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bioRxiv · 10.1101/2025.03.24.640716

Melatonin Protects Against Palmitate-Induced Lipid Accumulation and Leptin Resistance via PI3K/AKT in 3T3-L1 Cell line

Suriyagandhi, V.·Arunachalam, R.·Nachiappan, V.
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Abstract

BackgroundA high-fat diet (HFD) (which contains palmitate) is the primary factor for dietinduced obesity. Lack of sleep leads to the selection of HFD to maintain wakefulness. Sleep deprivation, along with HFD, induces obesity by leptin resistance. The sleep hormone melatonin secreted at night is responsible for the sleep-wake cycle based on circadian rhythm. It has various other functions in the central and peripheral axes, including food intake and energy expenditure. Primarily, melatonin regulates intracellular signaling via its receptors MT1 and MT2 (GPCR) in the cell membrane and can directly enter the cytoplasm. AimTo study the role of melatonin and its receptor-mediated signaling in palmitate-induced obesity and leptin resistance using the 3T3-L1 cell line. MethodsLipid accumulation was induced in differentiated 3T3-L1 cell lines by sodium palmitate (0.8 mM). Further, we exposed the cells to melatonin (1 mM) and melatonin receptor inhibitors (luzindole/and 4P-PDOT). Lipid accumulation and melatonins effect were studied using thin-layer chromatography and oil-red O staining, and the mRNA and protein expression of lipid-synthesizing genes and lipases were analyzed using qRT-PCR and western blotting. Leptin secretion was quantified by ELISA assay. Calcium imaging was done by Fura2-AM fluorescent staining. ResultsPalmitate induction in differentiated 3T3-L1 cell line elevated triacylglycerol (TAG) in lipid droplets along with an increase in the mRNA expression of PPAR{gamma}, SREBP1c, FASN, ACC1, and leptin secretion but decreased the lipases (HSL and ATGL) and PI3K and AKT. Treatment with melatonin restored the TAG level, lipid droplet size, and gene expression of PPAR{gamma}, SREBP1c, FASN, and ACC1, as well as leptin secretion, but increased protein expression of lipases. Melatonin receptor inhibitors, along with palmitate and melatonin, reversed the positive effects of melatonin on fat accumulation and leptin resistance. Intracellular calcium levels were reduced with palmitate induction, and melatonin rescued the calcium level equal to the control group through its receptor signaling. Melatonin restores the mRNA expression of PI3K and AKT genes in palmitate-induced conditions via its receptors. ConclusionMelatonin is vital for hormonal regulation and energy metabolism, including obesity and leptin secretion. Studying the role of melatonin in leptin regulation and lipid metabolism will help us combat the pathologies of obesity caused by HFD. From our study, the action of melatonin against lipid accumulation and the regulation of leptin secretion is mediated through its receptors MT1 and MT2 by activating the downstream PI3k/AKT signaling. HighlightsO_LIMelatonin restores palmitate-induced lipid accumulation via its receptors. C_LIO_LIMelatonin reduces lipogenesis and increases lipolysis in lipid-accumulated adipocytes. C_LIO_LIMelatonin rescues palmitate-induced leptin resistance through its receptors by altering the intracellular calcium levels. C_LIO_LIMelatonin, via its receptors, restores palmitate-induced lipid accumulation by activating the PI3K/AKT signaling. C_LI

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Suriyagandhi, V., Arunachalam, R., Nachiappan, V.. 2025-03-26. Melatonin Protects Against Palmitate-Induced Lipid Accumulation and Leptin Resistance via PI3K/AKT in 3T3-L1 Cell line. https://doi.org/10.1101/2025.03.24.640716

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