Melatonin decreases human adipose tissue insulin sensitivity Zambrano, Carolina Tena Garitaonaindia, Mireia Salmerón, Diego Pérez Sanz, Fernando Tchio, Cynthia Picinato, María Cecilia Sánchez De Medina López-Huertas, Fermín Luján, Juan A. J. L. Scheer, Frank Saxena, Richa Martínez Augustin, Olga Garaulet, Marta adipose tissue explants insulin sensitivity Melatonin is a pineal hormone that modulates the circadian system and exerts soporific and phase‐shifting effects. It is also involved in many other physiological processes, such as those implicated in cardiovascular, endocrine, immune, and metabolic functions. However, the role of melatonin in glucose metabolism remains contradictory, and its action on human adipose tissue (AT) explants has not been demonstrated. We aimed to assess whether melatonin (a pharmacological dose) influences insulin sensitivity in human AT. This will help better understand melatonin administration's effect on glucose metabolism. Abdominal AT (subcutaneous and visceral) biopsies were obtained from 19 participants with severe obesity (age: 42.84 ± 12.48 years; body mass index: 43.14 ± 8.26 kg/m2) who underwent a laparoscopic gastric bypass. AT biopsies were exposed to four different treatments: control (C), insulin alone (I) (10 nM), melatonin alone (M) (5000 pg/mL), and insulin plus melatonin combined (I + M). All four conditions were repeated in both subcutaneous and visceral AT, and all were performed in the morning at 8 a.m. (n = 19) and the evening at 8 p.m. (in a subsample of n = 12). We used western blot analysis to determine insulin signaling (using the pAKT/ tAKT ratio). Furthermore, RNAseq analyses were performed to better understand the metabolic pathways involved in the effect of melatonin on insulin signaling. As expected, insulin treatment (I) increased the pAKT/ tAKT ratio compared with control (p < .0001). Furthermore, the addition of melatonin (I +M) resulted in a decrease in insulin signaling as compared with insulin alone (I); this effect was significant only during the evening time (not in the morning time). Further, RNAseq analyses in visceral AT during the evening condition (at 8 p.m.) showed that melatonin resulted in a prompt transcriptome response (around 1 h after melatonin addition), particularly by downregulating the insulin signaling pathway. Our results show that melatonin reduces insulin sensitivity in human AT during the evening. These results may partly explain the previous studies showing a decrease in glucose tolerance after oral melatonin administration in the evening or when eating late when endogenous melatonin is present. 2025-01-08T12:48:24Z 2025-01-08T12:48:24Z 2024-06-11 journal article Zambrano, C. et. al. J Pineal Res. 2024;76:e12965. [https://doi.org/10.1111/jpi.12965] https://hdl.handle.net/10481/98714 10.1111/jpi.12965 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Wiley Online Library