Abstract
Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins—dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)—had the most potent effect on attenuating leptin resistance. TLR4 and NF-κB expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia.
Highlights
Leptin resistance is a major pathophysiology of obesity
It has been suggested that high-fat diet (HFD) increases the levels of plasma free fatty acids (FFAs), which raises the FFA levels in the hypothalamus, the main center of weight maintenance
saturated fatty acids (SFA) directly and quickly trigger inflammation in microglia [24], suggesting that both neurons and microglia are related to the changes in the hypothalamus induced by HFD
Summary
Leptin resistance is a major pathophysiology of obesity. Leptin plays a crucial role in the control of body weight and in regulating food intake by binding to the long isoform of leptin receptor (ObR). Toll-like receptor 4 (TLR4) in hypothalamic neurons and lead to leptin resistance [10,11,12]. Phlorotannins (e.g., eckol, dieckol, and phlorofucofuroeckol A) have anti-obesity effects in zebrafish [17], mice [18,19,20], and cell cultures [21]. Those studies evaluated anti-obesity effects mainly on the basis of the improvement in lipid metabolism such as inhibition of adipogenesis or lipid accumulation [17,19]. We evaluated whether extracts of E. cava would attenuate the ER stress induced by palmitate and decrease leptin resistance in hypothalamic neurons and microglia. We compared the leptin resistance–attenuating effect of 4 phlorotannin—dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol A (PFFA)
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