Chronic melatonin treatment improves obesity by inducing uncoupling of skeletal muscle SERCA-SLN mediated by CaMKII/AMPK/PGC1α pathway and mitochondrial biogenesis in female and male Zücker diabetic fatty rats Salagre Simón, Diego Navarro Alarcón, Miguel Villalón Mir, Marina Alcázar-Navarrete, Bernardino Gómez Moreno, Gerardo Tamimi, Faleh Agil Abdalla, Mhmad Ahmad CaMKII/AMPK/PGC1α Mitochondrial biogenesis Non-shivering thermogenesis Obesity SERCA-SLN Visceral fat Zücker diabetic fatty rat Melatonin acute treatment limits obesity of young Zücker diabetic fatty (ZDF) rats by non-shivering thermogenesis (NST). We recently showed melatonin chronically increases the oxidative status of vastus lateralis (VL) in both obese and lean adult male animals. The identification of VL skeletal muscle-based NST by uncoupling of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA)- sarcolipin (SLN) prompted us to investigate whether melatonin is a SERCA-SLN calcium futile cycle uncoupling and mitochondrial biogenesis enhancer. Obese ZDF rats and lean littermates (ZL) of both sexes were subdivided into two subgroups: control (C) and 12 weeks orally melatonin treated (M) (10 mg/kg/day). Compared to the control groups, melatonin decreased the body weight gain and visceral fat in ZDF rats of both sexes. Melatonin treatment in both sex obese rats restored the VL muscle skin temperature and sensitized the thermogenic effect of acute cold exposure. Moreover, melatonin not only raised SLN protein levels in the VL of obese and lean rats of both sexes; also, the SERCA activity. Melatonin treatment increased the SERCA2 expression in obese and lean rats (both sexes), with no effects on SERCA1 expression. Melatonin increased the expression of thermogenic genes and proteins (PGC1-α, PPARγ, and NRF1). Furthermore, melatonin treatment enhanced the expression ratio of P-CaMKII/CaMKII and P-AMPK/AMPK. In addition, it rose mitochondrial biogenesis. These results provided the initial evidence that chronic oral melatonin treatment triggers the CaMKII/AMPK/PGC1α axis by upregulating SERCA2-SLN-mediated NST in ZDF diabetic rats of both sexes. This may further contribute to the body weight control and metabolic benefits of melatonin. 2024-03-05T11:09:13Z 2024-03-05T11:09:13Z 2024-03 journal article Salagre D, Navarro-Alarcón M, Villalón-Mir M, Alcázar-Navarrete B, Gómez-Moreno G, Tamimi F, Agil A. Chronic melatonin treatment improves obesity by inducing uncoupling of skeletal muscle SERCA-SLN mediated by CaMKII/AMPK/PGC1α pathway and mitochondrial biogenesis in female and male Zücker diabetic fatty rats. Biomed Pharmacother. 2024 Mar;172:116314. doi: 10.1016/j.biopha.2024.116314. https://hdl.handle.net/10481/89797 10.1016/j.biopha.2024.116314 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional