Weight Loss Upregulates the Small GTPase DIRAS3 in Human White Adipose Progenitor Cells, Which Negatively Regulates Adipogenesis and Activates Autophagy via Akt–mTOR Inhibition

•Long-term weight loss (WL) induces DIRAS3 and IGF-1 in ASCs of sWAT in formerly obese humans.•DIRAS3 selectively down-regulates IGF-1R-Akt–mTOR signaling in ASCs and channels the IGF-1 stimulus to the ERK1/2 branch.•DIRAS3 inhibits adipogenesis and activates autophagy in ASCs.Long-term weight loss (WL) interventions reduce insulin serum levels, protect from obesity and postpone age-associated diseases. The impact of WL on adipose-derived stromal/progenitor cells (ASCs), stem cell-like cells in human subcutaneous white adipose tissue (sWAT), is not understood. We found that WL induced GTP-binding RAS-like 3 (DIRAS3) and insulin-like growth factor 1 (IGF-1), regulators of the IGF-1–mTOR signal transduction pathway, in ASCs in sWAT of formerly obese humans. We demonstrate that DIRAS3 selectively down-regulates IGF-1R–Akt–mTOR signaling in ASCs upon WL even in the presence of high IGF-1 level and that DIRAS3 inhibits adipogenesis and activates autophagy in these cells.

Long-term weight-loss (WL) interventions reduce insulin serum levels, protect from obesity, and postpone age-associated diseases. The impact of long-term WL on adipose-derived stromal/progenitor cells (ASCs) is unknown. We identified DIRAS3 and IGF-1 as long-term WL target genes up-regulated in ASCs in subcutaneous white adipose tissue of formerly obese donors (WLDs). We show that DIRAS3 negatively regulates Akt, mTOR and ERK1/2 signaling in ASCs undergoing adipogenesis and acts as a negative regulator of this pathway and an activator of autophagy. Studying the IGF-1–DIRAS3 interaction in ASCs of WLDs, we demonstrate that IGF-1, although strongly up-regulated in these cells, hardly activates Akt, while ERK1/2 and S6K1 phosphorylation is activated by IGF-1. Overexpression of DIRAS3 in WLD ASCs completely inhibits Akt phosphorylation also in the presence of IGF-1. Phosphorylation of ERK1/2 and S6K1 is lesser reduced under these conditions. In conclusion, our key findings are that DIRAS3 down-regulates Akt–mTOR signaling in ASCs of WLDs. Moreover, DIRAS3 inhibits adipogenesis and activates autophagy in these cells.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide