Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich , Zurich , Switzerland.
Zurich Centre for Integrative Human Physiology, University of Zurich , Zurich , Switzerland.
Am J Physiol Regul Integr Comp Physiol. 2018 Oct 1;315(4):R856-R865. doi: 10.1152/ajpregu.00179.2018. Epub 2018 Aug 22.
The pancreatic hormone amylin is released from beta cells following nutrient ingestion and contributes to the control of body weight and glucose homeostasis. Amylin reduces food intake by activating neurons in the area postrema (AP). Amylin was also shown to synergize with the adipokine leptin, with combination therapy producing greater weight loss and food intake reduction than either hormone alone. Although amylin and leptin were initially thought to interact downstream of the AP in the hypothalamus, recent findings show that the two hormones can act on the same AP neurons, suggesting a more direct relationship. The objective of this study was to determine whether amylin action depends on functional leptin signaling. We tested the ability of amylin to induce satiation and to activate its primary target neurons in the AP in two rodent models of LepR deficiency, the db/db mouse and the Zucker diabetic fatty (ZDF) rat. When compared with wild-type (WT) mice, db/db mice exhibited reduced amylin-induced satiation, reduced amylin-induced Fos in the AP, and a lower expression of calcitonin receptor (CTR) protein, the core component of all amylin receptors. ZDF rats also showed no reduction in food intake following amylin treatment; however, unlike the db/db mice, levels of amylin-induced Fos and CTR in the AP were no different than WT rats. Our results suggest that LepR expression is required for the full anorexic effect of amylin; however, the neuronal activation in the AP seems to depend on the type of LepR mutation.
胰岛激素胰淀素在摄入营养后从β细胞释放，并有助于控制体重和葡萄糖稳态。胰淀素通过激活穹窿下器（AP）中的神经元来减少食物摄入。研究还表明，胰淀素与脂肪因子瘦素协同作用，联合治疗比单独使用任何一种激素产生更大的体重减轻和食物摄入减少。尽管胰淀素和瘦素最初被认为在 AP 下游的下丘脑相互作用，但最近的发现表明，这两种激素可以作用于相同的 AP 神经元，这表明它们之间存在更直接的关系。本研究的目的是确定胰淀素的作用是否依赖于功能性瘦素信号。我们在两种 LepR 缺乏的啮齿动物模型，db/db 小鼠和 Zucker 糖尿病肥胖（ZDF）大鼠中，测试了胰淀素诱导饱腹感和激活其在 AP 中的主要靶神经元的能力。与野生型（WT）小鼠相比，db/db 小鼠表现出降低的胰淀素诱导饱腹感，降低的 AP 中胰淀素诱导的 Fos 表达，以及降钙素受体（CTR）蛋白表达降低，CTR 蛋白是所有胰淀素受体的核心组成部分。ZDF 大鼠在用胰淀素治疗后也没有减少食物摄入；然而，与 db/db 小鼠不同，AP 中胰淀素诱导的 Fos 和 CTR 水平与 WT 大鼠没有差异。我们的结果表明，LepR 表达是胰淀素完全厌食作用所必需的；然而，AP 中的神经元激活似乎取决于 LepR 突变的类型。
