Scarpace P J, Matheny M, Zhang Y, Tümer N, Frase C D, Shek E W, Hong B, Prima V, Zolotukhin S
Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, Gainesville, Florida 32608-1197, USA.
Neuropharmacology. 2002 Mar;42(4):548-61. doi: 10.1016/s0028-3908(02)00003-5.
The purpose of this study was to determine if long-term leptin treatment desensitizes leptin signal transduction and the subsequent downstream anorexic and thermogenic responses in normal and leptin-resistant age-related obese rats. To this end, we administered, i.c.v., recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control virus into young and aged-obese rats and after 9 or 46 days, examined food intake, oxygen consumption, body weight, serum leptin, STAT3 phosphorylation, hypothalamic NPY and POMC mRNAs, and UCP1 expression and protein level in brown adipose tissue (BAT). In young rats, rAAV-leptin depleted body fat and both anorexic and thermogenic mechanisms contributed to this effect. Moreover, leptin signal transduction was not desensitized, and there were persistent physiological responses. Similarly, in the aged-obese rats, there was unabated leptin signal transduction, however, both the anorexic and thermogenic responses completely attenuated sometime after day 9. This attenuation, downstream of the leptin receptor, may be contributing to the leptin-resistance and age-related weight gain in these aged-obese rats. Finally, in young rats, although the initial responses to rAAV-leptin were dominated by anorexic responses, by 46 days, the predominant response was thermogenic rather than anorexic, suggesting that energy expenditure may be an important component of long-term weight maintenance.
本研究的目的是确定长期给予瘦素治疗是否会使正常和瘦素抵抗的老龄肥胖大鼠的瘦素信号转导以及随后的下游厌食和产热反应脱敏。为此，我们通过脑室内注射，将编码大鼠瘦素cDNA的重组腺相关病毒（rAAV-瘦素）或对照病毒注入年轻和老龄肥胖大鼠体内，在9天或46天后，检测食物摄入量、耗氧量、体重、血清瘦素、STAT3磷酸化、下丘脑神经肽Y（NPY）和阿黑皮素原（POMC）mRNA，以及棕色脂肪组织（BAT）中的解偶联蛋白1（UCP1）表达和蛋白水平。在年轻大鼠中，rAAV-瘦素减少了体脂，厌食和产热机制均促成了这一效果。此外，瘦素信号转导未发生脱敏，且存在持续的生理反应。同样，在老龄肥胖大鼠中，瘦素信号转导未减弱，然而，厌食和产热反应在第9天后的某个时间完全减弱。这种在瘦素受体下游的减弱可能导致了这些老龄肥胖大鼠的瘦素抵抗和与年龄相关的体重增加。最后，在年轻大鼠中，尽管对rAAV-瘦素的初始反应以厌食反应为主，但到46天时，主要反应是产热而非厌食，这表明能量消耗可能是长期维持体重的重要组成部分。
