Combined Transcriptomic– ¹H NMR Metabonomic Study Reveals That Monoethylhexyl Phthalate Stimulates Adipogenesis and Glyceroneogenesis in Human Adipocytes

Abstract

Adipose tissue is a major storage site for lipophilic environmental contaminants. The environmental metabolic disruptor hypothesis postulates that some pollutants can promote obesity or metabolic disorders by activating nuclear receptors involved in the control of energetic homeostasis. In this context, monoethylhexyl phthalate (MEHP) is of particular concern since it was shown to activate the peroxisome proliferator-activated receptor γ (PPARγ) in 3T3-L1 murine preadipocytes. In the present work, we used an untargeted, combined transcriptomic- ¹H NMR-based metabonomic approach to describe the overall effect of MEHP on primary cultures of human subcutaneous adipocytes differentiated in vitro. MEHP stimulated rapidly and selectively the expression of genes involved in glyceroneogenesis, enhanced the expression of the cytosolic phosphoenolpyruvate carboxykinase, and reduced fatty acid release. These results demonstrate that MEHP increased glyceroneogenesis and fatty acid reesterification in human adipocytes. A longer treatment with MEHP induced the expression of genes involved in triglycerides uptake, synthesis, and storage; decreased intracellular lactate, glutamine, and other amino acids; increased aspartate and NAD, and resulted in a global increase in triglycerides. Altogether, these results indicate that MEHP promoted the differentiation of human preadipocytes to adipocytes. These mechanisms might contribute to the suspected obesogenic effect of MEHP.

Abstract

Using an untargeted combined transcriptomic- ¹H NMR-based metabonomic approach, we describe the overall effect of monoethyl-hexyl phthalate (MEHP) on primary cultures of human subcutaneous adipocytes differentiated in vitro. MEHP rapidly and selectively stimulated glyceroneogenesis, a metabolic pathway involved in the control of fatty acid release from adipose tissue. A longer treatment with MEHP promoted the differentiation of human preadipocytes to adipocytes. These mechanisms might contribute to an obesogenic effect of MEHP.