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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分析西方饮食、棕榈酸和 BMAL1 对小鼠下丘脑和 BMAL1 敲除细胞模型中神经肽 Y 表达的调节。


富含饱和脂肪和糖的西方饮食会扰乱昼夜节律，导致体重增加，并导致包括肥胖在内的代谢疾病。然而，昼夜节律改变和能量稳态之间的机制联系仍然知之甚少。在 C57BL/6J 小鼠中，采用西方饮食 16 周后，食物摄入量显着减少（在时间 12-16 时），这与下丘脑中促食欲神经肽、神经肽 Y (Npy) 和刺鼠相关肽 (AgRP) 的表达减少有关。为了研究西方饮食中最常见的饱和脂肪酸棕榈酸的急性影响，以及核心时钟基因 Bmal1 在调节下丘脑摄食神经肽中的作用，我们使用了异质克隆 BMAL1 敲除 (KO) 永生化下丘脑表达特定神经肽的细胞系，源自雄性（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 细胞的时钟基因 Per2 表达丧失昼夜节律。 BMAL1 的缺失还改变了 Npy 和阿黑皮素原的时间依赖性表达，并扰乱了 AgRP 节律。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（50 μM，24 小时）在异质和克隆表达 NPY 的雌性来源细胞模型中以 BMAL1 依赖性方式刺激 Npy 表达。这项研究的结果表明，Bmal1 的昼夜节律表达是西方饮食和棕榈酸盐引起的下丘脑进食相关神经肽正常节律模式破坏之间的机制联系。