Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight
Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight
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DOI：
10.1152/ajpregu.00862.2006
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发表时间：
2008-02-01
影响因子：
2.8
通讯作者：
Ronnett, Gabriele V.
中科院分区：
文献类型：
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作者：
Aja, Susan;Landree, Leslie E.;Ronnett, Gabriele V.
据报道，抑制脑肉毒碱棕榈酰转移酶-1（CPT-1）可降低大鼠的食物摄入量和体重。然而，脂肪酸合成酶（FAS）抑制剂和CPT-1刺激剂C75在脑室内（icv）给予啮齿动物时产生食欲减退和体重减轻。因此，脑CPT-1活性改变和脂肪酸氧化在这些现象中的作用和相对贡献仍然不清楚。我们通过单次icv推注向小鼠施用靶向FAS或CPT-1的化合物，并检查对进食和体重的急性和长期影响。在所有剂量（1-56 nmol）下，C75均快速有效地减少摄食量，并在第1天剂量依赖性地抑制摄食量。第1天的剂量依赖性体重减轻持续至注射后监测的4天。FAS抑制剂浅蓝菌素产生剂量依赖性（560 nmol）摄食减少1天，体重减轻2天，第3天体重恢复至溶媒对照。CPT-1抑制剂etomoxir（32，320 nmol）并没有改变整个第1天的喂养。然而，依托莫西酯减弱了C75产生的食欲减退，表明CPT-1刺激对C75的作用是重要的。一种新的化合物，C89 b，其特征在于在体外作为CPT-1的选择性刺激剂，不影响脂肪酸的合成。C89 b（100，320 nmol）减少小鼠摄食3天，并产生持续的体重减轻6天，而不产生条件性味觉厌恶。同样，腹膜内给药降低了摄食和体重，而不产生条件性味觉厌恶。这些结果表明脑CPT-1在调节能量平衡中的作用，并暗示CPT-1刺激作为减肥的药理学方法。
Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1-56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.