Obesity is a major risk factor for the development of Nonalcoholic fatty liver disease (NAFLD). We hypothesize that a dysfunctional subcutaneous white adipose tissue (scWAT) may lead to an accumulation of ectopic fat in the liver. Our aim was to investigate the molecular mechanisms involved in the causative role of scWAT in NALFD progression. We performed a RNA‐sequencing analysis in a discovery cohort (n = 45) to identify genes in scWAT correlated with fatty liver index, a qualitative marker of liver steatosis. We then validated those targets in a second cohort (n = 47) of obese patients who had liver biopsies available. Finally, we obtained scWAT mesenchymal stem cells (MSCs) from 13 obese patients at different stages of NAFLD and established in vitro models of human MSC (hMSC)‐derived adipocytes. We observed impaired adipogenesis in hMSC‐derived adipocytes as liver steatosis increased, suggesting that an impaired adipogenic capacity is a critical event in the development of NAFLD. Four genes showed a differential expression pattern in both scWAT and hMSC‐derived adipocytes, where their expression paralleled steatosis degree: SOCS3, DUSP1, SIK1, and GADD45B. We propose these genes as key players in NAFLD progression. They could eventually constitute potential new targets for future therapies against liver steatosis.

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