Department of Pathophysiology and Therapeutics, Hokkaido University Faculty of Pharmaceutical Sciences, N12 W6, Kita-ku, Sapporo 060-0812, Japan.
Endocrinology. 2010 Jan;151(1):244-52. doi: 10.1210/en.2009-0633. Epub 2009 Nov 11.
Aging is associated with decreased food intake, a phenomenon termed the anorexia of aging. In this study, we sought to clarify changes in peripheral and central appetite-related factors in aged mice. Furthermore, we investigated the effects of rikkunshito, a traditional Japanese medicine, on age-related anorexia. C57BL/6J mice that were 6 or 75 wk old were studied. We investigated changes in food intake, ghrelin and leptin levels, and the expression of appetite-related genes with age. In addition, we verified the effects of ghrelin, rikkunshito, phosphodiesterase 3 (PDE3), and phosphoinositide 3-kinase inhibitors on appetite. Food intake was significantly decreased in 75-wk-old mice compared with the 6-wk-old mice. In 75-wk-old mice, plasma acylated ghrelin levels under fasting conditions were lower than in 6-wk-old mice, whereas leptin levels under feeding conditions were substantially higher. The expression levels of hypothalamic preproghrelin under feeding conditions and the expression levels of neuropeptide Y and agouti-related protein under fasting conditions were lower compared with those of the 6-wk-old mice. Ghrelin supplementation (33 microg/kg) failed to increase food intake in 75-wk-old mice. Conversely, oral administration of LY294002, a phosphoinositide 3-kinase inhibitor, and cilostamide, a PDE3 inhibitor, increased food intake in 75-wk-old mice. Moreover, rikkunshito increased food intake in aged mice. The components of rikkunshito (nobiletin, isoliquiritigenin, and heptamethoxyflavone) had inhibitory effects on PDE3. These results suggest that dysregulation of ghrelin secretion and ghrelin resistance in the appetite control system occurred in aged mice and that rikkunshito ameliorated aging-associated anorexia via inhibition of PDE3.
衰老与食物摄入量减少有关，这种现象被称为衰老性厌食症。在这项研究中，我们试图阐明老年小鼠外周和中枢食欲相关因素的变化。此外，我们研究了日本传统药物 rikkunshito 对与年龄相关的厌食症的影响。我们研究了 6 或 75 周龄的 C57BL/6J 小鼠的变化，包括食物摄入量、胃饥饿素和瘦素水平以及与食欲相关的基因表达。此外，我们验证了胃饥饿素、rikkunshito、磷酸二酯酶 3（PDE3）和磷酸肌醇 3-激酶抑制剂对食欲的影响。与 6 周龄小鼠相比，75 周龄小鼠的食物摄入量显著减少。在 75 周龄小鼠中，空腹时酰化胃饥饿素水平较低，而进食时瘦素水平显著升高。与 6 周龄小鼠相比，进食条件下下丘脑前胃饥饿素的表达水平和空腹条件下神经肽 Y 和 agouti 相关蛋白的表达水平较低。胃饥饿素补充（33 微克/千克）未能增加 75 周龄小鼠的食物摄入量。相反，口服磷酸肌醇 3-激酶抑制剂 LY294002 和 PDE3 抑制剂 cilostamide 增加了 75 周龄小鼠的食物摄入量。此外，rikkunshito 增加了老年小鼠的食物摄入量。rikkunshito 的成分（川陈皮素、异甘草素和七甲氧基黄酮）对 PDE3 具有抑制作用。这些结果表明，食欲控制系统中胃饥饿素分泌失调和胃饥饿素抵抗发生在老年小鼠中，rikkunshito 通过抑制 PDE3 改善了与年龄相关的厌食症。
