in adipogenesis, we first examined the expression of TRB3, together with two other mouse Tribbles orthologs, TRB1 and TRB2, during adipocyte differentiation. 3T3-L1 preadipocytes and mouse embryonic fibroblasts (MEFs) were induced to differentiate with Mix, Dex, and insulin (MDI) and analyzed by quantitative PCR
Summary
Genetic studies using knock-out mice have identified several key transcription factors that regulate adipocyte development. Because TRB3 has been reported to function as an inhibitor for Akt [22] and TRBexpressing cells exhibited defects similar to Akt1/2 knock-out MEFs, we examined the possibility that TRBs inhibit adipogenesis via Akt. To this end, we analyzed the phosphorylation of Akt at Thr308 and Ser473, indicative of Akt activation [26]. To investigate whether mammalian Tribbles orthologs have similar function, we examined the level of C/EBP proteins during adipogenesis in cells expressing TRB2 or TRB3.
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