Hypoxia-Induced Alterations in Adipocyte Calcium Signaling: The Role of TRPV1 in Lipid Metabolism

Introduction: Adipocyte hypoxia has been recognized as a key contributor to the development of metabolic disorders such as obesity. However, the molecular pathways involved remain insufficiently characterized. Cytosolic calcium (Ca 2+ ) is a crucial regulator of adipocyte metabolism, influencing adipogenesis, lipid storage, and lipolysis. Despite this, the mechanisms governing Ca 2+ homeostasis and the functional roles of plasma membrane calcium transporters under hypoxic conditions remain largely unexplored. This study examines how hypoxia influences the gene expression of plasma membrane calcium transporters in murine and human adipocytes. Additionally, it evaluates the role of the calcium channel TRPV1 in adipocyte function under low-oxygen conditions. Methods: 3T3-L1 preadipocytes were differentiated into adipocytes and maintained under either normoxic (21% O 2 ) or hypoxic (4% O 2 ) conditions for 14 days. Human adipose tissue samples were obtained from patients diagnosed with sleep apnea syndrome. Gene expression profiling targeted 42 plasma membrane calcium transporters. The involvement of TRPV1 was further investigated by treating hypoxia-exposed adipocytes with either a TRPV1 agonist (1 µM capsaicin) or antagonist (1 µM capsazepine) over the 14-day period. Lipid accumulation, gene expression, and lipolysis were assessed. Statistical analysis was performed using a t-test or two-way ANOVA, with data presented as means ± SD (N=6). Results: Hypoxia induced significant alterations in the expression of calcium transporters in both murine and human adipocytes. Among these, TRPV1 exhibited the most pronounced response, with a 30-fold reduction in gene expression under hypoxia (1.02 ± 0.08 -fold to 0.03 ± 0.01 -fold, p<0.001) relative to normoxic conditions. Pharmacological modulation of TRPV1 during hypoxia influenced lipid metabolism: activation via capsaicin reduced lipid accumulation by 5% (1.89 ± 0.02 to 1.79 ± 0.02 OD 492nm , p<0.01), whereas inhibition with capsazepine increased lipid content by 8% (1.89 ± 0.02 to 2.05 ± 0.01 OD 492nm , p < 0.05). Additionally, capsazepine-mediated TRPV1 inhibition resulted in a 35% upregulation of FASN expression under hypoxia, consistent with the observed lipid accumulation. Conclusion: These findings indicate that hypoxia strongly suppresses TRPV1 expression, potentially altering calcium signaling pathways in adipocytes. Pharmacological modulation of TRPV1 activity directly impacts lipid accumulation, suggesting TRPV1 as a promising target for metabolic regulation in adipose tissue. Future research will explore its role in lipolysis and mitochondrial function to further elucidate its contribution to hypoxia-driven metabolic adaptations. Supported by Charles University GAUK 294822 and Cooperatio; National Institute for Research of Metabolic and Cardiovascular Diseases programme Exceles No. LX22NPO5104 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.