168 | GLP‑1 receptor signaling directs adipogenic repression and thermogenic activation in human adipose-derived stem cells

Carola Pia Giordano, Laura Tomasello, Luigi Di Rosa, Antonino Salvatore Fiore, Sonya Vasto, Sara Baldassano | Department of Biological, Chemical and Pharmaceutical Sciences and Technologies STEBICEF, University of Palermo, Italy.

Abstract

Glucagon-like peptide‑1 receptor agonists (GLP‑1RAs) are widely used for obesity management, yet their direct actions on human adipose tissue and its progenitors remain incompletely understood. Whether GLP‑1 receptor modulation influences the adipogenic and thermogenic fate of human adipose‑derived stem cells (ASCs) is still debated. Human ASCs isolated from subcutaneous adipose tissue of overweight donors were characterized and subjected to adipogenic (white) and thermogenic (brown/beige) differentiation. Cells were exposed to the GLP‑1R agonist beinaglutide (BN) or the antagonist Exendin 9‑39 (EX9‑39). Viability, cell‑cycle distribution, lipid accumulation, transcriptional profiles (NANOG, C/EBPα, PPARγ, UCP1), intracellular cAMP levels, and GLP‑1R protein expression were evaluated. Both BN and EX9‑39 preserved ASC viability and produced only a mild increase in G2/M cell‑cycle fraction. GLP‑1R modulation suppressed canonical white adipogenic differentiation, markedly downregulating C/EBPα and PPARγ, while inducing UCP1 expression even in undifferentiated ASCs, suggesting an early thermogenic shift. Effects were depot‑dependent: in BAT, EX9‑39 maintained PPARγ and UCP1 expression, whereas BN significantly reduced BAT‑specific markers; in WAT, both compounds induced partial browning, increasing UCP1 and modulating adipogenic transcription factors. cAMP responses also differed by phenotype, with BN increasing cAMP in WAT but decreasing it in BAT, and EX9‑39 showing the opposite pattern. Western blotting confirmed GLP‑1R expression in ASCs and revealed opposite regulatory effects of BN and EX9‑39 in BAT vs. WAT.  GLP‑1 receptor agonism and antagonism exert direct, phenotype‑dependent effects on human adipose progenitors, reshaping adipogenic repression and thermogenic activation programs. These findings uncover a previously underappreciated layer of depot‑specific adipose plasticity regulated by GLP‑1 signaling and offer mechanistic insights into the metabolic benefits of incretin‑based therapies.