Nuclear MEK1 Sequesters PPARγ and Bisects MEK1/ERK Signaling: A Non-Canonical Pathway of Retinoic Acid Inhibition of Adipocyte Differentiation

Abstract

Uncontrolled adipogenesis and adipocyte proliferation have been connected to human comorbidities. Retinoic acid (RA) is known to inhibit adipocyte differentiation, however the underlying mechanisms have not been adequately understood. This study reports that RA acting as a ligand to RA receptors (RARs and RXRs) is not a sine qua non to the inhibition of adipogenesis. Our intriguing observation of a negative correlation between increased retinoylation and adipogenesis led us to explore retinoylated proteins in adipocytes. Exportin (CRM1) was found to be retinoylated, which in turn can affect the spatio-temporal regulation of the important signaling molecule mitogen-activated protein kinase kinase 1 (MEK1), likely by disrupting its export from the nucleus. Nuclear enrichment of MEK1 physically sequesters peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipogenesis, from its target genes and thus inhibits adipogenesis while also disrupting the MEK1-extracellular-signal regulated kinase (ERK) signaling cascade. This study is first to report the inhibition of adipocyte differentiation by retinoylation.

Retinoids Regulate Adipogenesis Involving the TGFβ/SMAD and Wnt/β-Catenin Pathways in Human Bone Marrow Mesenchymal Stem Cells

“…RA also induces the nuclear enrichment of MEK1, which physically sequesters PPARγ from its target genes [32]. In the current study, we found that the RAR agonists inhibited the expression of adipogenic marker genes C/EBPα, PPARγ, and FABP4 during adipogenic differentiation at seven days in hBMSCs and SW872 cells, but the expression of C/EBPβ was increased.…”

MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injury

“…Interestingly, MEK1 was recently described to have important roles in T cell transcriptional responses through regulation of the nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone (SMRT) at the promoter of c-Fos (39). In addition, there have been reports describing the interactions between PPAR-γ and the activation of MEK1/2-ERK1/2 (40), and MEK1 itself can play a role in regulating nuclear localization and activation of PPAR-γ (41)(42)(43). PPARs have important roles in regulating macrophage responses to inflammation (44,45), and represents one of likely many potential mechanisms by which MEK1/2-ERK1/2 regulates macrophage responses.…”

Role of PPARγ in the nutritional and pharmacological actions of carotenoids

“…Rich MEK1 in the nucleus decreases PPARγ availability and thus inhibits adipogenesis, while also disrupting the MEK1-ERK signaling cascade. 66 This shows that the molecular mechanisms underlying RA effects on adipocyte differentiation and adipogenesis are complex and remain poorly understood. Furthermore, it is proposed that there is a high turnover of adipocytes at all adult ages in humans.…”