Gutgesell Robert M, Khalil Ahmed, Liskiewicz Arkadiusz, Maity-Kumar Gandhari, Novikoff Aaron, Grandl Gerald, Liskiewicz Daniela, Coupland Callum, Karaoglu Ezgi, Akindehin Seun, Castelino Russell, Curion Fabiola, Liu Xue, Garcia-Caceres Cristina, Cebrian-Serrano Alberto, Douros Jonathan D, Knerr Patrick J, Finan Brian, DiMarchi Richard D, Sloop Kyle W, Samms Ricardo J, Theis Fabian J, Tschöp Matthias H, Müller Timo D
Institute for Diabetes and Obesity, Helmholtz, Munich, Germany.
German Center for Diabetes Research, DZD, Neuherberg, Germany.
Nat Metab. 2025 Apr 29. doi: 10.1038/s42255-025-01294-x.
Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.
葡萄糖依赖性促胰岛素多肽受体（GIPR）的激动剂和拮抗剂可增强胰高血糖素样肽-1受体（GLP-1R）激动作用诱导的体重减轻。然而，虽然GIPR激动作用通过GABA能GIPR神经元以不依赖GLP-1R的方式降低体重和食物摄入量，但尚不清楚GIPR拮抗作用是否通过类似机制影响能量代谢。在此，我们表明，在全局缺失Gipr或Glp-1r的小鼠中，GIPR拮抗作用对体重和食物摄入量的影响被消除，但在中枢神经系统的GABA能神经元或外周神经系统中表达外周蛋白的神经元中缺失Gipr的小鼠中，这种影响得以保留。单核RNA测序显示，GIPR激动作用和拮抗作用在背迷走神经复合体中具有相反的作用，其中拮抗作用而非激动作用与GLP-1R信号传导非常相似。此外，GIPR拮抗作用和GLP-1R激动作用均调节与突触可塑性相关的基因。总体而言，我们表明GIPR激动作用和拮抗作用通过不同机制降低体重，与激动作用不同，GIPR拮抗作用依赖于功能性GLP-1R信号传导。
