OXPHOS xenobiotics alter adipogenic differentiation at concentrations found in human blood

Laura Llobet,Eduardo Ruiz-Pesini,Julio Montoya,Ester López-Gallardo,Janne M Toivonen

doi:10.1242/dmm.021774

Abstract

ABSTRACTAdipogenesis is accompanied by differentiation of adipose tissue-derived stem cells to adipocytes. As part of this differentiation, biogenesis of the oxidative phosphorylation system occurs. Many chemical compounds used in medicine, agriculture or other human activities affect oxidative phosphorylation function. Therefore, these xenobiotics could alter adipogenesis. We have analyzed the effects on adipocyte differentiation of some xenobiotics that act on the oxidative phosphorylation system. The tested concentrations have been previously reported in human blood. Our results show that pharmaceutical drugs that decrease mitochondrial DNA replication, such as nucleoside reverse transcriptase inhibitors, or inhibitors of mitochondrial protein synthesis, such as ribosomal antibiotics, diminish adipocyte differentiation and leptin secretion. By contrast, the environmental chemical pollutant tributyltin chloride, which inhibits the ATP synthase of the oxidative phosphorylation system, can promote adipocyte differentiation and leptin secretion, leading to obesity and metabolic syndrome as postulated by the obesogen hypothesis.

Highlights

The white adipose tissue (WAT) stores energy as triglycerides and secretes endocrine factors such as adipokines
Here, we have shown that the mitochondrial oxidative phosphorylation system (OXPHOS) system is important for regulation of adipogenesis in human adipose tissue-derived stem cells (hASCs) and that its inhibition at the level of mitochondrial DNA (mtDNA) replication (NRTIs), organelle protein synthesis or function (TBTC) can either inhibit or promote adipogenesis in vitro
Because important OXPHOS components are mtDNA-encoded and OXPHOS capacity is affected by mtDNA haplogroup (Gomez-Duran et al, 2010, 2012), genetic variability in mtDNA could affect adipocyte differentiation and related phenotypes such as obesity (Knoll et al, 2014; Nardelli et al, 2013; Yang et al, 2011)

Summary

Introduction

The white adipose tissue (WAT) stores energy as triglycerides and secretes endocrine factors such as adipokines. The number of these cells is remarkably stable because new adipocytes differentiate constantly to replace lost adipocytes (Spalding et al, 2008). The increased basal rate of oxygen consumption in adipocytes compared with preadipocytes could be a clear manifestation of augmented biogenesis of the oxidative. The levels of assembled OXPHOS complexes and mitochondrial DNA (mtDNA) copy number increase with the adipocyte differentiation of 3T3-L1 cells (Ryu et al, 2013; Shi et al, 2008)

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Conclusion