Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein

Abstract

Melatonin plays an important role in regulating circadian rhythms. It also acts as a potent antioxidant and regulates glucose and lipid metabolism, although the exact action mechanism is not clear. The α2-HS-glycoprotein gene (AHSG) and its protein, fetuin-A (FETUA), are one of the hepatokines and are known to be associated with insulin resistance and type 2 diabetes. The aim of this study was to determine whether melatonin improves hepatic insulin resistance and hepatic steatosis in a FETUA-dependent manner. In HepG2 cells treated with 300 μmol/L of palmitic acid, phosphorylated AKT expression decreased, and FETUA expression increased, but this effect was inhibited by treatment with 10 μmol/L of melatonin. However, melatonin did not improve insulin resistance in FETUA-overexpressing cells, indicating that improvement in insulin resistance by melatonin was dependent on downregulation of FETUA. Moreover, melatonin decreased palmitic acid-induced ER stress markers, CHOP, Bip, ATF-6, XBP-1, ATF-4, and PERK. In addition, in the high-fat diet (HFD) mice, oral treatment with 100 mg/kg/day melatonin for 10 weeks reduced body weight gain to one-third of that of the HFD group and hepatic steatosis. Insulin sensitivity and glucose intolerance improved with the upregulation of muscle p-AKT protein expression. FETUA expression and ER stress markers in the liver and serum of HFD mice were decreased by melatonin treatment. In conclusion, melatonin can improve hepatic insulin resistance and hepatic steatosis through reduction in ER stress and the resultant AHSG expression.

Melatonin application in targeting oxidative‐induced liver injuries: A review

“…The JNK pathway is known to be stimulated by oxidative stress (Mota, Banini, Cazanave, & Sanyal, ) and implicated in hepatocyte apoptosis induced by saturated free fatty acids. Heo found that oral treatment of 100 mg/kg/day melatonin for 10 weeks to HFD‐induced NAFLD mice improved insulin sensitivity and decreased plasma insulin (Heo, ). Melatonin has also been reported to reduce phosphorylation of JNK1/2 in a mouse model of HFD‐induced NAFLD (Sun et al, ).…”

“…Melatonin inhibits ischemia-induced overproduction of iNOS and NO (Rodriguez-Reynoso et al, 2001). Melatonin also reduces NF-kB activation (Kang et al, 2011) and increases nuclear translocation of Nrf2 with subsequent induction of HO-1 (Kang & Lee, 2012), GST (Kireev et al, 2013), and NQO1 (Chen et al, 2016) TABLE 2 Protection role of melatonin against liver ischemia-reperfusion injury (IRI) and the level of oxidative stress 100 mg/kg/day melatonin for 10 weeks to HFD-induced NAFLD mice improved insulin sensitivity and decreased plasma insulin (Heo, 2017).…”

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

“…In our previous research, melatonin ameliorates metaflammation‐induced pyroptosis through intracellular nuclear factor kappa‐light‐chain‐enhancer of activated B cell/Gasdermin D signal in adipose tissue, and it prevents adipocyte dysfunction under circadian rhythm disorder . On the other hand, melatonin has also been confirmed to protect liver during metabolic syndrome through various defined mechanisms . Melatonin triggers ER‐ and autophagy‐induced apoptosis in liver cancer, while it inhibits hepatocellular carcinoma proliferation and invasiveness via various transcription factors and signaling pathways .…”

“…30,31 In obese individuals and mice models, melatonin has also been identified to control the development of obesity, improve lipid metabolism, ameliorate hepatic oxidative stress and mitochondrial dysfunction, 3,4,[32][33][34][35][36] and alleviate local/systematical inflammation in different tissues and organs. 28,37,38 In our previous research, melatonin ameliorates metaflammation-induced pyroptosis through intracellular nuclear factor kappa-light-chain-enhancer of activated B cell/Gasdermin D signal in adipose tissue, and it prevents adipocyte dysfunction under circadian rhythm disorder. 28,39 On the other hand, melatonin has also been confirmed to protect liver during metabolic syndrome through various defined mechanisms.…”

“…However, intense investigations have gradually overthrew traditional standpoints and recognized melatonin as a broad‐spectrum regulatory molecule in multiple physiological activities, including improvements of reproduction, remissions of intestinal dysbacteriosis, anti‐inflammation, and anti‐cancer efforts . In obese individuals and mice models, melatonin has also been identified to control the development of obesity, improve lipid metabolism, ameliorate hepatic oxidative stress and mitochondrial dysfunction, and alleviate local/systematical inflammation in different tissues and organs . In our previous research, melatonin ameliorates metaflammation‐induced pyroptosis through intracellular nuclear factor kappa‐light‐chain‐enhancer of activated B cell/Gasdermin D signal in adipose tissue, and it prevents adipocyte dysfunction under circadian rhythm disorder .…”