PPAR?-dependent Remodeling of Translational Machinery in Adipose Progenitors is Impaired in Obesity [scRNA-seq]

Adipose tissue plays a pivotal role in energy homeostasis and metabolic regulation. However, in obesity, the remarkable adaptability of adipose tissue becomes impaired. The underlying mechanisms behind this limited adaptability remain poorly understood. In this study, we investigate a novel layer of regulation involving translation in the adipose stromal vascular fraction, examining its response to obesity and acute PPAR? agonist treatment with rosiglitazone. Using single-cell RNA sequencing, we establish a transcriptional profile atlas of cellular remodeling from obese to lean-like states in inguinal and epididymal adipose tissue following rosiglitazone treatment. Notably, both stromal fractions exhibit a downregulation of inflammation-related transcripts and an upregulation of lipid-related metabolism and ribosomal transcripts. Adipocyte progenitor and preadipocyte populations display enhanced ex-vivo differentiation potential and upregulation in ribosome and peptide chain elongation pathways. This ribosomal remodeling is directly driven by PPAR? binding to gene promoters of ribosomal factors. Furthermore, we have characterized the translatome in the epididymal stromal fraction, highlighting a buffering response and fat-exclusive preferential translation after rosiglitazone treatment. Enhanced translation efficiency in rosiglitazone-elicited polysomes promotes the translation of transcripts containing G-rich sequences in their 5' untranslated regions. Our findings shed light and provide a resource on how rosiglitazone remodels the adipose stromal vascular fraction, both dependent and independent of PPAR?. Importantly, we uncover translatome remodeling as a major new mechanism for maintaining translation homeostasis and preserving adipose tissue health in obesity. Overall design: Lepob/Lepob & C57Bl/6J mice were treated with 30mg/Kg of rosiglitazone or vehicle for 3 days. Stromal vascular fraction was isolated and used for scRNA- sequencing.