Drosophila Ste-20 Family Protein Kinase, Hippo, Modulates Fat Cell Proliferation

Hongling Huang,Xin-Yuan Liu,Lei Zhang,Wenqing Wu,Esther Marianna Verheyen

doi:10.1371/journal.pone.0061740

Abstract

BackgroundEvolutionarily conserved Hippo (Hpo) pathway plays a pivotal role in the control of organ size. Although the Hpo pathway regulates proliferation of a variety of epidermal cells, its function in non-ectoderm-derived cells is largely unknown.Methodology/Principal FindingsThrough methods including fat quantification assays, starvation assays, in vivo labeling assays, we show that overexpression of Hpo in Drosophila melanogaster fat body restricts Drosophila body growth and reduces fat storage through regulation of adipocyte proliferation rather than through influencing the size of fat cells and lipid metabolism, whereas compromising Hpo activity results in weight gain and greater fat storage. Furthermore, we provide evidence that Yorkie (Yki, a transcriptional coactivator that functions in the Hpo pathway) antagonizes Hpo to modulate fat storage in Drosophila.Conclusions/SignificanceOur findings specify a role of Hpo in controlling mesoderm-derived cell proliferation. The observed anti-obesity effects of Hpo may indicate great potential for its utilization in anti-obesity therapeutics.

Highlights

The evolutionarily conserved Hippo (Hpo) signaling pathway has emerged as a pivotal pathway in the control of organ size
The core kinase cassette of the Hpo pathway, which consists of the serine/threonine Ste20-like kinase Hpo [4,5], the nuclear Dbf-2-related (NDR) family kinase Wts, and their scaffold proteins Salvador (Sav) [6] and Mob as tumor suppressor (Mats) [7], acts through sequential phosphorylation events to sequester the growth-promoting transcriptional coactivator Yorkie (Yki) [8] in the cytoplasm
In order to determine whether the Hpo pathway regulates Drosophila fat storage, we generated transgenic flies that express fat body-restricted Hpo under the control of the Dcg-Gal4 driver

Summary

Introduction

The evolutionarily conserved Hippo (Hpo) signaling pathway has emerged as a pivotal pathway in the control of organ size. The critical role of the Hpo pathway in regulating epidermal cells has been well established, whether the pathway controls non-ectoderm-derived cells is elusive. It has been reported that the Hpo pathway can restrain cardiomyocyte proliferation and heart size through inhibition of Wnt signaling [19], indicating that the Hippo pathway may control the proliferation of cells derived from different cell layers. Conserved Hippo (Hpo) pathway plays a pivotal role in the control of organ size. The Hpo pathway regulates proliferation of a variety of epidermal cells, its function in non-ectoderm-derived cells is largely unknown

Methods

Results

Conclusion