Sustained Activation of TNFα-Induced DNA Damage Response in Newly Differentiated Adipocytes.

Mahara Valverde,Aarón Sánchez-Brito

doi:10.3390/ijms221910548

Mahara Valverde, Aarón Sánchez-Brito

Open Access

https://doi.org/10.3390/ijms221910548

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Abstract

The response to DNA damage is the mechanism that allows the interaction between stress signals, inflammatory secretions, DNA repair, and maintenance of cell and tissue homeostasis. Adipocyte dysfunction is the cellular trigger for various disease states such as insulin resistance, diabetes, and obesity, among many others. Previously, our group demonstrated that adipogenesis per se, from mesenchymal/stromal stem cells derived from human adipose tissue (hASCs), involves an accumulation of DNA damage and a gradual loss of the repair capacity of oxidative DNA damage. Therefore, our objective was to identify whether healthy adipocytes differentiated for the first time from hASCs, when receiving inflammatory signals induced with TNFα, were able to persistently activate the DNA Damage Response and thus trigger adipocyte dysfunction. We found that TNFα at similar levels circulating in obese humans induce a sustained response to DNA damage response as part of the Senescence-Associated Secretory Phenotype. This mechanism shows the impact of inflammatory environment early affect adipocyte function, independently of aging.

Highlights

In a healthy state, are the cell type used for the present study, in which we will show the effect of exposure to TNFα as an obesogenic stimulus in vitro [11]
The results indicate thereconditioned is autocrine medium regulation of TNFα by hASCs that initiate adipogenesis were exposed to since day of of the their determinations in culture media [Figure 5b], where it is evident that the levels differentiation process, adipogenesis inhibition, secretion are higher in theinducing culturesaofstrong adipocytes treated with
We show evidence of the alteration in the adipogenesis from hASCs caused by the secretome of untreated adipocytes, called control conditioned medium (CCM), and that of adipocytes treated with TNFα, called treated conditioned medium (TCM)

Summary

Introduction

Mol. The maintenance of cellular and tissular homeostasis relies on the optimal functioning of the DNA. The importance of precise control of DNA damage repair mechanisms by recruiting repair factors to damaged sites and activating checkpoint regulators to halt cell cycle progression, recognized as DNA damage response (DDR) [1]. DDR is initiated through a series of post-transcriptional modifications responsible for the propagation of the response. Molecular damage “sensors” are required to locate distortions or lesions in the DNA. This census function is realized by kinases such as: ATM

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