Province Haley S, Hayes Nikolas W, Leong Nathan A, Lorch Carolyn M, Pekerman Alexandra, Xia Jessica L, Beutler Lisa R
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA.
Northwestern Interdepartmental Neuroscience Graduate Program, Northwestern University, Chicago, IL 60611, USA.
bioRxiv. 2025 Aug 15:2025.08.12.669936. doi: 10.1101/2025.08.12.669936.
Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone, and pharmacologic modulation of central GIP receptors (GIPR) improves energy homeostasis. Recent reports have demonstrated that GIPR agonism is also anti-aversive. However, the mechanisms by which GIPR signaling impact food intake and aversion are incompletely understood. Here, we show that GIPR agonism abrogates the aversive and enhances the anorexigenic effects of the pro-inflammatory cytokine interleukin-1β (IL-1β). Aversion-encoding parabrachial calcitonin-gene related peptide (CGRP) neurons were required for IL-1β-induced conditioned taste avoidance (CTA) but not anorexia. Moreover, systemic IL-1β increased CGRP neural activity, and this was significantly attenuated by co-administration of a GIPR agonist. By contrast, GIPR in the dorsal vagal complex were required for the acute anorectic effect of GIPR agonism but not its anti-aversive effect. Taken together, our data suggest that GIPR agonism reduces food intake and prevents aversion via distinct circuits, and that GIPR agonism may represent an effective approach to alleviate inflammation-induced aversion.
葡萄糖依赖性促胰岛素多肽（GIP）是一种源自肠道的肠促胰岛素激素，对中枢GIP受体（GIPR）进行药理学调节可改善能量平衡。最近的报告表明，GIPR激动作用也具有抗厌恶作用。然而，GIPR信号传导影响食物摄入和厌恶的机制尚未完全明确。在此，我们表明GIPR激动作用可消除促炎细胞因子白细胞介素-1β（IL-1β）的厌恶作用，并增强其厌食作用。编码厌恶的臂旁降钙素基因相关肽（CGRP）神经元是IL-1β诱导的条件性味觉回避（CTA）所必需的，但不是厌食所必需的。此外，全身性IL-1β增加了CGRP神经活动，而GIPR激动剂的共同给药可显著减弱这种活动。相比之下，迷走神经背侧复合体中的GIPR是GIPR激动作用的急性厌食作用所必需的，但不是其抗厌恶作用所必需的。综上所述，我们的数据表明，GIPR激动作用通过不同的神经回路减少食物摄入并防止厌恶，并且GIPR激动作用可能是减轻炎症诱导的厌恶的有效方法。
