Western diets that are high in saturated fat and sugar disrupt circadian rhythms, induce weight gain, and lead to metabolic diseases including obesity. However, the mechanistic link between altered circadian rhythms and energy homeostasis remains poorly understood. In C57BL/6J mice, consuming a Western diet for 16 weeks significantly reduced food intake (at zeitgeber 12-16), in association with decreases in hypothalamic expression of the orexigenic neuropeptides, neuropeptide Y (Npy) and agouti-related peptide (AgRP). To examine the acute effects of the most prevalent saturated fatty acid in a Western diet, palmitate, and the role of the core clock gene, Bmal1, in the regulation of hypothalamic feeding neuropeptides, we used heterogeneous and clonal BMAL1 knockout (KO) immortalized hypothalamic cell lines, expressing specific neuropeptides, derived from male (M) and female (F) mice. Both mHypoA-BMAL1-KO/F and mHypoA-BMAL1-KO/M cells demonstrated a loss of circadian rhythmicity in expression of the clock gene, Per2, as compared to wild-type (control) cultures. Loss of BMAL1 also altered the time-dependent expression of Npy and proopiomelanocortin, and disrupted AgRP rhythmicity. Furthermore, palmitate increased BMAL1 binding to the Npy promotor region, and palmitate treatment (50 μM for 24 h) stimulated Npy expression in a BMAL1-dependent manner in both heterogeneous and clonal NPY-expressing female-derived cell models. The results of this study demonstrate that circadian expression of Bmal1 serves as a mechanistic link between Western diet- and palmitate-induced disruptions of the normal rhythmic patterns in hypothalamic feeding-related neuropeptides.

中文翻译：

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分析了小鼠下丘脑和BMAL1基因敲除细胞模型中西方饮食，棕榈酸酯和BMAL1对神经肽Y表达的调控。

富含饱和脂肪和糖的西方饮食会破坏昼夜节律，引起体重增加，并导致包括肥胖在内的代谢性疾病。然而，昼夜节律改变与能量稳态之间的机械联系仍然知之甚少。在C57BL / 6J小鼠中，进食西式饮食16周会显着减少食物摄入量（在12-12岁时），同时还会降低下丘脑的食源性神经肽，神经肽Y（Npy）和刺骨相关肽（AgRP）的表达。若要检查西方饮食中最普遍的饱和脂肪酸棕榈酸酯的急性作用以及核心时钟基因Bmal1在下丘脑喂养神经肽的调节中的作用，我们使用了异源和克隆的BMAL1敲除（KO）永生化的下丘脑表达特定神经肽的细胞系 衍生自雄性（M）和雌性（F）小鼠。与野生型（对照）培养物相比，mHypoA-BMAL1-KO / F和mHypoA-BMAL1-KO / M细胞均表现出时钟基因Per2表达的昼夜节律性降低。BMAL1的丢失也改变了Npy和proopiomelanocortin的时间依赖性表达，并破坏了AgRP的节律性。此外，棕榈酸酯增加了BMAL1与Npy启动子区域的结合，并且棕榈酸酯处理（50μM，持续24 h）在异源和克隆表达NPY的雌性女性细胞模型中均以BMAL1依赖性方式刺激了Npy表达。这项研究的结果表明，Bmal1的昼夜节律表达是下丘脑喂养相关神经肽中西方饮食和棕榈酸酯诱导的正常节律模式破坏之间的机制联系。