Phthalate exposure causes browning-like effects on adipocytes in vitro and in vivo

Jhih-Wei Hsu; Chung-Yi Nien; Szu-Ching Yeh; Feng-Yuan Tsai; Hsin-Wei Chen; Tzong-Shyuan Lee; Shen-Liang Chen; Yung-Hsi Kao; Tsui-Chun Tsou

doi:10.1016/j.fct.2020.111487

Phthalate exposure causes browning-like effects on adipocytes in vitro and in vivo

Food Chem Toxicol. 2020 Aug:142:111487. doi: 10.1016/j.fct.2020.111487. Epub 2020 Jun 6.

Authors

Jhih-Wei Hsu¹, Chung-Yi Nien², Szu-Ching Yeh³, Feng-Yuan Tsai³, Hsin-Wei Chen³, Tzong-Shyuan Lee⁴, Shen-Liang Chen², Yung-Hsi Kao², Tsui-Chun Tsou⁵

Affiliations

¹ National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan; Department of Life Sciences, National Central University, Zhongli, Taoyuan City, 320, Taiwan.
² Department of Life Sciences, National Central University, Zhongli, Taoyuan City, 320, Taiwan.
³ National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan.
⁴ Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.
⁵ National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan. Electronic address: tctsou@nhri.edu.tw.

PMID: 32522588
DOI: 10.1016/j.fct.2020.111487

Abstract

Mono(2-ethylhexyl)phthalate (MEHP) promotes adipogenesis via PPARγ. PPARγ agonists, e.g., rosiglitazone (RSG), enhance adipocyte browning. However, scientific evidence regarding MEHP as a browning chemical is lacking. This study combined 3T3-L1 adipocytes and C57BL/6J mice to examine the potential roles of MEHP in browning. MEHP and the browning agent RSG caused similar energy metabolism in adipocytes. Both MEHP and RSG caused transcriptional changes involved in browning-associated thermogenesis, energy homeostasis, inflammatory response, and glucose uptake. MEHP-treated adipocytes exhibited brown adipocyte-like characteristics, i.e., increased mitochondrial proton leak, triiodothyronine-induced Bmp8b expression, decreased inflammation, and smaller lipid droplets. Increased PDK4 and PEPCK1 in MEHP/RSG-treated adipocytes could block glucose utilization for mitochondrial respiration. Mitochondrial/peroxisomal biogenesis and fatty acid β-oxidation in MEHP-treated adipocytes were enhanced. Candidate genes in promoting browning of MEHP-treated adipocytes were highlighted. In di(2-ethylhexyl)phthalate (DEHP)-treated mice, transcriptional changes in white adipose tissue (WAT) were associated with adipocyte differentiation, lipid synthesis, carbohydrate uptake, and WAT/brown adipose tissue (BAT) quantity. PPARγ and NR4A1 were predicted as the top two upstream regulators in orchestrating transcriptional changes. DEHP-treated mice exhibited actively expressed browning marker genes (i.e., Pparg, Adrb1, Adrb3, Ppargc1a, and Ucp1) in WAT, increased blood FGF21 levels, and higher amounts of BAT, supporting the browning-like effects in vivo.

Keywords: Energy metabolism; Fat cells; Fatty acid oxidation; Mitochondria; Peroxisomes; Plasticizer.

MeSH terms

3T3-L1 Cells
Adipocytes, Brown / drug effects*
Adipocytes, Brown / metabolism
Animals
Diethylhexyl Phthalate / analogs & derivatives*
Diethylhexyl Phthalate / toxicity
Energy Metabolism / drug effects
Gene Expression / drug effects
Glucose / metabolism
In Vitro Techniques
Male
Mice
Mice, Inbred C57BL
Mitochondria / metabolism
Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase

Substances

Pdk4 protein, mouse
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Diethylhexyl Phthalate
Phosphoenolpyruvate Carboxykinase (ATP)
mono-(2-ethylhexyl)phthalate
Glucose