Samms Ricardo J, Sloop Kyle W
Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
Diabetes. 2025 Aug 1;74(8):1326-1333. doi: 10.2337/dbi24-0026.
In combatting the obesity crisis, leveraging mechanisms that lower body weight is critical. The finding that treatment with tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, produces profound weight loss highlights the value of activating the incretin receptors. Supporting this, recent studies have revealed mechanisms by which GIP receptor (GIPR) activation is beneficial in pancreatic islets, the central nervous system (CNS), and adipose tissue. Paradoxically, a hypothesis has emerged that GIPR antagonism could be an additional option in treating obesity. This concept stems from concern that GIP facilitates lipid uptake and storage in adipose tissue, although the lipid-buffering capacity of adipocytes versus other cell types is metabolically favorable. In this article, we highlight the natural physiology of the incretins, noting GIP as the primary incretin. In the CNS, GIPR agonism attenuates nausea and suppresses appetite, features that also help GLP-1 receptor agonism promote a negative energy balance. Further, we provide rationale that, in protecting against ectopic fat distribution and augmenting substrate utilization to promote insulin sensitivity, GIPR activity in adipose tissue is advantageous. Collectively, these attributes support GIPR agonism in the treatment of obesity and metabolic disease.
在应对肥胖危机时，利用降低体重的机制至关重要。葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）受体激动剂替尔泊肽治疗可导致显著体重减轻，这一发现凸显了激活肠促胰岛素受体的价值。支持这一点的是，最近的研究揭示了GIP受体（GIPR）激活在胰岛、中枢神经系统（CNS）和脂肪组织中有益的机制。矛盾的是，一种假说出现了，即GIPR拮抗作用可能是治疗肥胖的另一种选择。这一概念源于人们担心GIP会促进脂肪组织中的脂质摄取和储存，尽管与其他细胞类型相比，脂肪细胞的脂质缓冲能力在代谢方面更有利。在本文中，我们强调了肠促胰岛素的自然生理学，指出GIP是主要的肠促胰岛素。在中枢神经系统中，GIPR激动作用可减轻恶心并抑制食欲，这些特征也有助于GLP-1受体激动作用促进负能量平衡。此外，我们提出理由，即脂肪组织中的GIPR活性在防止异位脂肪分布和增加底物利用以促进胰岛素敏感性方面具有优势。总的来说，这些特性支持GIPR激动作用用于治疗肥胖和代谢疾病。
