Zhang J, Matheny M K, Tümer N, Mitchell M K, Scarpace P J
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
Am J Physiol Regul Integr Comp Physiol. 2007 Feb;292(2):R868-74. doi: 10.1152/ajpregu.00213.2006. Epub 2006 Oct 5.
High-fat (HF) feeding induces a transient increase in caloric intake and enhances energy expenditure. We hypothesized that leptin is necessary for homeostatic restoration of the HF-enhanced caloric intake and may mediate the increase in uncoupling protein-1 (UCP1) in brown adipose tissue (BAT). We employed a leptin antagonist to examine the role of leptin in these biological processes. Simultaneous central administration of leptin and increasing doses of the leptin antagonist revealed a dose-dependent inhibition of leptin-induced hypothalamic signal transducer and activator of transcription-3 phosphorylation, and 7 days of infusion of the leptin antagonist produced the predicted increase in food intake and weight gain. When delivered with exogenous leptin in a 7-day infusion, the leptin antagonist blocked leptin-mediated anorexic effects as well as the increase in BAT UCP1 protein and signal transducer and activator of transcription-3 phosphorylation. Rats were then fed an HF diet (60% kcal as fat) or chow and simultaneously infused with antagonist (25 microg/day into the lateral ventricle) for 7 days and compared with vehicle-infused chow-fed rats. Daily caloric intake of both HF groups peaked on day 2. HF feeding elevated caloric intake, which nearly normalized by day 7, whereas in the presence of the antagonist, caloric intake remained elevated. Moreover, the HF-mediated augmentation in UCP1 in BAT was prevented by the antagonist. These results demonstrate that leptin is essential for the homeostatic restoration of caloric intake after HF feeding and that this leptin antagonist is able to block central leptin signaling and leptin-mediated UCP1 elevation.
高脂（HF）喂养会导致热量摄入短暂增加并增强能量消耗。我们推测，瘦素对于HF增强的热量摄入的稳态恢复是必需的，并且可能介导棕色脂肪组织（BAT）中解偶联蛋白-1（UCP1）的增加。我们使用瘦素拮抗剂来研究瘦素在这些生物学过程中的作用。同时向中枢给予瘦素和递增剂量的瘦素拮抗剂，结果显示对瘦素诱导的下丘脑信号转导子和转录激活子3磷酸化存在剂量依赖性抑制，并且输注瘦素拮抗剂7天会导致预期的食物摄入量增加和体重增加。当在7天的输注中与外源性瘦素一起给予时，瘦素拮抗剂阻断了瘦素介导的厌食作用以及BAT中UCP1蛋白的增加和信号转导子和转录激活子3磷酸化。然后给大鼠喂食HF饮食（60%千卡为脂肪）或普通饲料，并同时向侧脑室输注拮抗剂（25微克/天）7天，并与输注溶媒的普通饲料喂养大鼠进行比较。两个HF组的每日热量摄入在第2天达到峰值。HF喂养使热量摄入增加，到第7天几乎恢复正常，而在存在拮抗剂的情况下，热量摄入仍然升高。此外，拮抗剂阻止了HF介导的BAT中UCP1的增加。这些结果表明，瘦素对于HF喂养后热量摄入的稳态恢复至关重要，并且这种瘦素拮抗剂能够阻断中枢瘦素信号传导和瘦素介导的UCP1升高。
