The Role of Adipocyte PD-L1 Signaling in Modulating Metabolic Plasticity

White adipose tissues (WATs) play a crucial role in regulating whole-body energy homeostasis and endocrine control. However, pathological expansion due to excessive calorie intake leads to obesity and its related comorbidities, contributing to global morbidity and mortality. Adipocyte dysfunction and senescence are key factors in this process. While the interplay between adipocytes and leukocytes is vital for maintaining adipose tissue (AT) homeostasis, exacerbated metabolic health is observed in patients receiving the Programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) treatment. We and others also showed that PD-L1 mAb received C57BL/6 mice displayed worsened metabolic status. The immune checkpoint protein PD-L1, expressed on adipocytes, remains poorly understood in regulating AT homeostasis and its modulation against obesity. We hypothesized that functional PD-L1 may preserve the AT homeostasis through reprogramming cellular metabolism in adipocyte. We generated adipocyte specific PD-L1 knockout mice (Pdl1 AKO ) by crossbreeding Pdl1 floxed knockin (Pdl1 f/f ; Pdl1 AWT ) and adiponectin-cre (Adipoq cre/+ ) mice. 6-week-old male Pdl1 AWT and Pdl1 AKO mice were fed with either normal chow diet (NCD) or high fat diet (HFD; 58% fat) for 14 weeks. Deletion of PD-L1 in adipocytes resulted in increased weight gain, as well as greater subcutaneous and epididymal AT deposition compared with Pdl1 AWT mice. HFD-fed Pdl1 AKO mice showed lowered glucose tolerance and increased insulin resistance. Besides, AT health is associated with interorgan crosstalk. We found that HFD-induced hepatic lipid accumulation was exacerbated in mice lacking adipocyte PD-L1 compared with Pdl1 AWT mice. In summary, these findings highlighted the unmentioned role of adipocyte PD-L1 in regulating the adipocyte’s metabolism and disease progression. This project was supported by the General Research Fund 14105022 from the Hong Kong Research Grant Council. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.