Rikkunshito ameliorates the aging-associated decrease in ghrelin receptor reactivity via phosphodiesterase III inhibition.
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.
Takeda
Hiroshi
H
Department of Pathophysiology and Therapeutics, Hokkaido University Faculty of Pharmaceutical Sciences, N12 W6, Kita-ku, Sapporo 060-0812, Japan. h_takeda@pharm.hokudai.ac.jp
Muto
Shuichi
S
Hattori
Tomohisa
T
Sadakane
Chiharu
C
Tsuchiya
Kazuaki
K
Katsurada
Takehiko
T
Ohkawara
Tatsuya
T
Oridate
Nobuhiko
N
Asaka
Masahiro
M
D000375:Aging / Q000097:blood / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000855:Anorexia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000494:pharmacology* / Q000627:therapeutic use; D004435:Eating / Q000187:drug effects; D054439:Ghrelin / Q000097:blood / Q000494:pharmacology; D013006:Growth Hormone / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism*
D054369:Agouti-Related Protein; D004365:Drugs, Chinese Herbal; D054439:Ghrelin; D020738:Leptin; D009478:Neuropeptide Y; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D054440:Receptors, Ghrelin; C084136:liu-jun-zi-tang; D013006:Growth Hormone