Wolden-Hanson Tami, Marck Brett T, Matsumoto Alvin M
Geriatric Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System (S-182-GRECC), University of Washington School of Medicine, 1660 South Columbian Way, Seattle, WA 98108-1597, USA.
Exp Gerontol. 2002 May;37(5):679-91. doi: 10.1016/s0531-5565(01)00233-9.
Compared to younger animals, aged male Brown Norway (BN) rats demonstrate increased body fat and serum insulin, and lower prepro-neuropeptide Y (ppNPY) mRNA content in the arcuate nucleus (ARC), and blunted food intake (FI) and body weight (BW) gain in response to a 72 h fast. Since centrally administered insulin decreases FI and weight of young rats and inhibits fasting-induced increases of NPY gene expression, we hypothesized that hyperinsulinemia in old rats contributes to an age-related central dysregulation of energy balance. Young, middle-aged and old BN rats were fed chow with troglitazone (Trog; 200 mg/kg BW/d) or without drug for 75 d (Experiment 1) or 66 d (Experiment 2). Rats were then fasted for 72 h, refed for 2 weeks and sacrificed after an overnight fast (Experiment 1) or fasted for 72 h and sacrificed (Experiment 2). Serum insulin and leptin were measured from trunk blood and brains were analyzed for ppNPY mRNA by in situ hybridization. In Experiment 1, troglitazone treatment resulted in increased post-fast weight gain, rate of gain and FI in old rats. Troglitazone decreased serum insulin by 50% in old rats, while leptin levels decreased 20-30% in all age groups in Experiment 1. No differences in serum insulin or leptin were detectable with troglitazone treatment in Experiment 2, due to the extreme suppression caused by the 72 h fast. Troglitazone treatment did not increase ARC NPY gene expression either after a 72 h fast and re-feeding for 2 weeks (Experiment 1) or immediately after a 72 h fast (Experiment 2). These findings suggest that increased insulin levels may contribute to age-related impairments of FI and BW regulation. However, improvements in these defects in energy regulation induced by troglitazone do not appear to result from changes in NPY gene expression, and may be due to alterations in other hypothalamic neuropeptides that regulate energy balance.
与年轻动物相比，老年雄性棕色挪威（BN）大鼠体脂和血清胰岛素增加，弓状核（ARC）中前神经肽Y原（ppNPY）mRNA含量降低，且在72小时禁食后食物摄入量（FI）和体重（BW）增加减弱。由于中枢给予胰岛素可降低年轻大鼠的食物摄入量和体重，并抑制禁食诱导的NPY基因表达增加，我们推测老年大鼠的高胰岛素血症导致了与年龄相关的能量平衡中枢调节异常。将年轻、中年和老年BN大鼠喂食含曲格列酮（Trog；200mg/kg体重/天）或不含药物的食物75天（实验1）或66天（实验2）。然后将大鼠禁食72小时，再喂食2周，并在过夜禁食后处死（实验1）或禁食72小时后处死（实验2）。从躯干血中测量血清胰岛素和瘦素，并通过原位杂交分析大脑中的ppNPY mRNA。在实验1中，曲格列酮治疗导致老年大鼠禁食后体重增加、增重率和食物摄入量增加。曲格列酮使老年大鼠血清胰岛素降低50%，而在实验1中所有年龄组的瘦素水平降低20 - 30%。在实验2中，由于72小时禁食引起的极端抑制，曲格列酮治疗未检测到血清胰岛素或瘦素的差异。曲格列酮治疗在72小时禁食并再喂食2周后（实验1）或72小时禁食后立即（实验2）均未增加ARC NPY基因表达。这些发现表明胰岛素水平升高可能导致与年龄相关的食物摄入量和体重调节受损。然而，曲格列酮诱导的这些能量调节缺陷的改善似乎并非源于NPY基因表达的变化，可能是由于调节能量平衡的其他下丘脑神经肽的改变。
