Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes

Saturated fatty acids, such as palmitate, lead to circadian disruption. We aimed at studying the effect of low doses of palmitate on circadian metabolism and to decipher the mechanism by which fatty acids convey their effect in adipocytes. Mice were fed non-obesogenic doses of palm or olive oil and adipocytes were treated with palmitate and oleate. Cultured adipocytes treated with oleate showed increased AMPK activity and induced the expression of mitochondrial genes indicating increased fatty acid oxidation, while palmitate increased ACC activity and induced the expression of lipogenic genes, indicating increased fatty acid synthesis. Low doses of palmitate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins including GSK3β and AKT. Palmitate-induced AKT and GSK3β activation led to the phosphorylation of BMAL1 that resulted in low levels as well as high amplitude of circadian clock expression. In adipocytes, the detrimental metabolic alteration of palmitate manifests itself early on even at non-obesogenic levels. This is accompanied by modulating BMAL1 expression and phosphorylation levels, which lead to dampened clock gene expression.

饱和脂肪酸（saturated fatty acids）如棕榈酸（palmitate）可引发昼夜节律紊乱。本研究旨在探究低剂量棕榈酸对昼夜节律代谢的影响，并解析脂肪酸在脂肪细胞（adipocytes）中发挥调控作用的分子机制。实验中，小鼠被喂食非致肥胖剂量的棕榈油与橄榄油，同时对体外培养的脂肪细胞分别施以棕榈酸与油酸（oleate）处理。经油酸处理的体外培养脂肪细胞可检测到腺苷酸活化蛋白激酶（AMPK）活性上调，且线粒体基因表达水平升高，提示脂肪酸氧化过程增强；而棕榈酸处理则可提升乙酰辅酶A羧化酶（ACC）活性，并诱导生脂基因表达，表明脂肪酸合成过程增强。低剂量棕榈酸即可通过改变包括糖原合成激酶3β（GSK3β）与蛋白激酶B（AKT）在内的关键代谢蛋白的表达及/或活性，从而扰乱昼夜节律。棕榈酸诱导的AKT与GSK3β激活可导致脑和肌肉芳香烃受体核转位蛋白样1（BMAL1）发生磷酸化，进而使昼夜节律钟的表达水平降低但振幅升高。在脂肪细胞中，即便处于非致肥胖剂量水平，棕榈酸所介导的有害代谢改变仍会早期显现，这一过程伴随BMAL1表达与磷酸化水平的异常调控，最终导致节律钟基因表达受抑制。