Depot-Specific Insulin Receptor Isoform Dynamics During Human Adipose-Derived Stem Cell Adipogenesis

Objective: The insulin receptor (IR) and the insulin-like growth factor I receptor (IGF-IR) regulate adipose tissue (AT) differentiation. This study investigated the expression of IGF-IR, IR, and the IR isoforms (IRa and IRb) in human subcutaneous (S-ASC) and visceral (V-ASC) adipose-derived stem cells. Methods: S-AT and V-AT biopsies were obtained from human donors and ASC were differentiated into adipocytes. mRNA levels of all receptors were quantified by qPCR at baseline and after differentiation. IR protein expression and adipogenic efficiency were assessed by flow cytometry. Results: In undifferentiated ASC, IGF-IR transcripts exceeded IR and were higher in S-ASC than V-ASC. Upon differentiation, IGF-IR decreased in S-ASC but remained unchanged in V-ASC, whereas IR increased in both depots. S-ASC displayed ~twofold higher IRa expression and greater insulin-induced Akt activation. During adipogenesis, IR expression rose in both depots, with IRb exceeding IRa particularly in V-ASC (+50%). In whole AT, IR exceeded IGF-IR, and no depot-specific differences were observed between IR isoforms. Adipogenic conversion was higher in S-ASC (60%) than V-ASC (20%). Only ~77% of S-ASC- and ~61% of V-ASC-derived adipocytes expressed surface IR. Conclusions: Depot-specific dynamics of IR isoforms may influence adipogenic capacity and insulin responsiveness and suggest partially receptor-independent pathways of adipocyte differentiation. (Figure presented.).