| Hippo signaling has emerged as an essential modulator of tissue and organ development. First identified in Drosophila and highly conserved in mammals, the Hippo pathway suppresses tissue growth and controls organ size. Lats2is one of the core kinases of the Hippo pathway and plays major roles in cell proliferation and apoptosis by interacting with the downstream transcriptional cofactors YAP and TAZ. Although the function of the Hippo pathway and Lats2is relatively well understood in several tissues and organs, less is known about the function of Lats2and Hippo signaling in adipose development. Adipose tissue is essential for whole-body energy balance, but many aspects of the regulatory mechanisms underlying adipogenesis are unclear. So our research focuses on exploring the function of Lats2and Hippo signaling in adipose development.Firstly, we investigated the effects that Lats2exerts on its downstream factors YAP and TAZ. We constructed Lats2-expressing vector and obtained positive clones with stably integrated Lats2. Lats2-overexpressing3T3L1cells have high levels of Lats2and phosphorylated Lats2(its active form). And Lats2localizes predominantly to the cytoplasm. Lats2enhances the phosphorylation and cytoplasmic accumulation of YAP and TAZ in preadipocytes.Given the above results, we next investigated the phenotypic effects caused by Lats2in3T3L1cells. TEAD3localizes to the nucleus, but YAP and TAZ remain in the cytoplasm due to phosphorylation by Lats2, thus the expression of Hippo target genes is suppressed. Therefore, the cell cycle progression and proliferation of preadipocytes are significantly inhibited by Lats2via Hippo signaling.Next, we investigated the function of Lats2in adipocyte differentiation. The expression of Lats2is up-regulated during differentiation, essentially in parallel with that of the adipogenic transcriptional factors and the adipocyte marker genes. We assessed the transcriptional activity of PPARy through luciferase activity assays. PPARy retrieves its transcriptional activity, thus the expression of PPARy-driven genes is promoted by Lats2. We induced differentiation in3T3L1cells, and found that Lats2can accelerate differentiation of preadipocytes into mature adipocytes via Hippo signaling.Furthermore, we explored additional mechanism of Lats2action in preadipocytes and found that Lats2is a negative regulator of Wnt signaling. During preadipocytes differentiation, some Wnt pathway components and its target genes are inhibited, this inhibition might be partly mediated by Lats2. The levels of DVL2phosphorylation and thus β-catenin protein are reduced by Lats2, and the transcriptional activity of TCF is also inhibited by Lats2, thus Lats2suppresses the expression of Wnt target genes.In conclusion, Lats2is an important modulator of adipocyte proliferation and differentiation via the Hippo pathway that regulates the balance between proliferation and differentiation during adipose development. |
