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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
TRB2, a mouse Tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBPbeta
Takahiro Naiki1, Eiko Saijou, Yuichiro Miyaoka
1Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Tokyo 113-0032, Japan.
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.
Insights
Mammalian Tribbles (TRBs) regulate adipocyte differentiation. TRB2 and TRB3 suppress fat cell formation by inhibiting Akt activation and promoting C/EBPbeta degradation, revealing their roles in adipogenesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Adipocyte differentiation is a complex process regulated by various signaling pathways and transcription factors.
- Mammalian Tribbles (TRBs) are homologs of Drosophila Tribbles and their role in adipogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of TRB proteins in the regulation of adipocyte differentiation.
- To elucidate the molecular mechanisms by which TRB2 and TRB3 affect adipogenesis.
Main Methods:
- Using 3T3-L1 preadipocytes to study adipocyte differentiation.
- Employing forced expression and knockdown (siRNA) of TRB genes.
- Assessing Akt activation and C/EBPbeta levels.
- Utilizing proteasome inhibition assays.
Main Results:
- TRB2 and TRB3 were down-regulated by differentiation stimuli in 3T3-L1 cells.
- Forced expression of TRB2 and TRB3 inhibited adipocyte differentiation.
- TRB3 severely inhibited Akt activation, while TRB2 reduced C/EBPbeta levels via proteasome-dependent degradation.
- Knockdown of endogenous TRB2 enhanced adipocyte differentiation.
Conclusions:
- TRB2 and TRB3 play inhibitory roles in adipocyte differentiation.
- TRB2's strong inhibitory effect is attributed to both Akt inhibition and C/EBPbeta degradation.
- TRB proteins are key regulators of adipogenesis, offering potential therapeutic targets.
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