Wean Jordan, Kowalsky Allison Ho, Laker Rhianna, Will Sarah, Drucker Daniel J, Rhodes Christopher J, Seeley Randy J
Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Mol Metab. 2025 May;95:102074. doi: 10.1016/j.molmet.2024.102074. Epub 2024 Nov 26.
Dual incretin agonists are among the most effective pharmaceutical treatments for obesity and type 2 diabetes to date. Such therapeutics can target two receptors, such as the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor in the case of tirzepatide, to improve glycemia and reduce body weight. Regarding body weight effects, GIPR signaling is thought to involve at least two relevant mechanisms: the enhancement of food intake reduction and the attenuation of aversive effects caused by GLP-1R agonists. Although it is known that dual GLP-1R-GIPR agonism produces greater weight loss than GLP-1R agonism alone, the precise mechanism is unknown.
To address this question, we used mice lacking GIPR in the whole body, GABAergic neurons, or glutamatergic neurons. These mice were given various combinations of GLP-1R and GIPR agonist drugs with subsequent food intake and conditioned taste aversion measurements.
A GIPR knockout in either the whole body or selectively in inhibitory GABAergic neurons protects against diet-induced obesity, whereas a knockout in excitatory glutamatergic neurons had a negligible effect. Furthermore, we found that GIPR in GABAergic neurons is essential for the enhanced weight loss efficacy of dual incretin agonism, yet, surprisingly, its removal enhances the effect of GLP-1R agonism alone. Finally, GIPR knockout in GABAergic neurons prevents the anti-aversive effects of GIPR agonism.
Our findings are consistent with GIPR research at large in that both enhancement and removal of GIPR signaling are metabolically beneficial. Notably, however, our findings suggest that future obesity therapies designed to modulate GIPR signaling, whether by agonism or antagonism, would be best targeted towards GABAergic neurons.
双肠促胰岛素激动剂是迄今为止治疗肥胖症和2型糖尿病最有效的药物之一。这类疗法可以作用于两种受体，比如替尔泊肽可作用于胰高糖素样肽-1（GLP-1）受体和葡萄糖依赖性促胰岛素多肽（GIP）受体，以改善血糖并减轻体重。关于体重影响，GIPR信号传导被认为至少涉及两个相关机制：增强食物摄入量减少以及减轻GLP-1R激动剂引起的厌恶效应。尽管已知双重GLP-1R-GIPR激动作用比单独的GLP-1R激动作用能产生更大的体重减轻，但确切机制尚不清楚。
为解决这个问题，我们使用了全身、GABA能神经元或谷氨酸能神经元中缺乏GIPR的小鼠。给这些小鼠给予GLP-1R和GIPR激动剂药物的各种组合，随后进行食物摄入量和条件性味觉厌恶测量。
全身或选择性地在抑制性GABA能神经元中敲除GIPR可预防饮食诱导的肥胖，而在兴奋性谷氨酸能神经元中敲除则效果可忽略不计。此外，我们发现GABA能神经元中的GIPR对于双肠促胰岛素激动作用增强的体重减轻效果至关重要，然而，令人惊讶的是，去除它会增强单独的GLP-1R激动作用的效果。最后，GABA能神经元中敲除GIPR可防止GIPR激动作用的抗厌恶效应。
我们的研究结果与整体的GIPR研究一致，即GIPR信号传导的增强和去除在代谢方面都是有益的。然而，值得注意的是，我们的研究结果表明，未来旨在调节GIPR信号传导的肥胖症治疗方法，无论是通过激动还是拮抗作用，最好以GABA能神经元为靶点。
