The Circadian Nobiletin-ROR Axis Suppresses Adipogenic Differentiation and IκBα/NF-κB Signaling in Adipocytes.
The Circadian Nobiletin-ROR Axis Suppresses Adipogenic Differentiation and IκBα/NF-κB Signaling in Adipocytes.
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DOI：
10.3390/nu15183919
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发表时间：
2023-09-09
期刊：
影响因子：
5.9
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Kim E;Mawatari K;Yoo SH;Chen Z
肥胖是代谢疾病的已知危险因素，通常与脂肪组织的慢性炎症有关。我们之前发现聚氧基黄酮类黄酮（NOB）是一种昼夜节律时钟调节剂，直接结合并激活核心振荡器中的ROR受体，显著改善肥胖小鼠的代谢适应性。在这里，我们发现NOB增强了分化3T3-L1脂肪细胞中核心时钟基因的振荡，包括ROR靶基因Bmal1、Cry1、Dec1和Dec2。NOB抑制3T3-L1和SVF细胞的脂质积累，同时伴有脂肪生成分化相关基因（包括Cebpb、Pparg、Lpl、Scd1和Fas）的昼夜表达失调。重要的是，3T3-L1细胞中RORα/RORγ双敲低（Ror DKD）显著减弱了NOB对昼夜基因表达和脂质积累的影响。此外，NOB上调RORs的靶点i -κB α的表达，抑制NF-κB的激活和促炎细胞因子的表达，而Ror DKD细胞则表现出NF-κB通路的激活增强，进一步表明RORs在NOB对脂肪细胞的作用中发挥了必要的作用。总之，这些结果突出了NOB-ROR轴在脂肪细胞中生物钟和生物钟控制基因的昼夜节律表达中的重要调节功能，从而控制脂肪生成分化、脂肪生成和炎症。
Obesity is a known risk factor for metabolic diseases and is often associated with chronic inflammation in adipose tissue. We previously identified the polyethoxylated flavonoid Nobiletin (NOB) as a circadian clock modulator that directly binds to and activates the ROR receptors in the core oscillator, markedly improving metabolic fitness in obese mice. Here, we show that NOB enhanced the oscillation of core clock genes in differentiated 3T3-L1 adipocytes, including ROR target genes such as Bmal1, Cry1, Dec1, and Dec2. NOB inhibited lipid accumulation in 3T3-L1 and SVF cells, concomitant with the dysregulated circadian expression of adipogenic differentiation-related genes including Cebpb, Pparg, Lpl, Scd1, and Fas. Importantly, RORα/RORγ double knockdown in 3T3-L1 cells (Ror DKD) significantly attenuated the effects of NOB on circadian gene expression and lipid accumulation. Furthermore, whereas NOB upregulated the expression of IκBα, a target of RORs, to inhibit NF-κB activation and proinflammatory cytokine expression, Ror DKD cells exhibited a heightened activation of the NF-κB pathway, further indicating a requisite role of RORs for NOB efficacy in adipocytes. Together, these results highlight a significant regulatory function of the NOB–ROR axis in the circadian expression of clock and clock-controlled genes in adipocytes, thereby governing adipogenic differentiation, lipogenesis, and inflammation.
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DOI：
10.1155/2016/2918796
发表时间：
2016
期刊：
Evidence-based complementary and alternative medicine : eCAM
影响因子：
--
作者：
Huang H;Li L;Shi W;Liu H;Yang J;Yuan X;Wu L
通讯作者：
Wu L
影响因子：
6
作者：
Dykstra JA;Facile T;Patrick RJ;Francis KR;Milanovich S;Weimer JM;Kota DJ
通讯作者：
Kota DJ
影响因子：
5.2
作者：
Jetten AM;Kang HS;Takeda Y
通讯作者：
Takeda Y
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM
影响因子：
7.7
作者：
Delerive, P;Monté, D;Staels, B
通讯作者：
Staels, B