Prokineticin Receptor 1 as a Novel Suppressor of Preadipocyte Proliferation and Differentiation to Control Obesity

Cécilia Szatkowski,Nadia Messaddeq,Phillippe Valet,Judith Vallet,Daniel Metzger,Mojdeh Dormishian,Canan G Nebigil,Mounia Boulberdaa,Pierre Chambon

doi:10.1371/journal.pone.0081175

Abstract

BackgroundAdipocyte renewal from preadipocytes occurs throughout the lifetime and contributes to obesity. To date, little is known about the mechanisms that control preadipocyte proliferation and differentiation. Prokineticin-2 is an angiogenic and anorexigenic hormone that activate two G protein-coupled receptors (GPCRs): PKR1 and PKR2. Prokineticin-2 regulates food intake and energy metabolism via central mechanisms (PKR2). The peripheral effect of prokineticin-2 on adipocytes/preadipocytes has not been studied yet.Methodology/Principal FindingsSince adipocytes and preadipocytes express mainly prokineticin receptor-1 (PKR1), here, we explored the role of PKR1 in adipose tissue expansion, generating PKR1-null (PKR1−/−) and adipocyte-specific (PKR1ad−/−) mutant mice, and using murine and human preadipocyte cell lines. Both PKR1−/− and PKR1ad−/− had excessive abdominal adipose tissue, but only PKR1−/− mice showed severe obesity and diabetes-like syndrome. PKR1ad−/−) mice had increased proliferating preadipocytes and newly formed adipocyte levels, leading to expansion of adipose tissue. Using PKR1-knockdown in 3T3-L1 preadipocytes, we show that PKR1 directly inhibits preadipocyte proliferation and differentiation. These PKR1 cell autonomous actions appear targeted at preadipocyte cell cycle regulatory pathways, through reducing cyclin D, E, cdk2, c-Myc levels.Conclusions/SignificanceThese results suggest PKR1 to be a crucial player in the preadipocyte proliferation and differentiation. Our data should facilitate studies of both the pathogenesis and therapy of obesity in humans.

Highlights

Obesity causes many serious diseases such as type-2 diabetes mellitus, cardiovascular diseases and certain types of cancer, and has contributed to increases in mortality and morbidity rates [1]
We investigated whether prokineticin receptor-1 (PKR1) deficiency increased white adipose tissues (WATs) mass by the hypertrophy or by hyperplasia of white adipocytes, by measuring the numbers and diameters of WAT in the visceral region of PKR12/2 and wild-type mice
We provide in vivo and in vitro evidence for distinct roles of prokineticin receptor-1 (PKR1) in maintenance of proliferation and conversion of preadipocytes to adipocytes, controlling abdominal adipocyte numbers and adipose tissue mass

Summary

Introduction

Obesity causes many serious diseases such as type-2 diabetes mellitus, cardiovascular diseases and certain types of cancer, and has contributed to increases in mortality and morbidity rates [1]. Obesity is characterized by an expansion of adipose tissue mass due to hypertrophy, an increase in adipocyte size [2], and hyperplasia, an increase in cell number [3]. Adipocyte hyperplasia in adults requires the generation of new adipocytes from precursor cells (preadipocytes) and stem cells resident in the stromal-vascular compartment of white adipose tissues (WATs). Preadipocytes are capable of proliferating and differentiating into an adipose deposit [7]. Preadipocytes can proliferate and subsequently differentiate into mature adipocytes [8]. Understanding the mechanisms controlling preadipocyte proliferation and conversion to adipocyte provides insights into the etiology and prevention of obesity and its associated pathologies. Little is known about the mechanisms that control preadipocyte proliferation and differentiation. The peripheral effect of prokineticin-2 on adipocytes/preadipocytes has not been studied yet

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Conclusion