T-Cadherin Finetunes the Proliferation–Differentiation During Adipogenesis via PI3K–AKT Signaling Pathway

Adipose tissue renewal requires precise coordination of stem/progenitor cell prolifera-tion, preadipocyte commitment, and terminal adipocyte differentiation. T-cadherin (CDH13), an atypical GPI-anchored cadherin, is expressed in adipose tissue and functions as a receptor for high-molecular-weight (HMW) adiponectin—a key adipokine produced by adipose tissue and involved in metabolic regulation. While T-cadherin is implicated in cardiovascular and metabolic homeostasis, its role in adipogenesis still remains poorly understood. In this study, we used the 3T3-L1 preadipocyte model to investigate the function of T-cadherin in adipocyte differentiation. We analyzed T-cadherin expression dynamics during differentiation and assessed how T-cadherin overexpression or knockdown affects lipid accumulation, expression of adipogenic markers, and activation of key signaling pathways including ERK, PI3K–AKT, AMPK, and mTOR. Our findings demonstrate that T-cadherin acts as a negative regulator of adipogenesis. T-cadherin overexpression ensured a proliferative, undifferentiated cell state, suppressing lipid droplet accumulation and adipogenic marker expression. In contrast, T-cadherin downregulation accelerated differentiation, enhanced lipid accumulation, and increased insulin responsiveness, as indicated by elevated PI3K and phosphorylated AKT levels. These results position T-cadherin as a key modulator of adipose tissue plasticity, regu-lating the balance between progenitor expansion and terminal differentiation, with po-tential relevance to obesity and metabolic disease.