Abstract

Inhibition of Akt-mTOR signaling protects from obesity and extends life span in animals. In the present study, we analyse the impact of the small GTPase, GTP-binding RAS-like 3 (DIRAS3), a recently identified weight-loss target gene, on cellular senescence in adipose stromal/progenitor cells (ASCs) derived from human subcutaneous white adipose tissue (sWAT). We demonstrate that DIRAS3 knock-down (KD) in ASCs induces activation of Akt-mTOR signaling and proliferation arrest. DIRAS3 KD ASCs lose the potential to form colonies and are negative for Ki-67. Moreover, silencing of DIRAS3 results in a premature senescence phenotype. This is characterized by senescence-associated β-galactosidase positive enlarged ASCs containing increased p16INK4A level and activated retinoblastoma protein. DIRAS3 KD ASCs form senescence-associated heterochromatic foci as shown by increased level of γ-H2A.X positive foci. Furthermore, these cells express a senescence-associated secretory phenotype characterized by increased interleukin-8 secretion. Human DIRAS3 KD ASCs develop also a senescence phenotype in sWAT of SCID mice. Finally, we show that DIRAS3 KD in ASCs stimulates both adipogenic differentiation and premature senescence. In conclusion, our data suggest that silencing of DIRAS3 in ASCs and subsequently hyper-activation of Akt-mTOR drives adipogenesis and premature senescence. Moreover, differentiating ASCs and/or mature adipocytes may acquire features of cellular senescence.

Highlights

  • Obesity is a major public-health problem worldwide

  • DIRAS3 KD leads to increased activity of Akt-mechanistic target of rapamycin (mTOR) signaling in adipose stromal/progenitor cells (ASCs) (Fig. 1B)

  • As mTOR activity is essential for cell proliferation but a persistent mTOR complex 1 activation leads to exhaustion of stem cells [18, 30], we investigated the effect of DIRAS3 KD on proliferation of ASCs

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Summary

Introduction

Obesity is a major public-health problem worldwide Underlying cause of this epidemic is the inherent expansion and renewal capacity of adipocytes, which differentiate from adipose stromal/progenitor cells (ASCs) in a process referred to as adipogenesis [1,2,3]. Adipogenesis involves ASC determination and terminal differentiation into adipocytes, which express fat cell specific genes and accumulate lipids [6, 7] This process is governed by a complex signal transducing network including Delta-like protein 1/Preadipocyte factor 1-, Wnt-, insulin-, IGF-1-signaling and numerous additional pathways, which eventually activate or repress a cascade of adipogenic transcription factors. Akt-mTOR signaling is well-known as www.aging-us.com positive regulator of adipogenesis and inhibition of this pathway protects from obesity [15] This underscores the role of DIRAS3 as WL target gene

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