Adipose tissue plays a decisive role in the body's metabolic homeostasis. Its capacity to efficiently store lipids protects other organs, such as muscle and liver, from toxic fat exposure. When caloric intake becomes excessive, adipose tissue expands through two modalities: hyperplasia, namely the increase in adipocyte number through progenitor differentiation, and hypertrophy, namely the increase in cell size through lipid accumulation. The balance between these two processes determines metabolic health: hypertrophy is associated with adipose tissue dysfunction and an increased risk of type 2 diabetes, independently of weight status. While the transcription factors orchestrating adipogenesis—particularly PPARγ and the C/EBP family proteins—are now well identified, the role of the coregulators that translate regulatory signals into epigenetic modifications and transcriptional responses remains poorly understood. Within this framework, the present work examines the pathways controlled by the coregulator GPS2 (G protein pathway suppressor 2) during human adipocyte differentiation.
To this end, the authors developed a loss-of-function model by depleting GPS2 through RNA interference in human multipotent adipose-derived stem cells (hMADS). They characterized in detail the alterations resulting from this depletion by combining transcriptome analysis (RNA-seq), epigenome analysis (H3K27 acetylation ChIP-seq), cistrome analysis (GPS2 ChIP-seq), and lipidome analysis. The in vivo relevance of the identified pathways was then verified in the omental adipose tissue of obese patients, whether diabetic or not.
Loss of GPS2 amplifies the responses to the adipogenic cocktail and reprograms differentiation-related processes. In particular, it increases the expression of BMP4, which triggers the commitment of fibroblastic progenitors toward the adipocyte lineage, as well as that of inflammatory and metabolic genes. GPS2-depleted adipocytes exhibit hypertrophy, triglyceride and phospholipid accumulation, and sphingomyelin depletion. These changes likely result from the increased expression of the ABCG1 transporter, which mediates sphingomyelin efflux and modulates lipoprotein lipase (LPL) activity. The authors identify ABCG1 as a direct transcriptional target: GPS2 depletion leads to coordinated changes in transcription and H3K27 acetylation at promoters and enhancers occupied by GPS2 in wild-type adipocytes. In obese subjects, GPS2 levels in omental adipose tissue correlate with those of ABCG1, with diabetic status, and with lipid metabolic status.
This work thus highlights a dual regulatory role for GPS2, acting both on the chromatin landscape and on gene expression during human adipocyte differentiation. The authors propose that GPS2 controls commitment to the adipocyte lineage at early stages and then sphingolipid metabolism via ABCG1 at later stages. They describe a previously unknown GPS2–ABCG1 pathway, potentially linked to adipocyte hypertrophy in humans.