Williams Diana L, Baskin Denis G, Schwartz Michael W
University of Washington, Harborview Medical Center, 325 9th Ave., Box 359675, Seattle, WA 98104, USA.
Diabetes. 2006 Dec;55(12):3387-93. doi: 10.2337/db06-0558.
Leptin reduces food intake in part by enhancing satiety responses to gastrointestinal signals produced in response to food consumption. Glucagon-like peptide 1 (GLP-1), secreted by the intestine when nutrients enter the gut, is one such putative satiety signal. To investigate whether leptin enhances the anorexic effects of GLP-1, rats received either saline or a subthreshold dose of leptin before intraperitoneal injection of either GLP-1 or Exendin-4 (Ex4; a GLP-1 receptor agonist). Leptin pretreatment strongly enhanced anorexia and weight loss induced by GLP-1 or Ex4 over 24 h. Conversely, fasting attenuated the anorexic response to GLP-1 or Ex4 treatment via a leptin-dependent mechanism, as demonstrated by our finding that the effect of fasting was reversed by physiological leptin replacement. As expected, Ex4 induced expression of c-Fos protein, a marker of neuronal activation, in hindbrain areas that process afferent input from satiety signals, including the nucleus of the solitary tract and area postrema. Unexpectedly, leptin pretreatment blocked this response. These findings identify physiological variation of plasma leptin levels as a potent regulator of GLP-1 receptor-mediated food intake suppression and suggest that the underlying mechanism is distinct from that which mediates interactions between leptin and other satiety signals.
瘦素部分通过增强对食物摄入所产生的胃肠道信号的饱腹感反应来减少食物摄入量。胰高血糖素样肽1（GLP-1）是一种假定的饱腹感信号，当营养物质进入肠道时由肠道分泌。为了研究瘦素是否增强GLP-1的厌食作用，在腹腔注射GLP-1或艾塞那肽-4（Ex4；一种GLP-1受体激动剂）之前，给大鼠注射生理盐水或亚阈值剂量的瘦素。瘦素预处理在24小时内强烈增强了由GLP-1或Ex4诱导的厌食和体重减轻。相反，禁食通过一种瘦素依赖机制减弱了对GLP-1或Ex4治疗的厌食反应，正如我们的发现所示，禁食的影响通过生理性瘦素替代得以逆转。正如预期的那样，Ex4在处理来自饱腹感信号传入输入的后脑区域，包括孤束核和最后区，诱导了神经元激活标志物c-Fos蛋白的表达。出乎意料的是，瘦素预处理阻断了这种反应。这些发现确定血浆瘦素水平的生理变化是GLP-1受体介导的食物摄入抑制的有效调节因子，并表明其潜在机制不同于介导瘦素与其他饱腹感信号之间相互作用的机制。
