Greco James A, Oosterman Johanneke E, Belsham Denise D
Department of Physiology, University of Toronto, Toronto, Ontario, Canada;
Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Am J Physiol Regul Integr Comp Physiol. 2014 Oct 15;307(8):R1049-60. doi: 10.1152/ajpregu.00100.2014. Epub 2014 Aug 20.
Diets high in saturated fatty acids (SFAs) are associated with the development of circadian dysregulation, obesity, and Type 2 diabetes mellitus. Conversely, polyunsaturated fatty acids (PUFAs) have recently been identified to improve insulin sensitivity, reduce weight gain, and relieve obesity-induced inflammation. While saturated fatty acids, such as the prevalent dietary fatty acid palmitate, have been implicated in circadian disruption, there is a paucity of studies regarding the effects of PUFAs on circadian parameters. Therefore, the immortalized murine neuronal model, mHypoE-37, was utilized to examine the effects of the SFA palmitate and omega-3 PUFA docosahexaenoic acid (DHA) on circadian rhythms. The mHypoE-37 neurons express the core clock genes, Bmal1, Per2, and Rev-erbα, in a circadian manner. 25 μM of palmitate significantly increased the transcriptional expression of Bmal1, without altering the expression of inflammatory markers TLR4, IκBα, and IL-6, nor the orexigenic neuropeptide AgRP, suggesting that the observed disruption of the molecular clock is the result of a mechanism distinct from that of hypothalamic cellular inflammation. Furthermore, treatment with the PUFA DHA resulted in alterations in the circadian expression profile of Bmal1, although differentially from the effects of palmitate. In the presence of DHA, the disruptive effects of palmitate on Bmal1 were less pronounced, suggesting a protective effect of DHA. These studies are the first to identify the potential for omega-3 PUFAs to protect against palmitate-mediated dysregulation of circadian parameters and will ultimately improve the understanding of circadian control mechanisms.
高饱和脂肪酸（SFA）饮食与昼夜节律失调、肥胖和2型糖尿病的发生有关。相反，最近发现多不饱和脂肪酸（PUFA）可改善胰岛素敏感性、减轻体重增加并缓解肥胖引起的炎症。虽然饱和脂肪酸，如常见的膳食脂肪酸棕榈酸酯，已被认为与昼夜节律紊乱有关，但关于PUFA对昼夜节律参数影响的研究却很少。因此，利用永生化小鼠神经元模型mHypoE-37来研究饱和脂肪酸棕榈酸酯和ω-3多不饱和脂肪酸二十二碳六烯酸（DHA）对昼夜节律的影响。mHypoE-37神经元以昼夜节律的方式表达核心生物钟基因Bmal1、Per2和Rev-erbα。25μM的棕榈酸酯显著增加了Bmal1的转录表达，而没有改变炎症标志物TLR4、IκBα和IL-6的表达，也没有改变促食欲神经肽AgRP的表达，这表明观察到的分子生物钟破坏是一种不同于下丘脑细胞炎症的机制的结果。此外，用多不饱和脂肪酸DHA处理导致Bmal1的昼夜表达谱发生改变，尽管与棕榈酸酯的作用不同。在存在DHA的情况下，棕榈酸酯对Bmal1的破坏作用不太明显，表明DHA具有保护作用。这些研究首次确定了ω-3多不饱和脂肪酸具有预防棕榈酸酯介导的昼夜节律参数失调的潜力，并最终将增进对昼夜节律控制机制的理解。
