Abstract
Adipocytes play a central role in maintaining metabolic homeostasis in the body. Differentiation of adipocyte precursor cells requires the transcriptional activity of peroxisome proliferator-activated receptor-γ (Pparγ) and CCAAT/enhancer binding proteins (C/Ebps). Transcriptional activity is regulated by signaling modules activated by a plethora of hormones and nutrients. Mechanistic target of rapamacin complexes (mTORC) 1 and 2 are central for the coordination of hormonal and nutritional inputs in cells and are essential for adipogenesis. Serum glucocorticoid kinase 1 (Sgk1)-dependent phosphorylation of N-Myc downstream-regulated gene 1 (Ndrg1) is a hallmark of mTORC2 activation in cells. Moreover, Pparγ activation promotes Ndrg1 expression. However, the impact of Ndrg1 on adipocyte differentiation and function has not yet been defined. Here, we show that Ndrg1 expression and its Sgk1-dependent phosphorylation are induced during adipogenesis. Consistently, we demonstrate that Ndrg1 promotes adipocyte differentiation and function by inducing Pparγ expression. Additionally, our results indicate that Ndrg1 is required for C/Ebpα phosphorylation. Moreover, we found that Ndrg1 phosphorylation by Sgk1 promotes adipocyte formation. Taken together, we show that induction of Ndrg1 expression by Pparγ and its phosphorylation by Sgk1 kinase are required for the acquisition of adipocyte characteristics by precursor cells.
Highlights
White adipocytes are central for the regulation of lipid and metabolic homeostasis[1]
To test whether Ndrg[1] could regulate adipocyte differentiation, we first measured its expression in the 3t3l1 pre-adipocyte cell line, which was subjected to an adipocyte-differentiation cocktail for different time points
Using a phospho-specific antibody, we found that the levels of Ndrg[1] phosphorylated by Sgk[1] on T346 increased during adipocyte differentiation (Fig. 1B)
Summary
White adipocytes are central for the regulation of lipid and metabolic homeostasis[1]. Peroxisome proliferator-activated receptor-γ (Pparγ) and CCAAT/ enhancer binding proteins (C/Ebps) are major transcription factors promoting the acquisition of molecular adipocyte characteristics by precursor cells[2]. A plethora of extracellular signals, including hormones and nutrients, activate intracellular signaling cascades that modulate Pparγ, C/Ebps and other transcription factors to regulate adipogenesis[3]. Depletion of raptor abrogates the activity of mTORC1, while rictor is required for mTORC2 function[4]. Genetic and pharmacological studies revealed that both mTORC1 and mTORC2 are required for adipogenesis and promote adipocyte function[5,6,7,8]. A number of studies suggest that Ndrg[1] might regulate other signaling cascades that influence adipocyte differentiation. Our results suggest that Sgk1-dependent phosphorylation of threonine 346 on Ndrg[1] promotes adipocyte differentiation
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