Yamazaki Yoshimitsu, Kawano Yasuhiro, Uebayasi Masami
Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
Life Sci. 2008 Jan 30;82(5-6):290-300. doi: 10.1016/j.lfs.2007.11.016. Epub 2007 Dec 5.
Adiponectin, the adipose-derived cytokine, plays an important role in preventing metabolic syndromes. To develop new adiponectin inducers, eight species of ferulic esters and amides, and five related compounds were synthesized and tested on the stimulation of adiponectin production in mouse 3T3-L1 and normal human preadipocytes. The ferulamides with an aromatic ring in the N-substituent are very active in inducing adiponectin as compared with the known active compounds, curcumin, [6]-gingerol, and capsaicin, and furthermore the activities of these ferulamides are remarkably stronger than those of the corresponding esters or the straight chain octylamide. The most active compound, N-(2-phenylethyl)ferulamide (7), was found to activate the PPAR (peroxisome proliferator-activated receptor) gamma-RXR (retinoid X receptor) alpha heterodimeric complex in the PPRE (PPAR-responsive element)-driven luciferase reporter assay. The adiponectin production by 7 is synergistically enhanced by coaddition of a PPARgamma-specific agonist, pioglitazone (PGZ), or another PPARgamma agonist, docosahexaenoic acid (DHA), in cultured preadipocytes. The compound 7 alone did not show a statistically significant effect on the plasma adiponectin level in KK-A(y)/Ta mice, while 1% 7 in the diets significantly lowered the blood glucose and triglyceride levels and 0.3% 7 mixed with DHA oil in the diets significantly increased the adiponectin level as compared with the control. These results suggest that the present ferulamides would be useful lead compounds in developing more potent agents for treatment of metabolic syndromes through promoting the endogenous adiponectin production, and that such an activity is possibly enhanced by the coadministration with DHA.
脂联素是一种脂肪来源的细胞因子，在预防代谢综合征中发挥重要作用。为了开发新的脂联素诱导剂，合成了8种阿魏酸酯和酰胺以及5种相关化合物，并测试了它们对小鼠3T3-L1和正常人前脂肪细胞中脂联素产生的刺激作用。与已知的活性化合物姜黄素、[6]-姜醇和辣椒素相比，N-取代基中带有芳香环的阿魏酰胺在诱导脂联素方面非常活跃，此外，这些阿魏酰胺的活性明显强于相应的酯或直链辛酰胺。在PPRE（PPAR反应元件）驱动的荧光素酶报告基因检测中，发现活性最强的化合物N-(2-苯乙基)阿魏酰胺（7）能激活PPAR（过氧化物酶体增殖物激活受体）γ-RXR（视黄酸X受体）α异二聚体复合物。在培养的前脂肪细胞中，通过共同添加PPARγ特异性激动剂吡格列酮（PGZ）或另一种PPARγ激动剂二十二碳六烯酸（DHA），可协同增强7诱导的脂联素产生。单独使用化合物7对KK-A(y)/Ta小鼠的血浆脂联素水平没有统计学上的显著影响，而饮食中1%的7能显著降低血糖和甘油三酯水平，与对照组相比，饮食中0.3%的7与DHA油混合能显著提高脂联素水平。这些结果表明,目前的阿魏酰胺可能是有用的先导化合物，通过促进内源性脂联素的产生来开发更有效的治疗代谢综合征的药物，并且这种活性可能通过与DHA共同给药而增强。
