Thupari Jagan N, Kim Eun-Kyoung, Moran Timothy H, Ronnett Gabriele V, Kuhajda Francis P
Johns Hopkins Univ. School of Medicine, Bldg. AA, Rm. 154A, 4940 Eastern Ave., Baltimore, MD 21224, USA.
Am J Physiol Endocrinol Metab. 2004 Jul;287(1):E97-E104. doi: 10.1152/ajpendo.00261.2003. Epub 2004 Jan 21.
Obesity and its attendant disorders, such as type 2 diabetes, are global health problems. We previously reported that C75, an inhibitor of fatty acid synthase (FAS) and stimulator of carnitine palmitoyltransferase I (CPT I), caused anorexia and profound weight loss in lean and genetically obese mice. To approximate human obesity, we utilized a chronic C75 treatment model for diet-induced obese (DIO) mice. Chronic C75 treatment decreased food consumption and increased energy expenditure due to increased fatty acid oxidation in both DIO and lean mice. There was a substantial loss of adipose tissue and resolution of hepatic steatosis in C75-treated DIO mice. Analysis of changes in the expression of hypothalamic neuropeptides demonstrated that the reduced food consumption in C75-treated DIO mice was accompanied by an increase in cocaine and amphetamine-related transcript expression but not by changes in neuropeptide Y such as seen with acute C75 treatment of lean mice. Inhibition of FAS and stimulation of CPT I provide a means to achieve stable, sustained weight loss in DIO mice.
肥胖及其相关疾病，如2型糖尿病，是全球性的健康问题。我们之前报道过，C75作为脂肪酸合酶（FAS）的抑制剂和肉碱棕榈酰转移酶I（CPT I）的刺激剂，可导致瘦型和遗传性肥胖小鼠出现厌食和显著体重减轻。为了模拟人类肥胖，我们利用慢性C75处理模型来研究饮食诱导肥胖（DIO）小鼠。慢性C75处理可减少DIO小鼠和瘦型小鼠的食物摄入量，并因脂肪酸氧化增加而提高能量消耗。C75处理的DIO小鼠的脂肪组织大量减少，肝脂肪变性得到缓解。对下丘脑神经肽表达变化的分析表明，C75处理的DIO小鼠食物摄入量减少的同时，可卡因和苯丙胺相关转录本的表达增加，但神经肽Y没有变化，而瘦型小鼠急性C75处理时神经肽Y会发生变化。抑制FAS和刺激CPT I为实现DIO小鼠稳定、持续的体重减轻提供了一种方法。
