减重药物界最大全球谜团破解！同一受体“激活”或“抑制”都能减肥？《自然·代谢》深度揭秘GIPR双重作用机制的生命科学新革命

Core Insights - The article highlights the significant advancements in weight loss medications, particularly focusing on the role of GLP-1R agonists like semaglutide and the emerging interest in GIPR as a target for obesity treatment [5][8]. Group 1: Mechanisms of Action - Semaglutide, a GLP-1R agonist, has revolutionized weight loss by stimulating insulin secretion, regulating metabolism, and suppressing appetite [5]. - GIPR, another member of the incretin hormone family, has shown perplexing effects where both its activation and inhibition can lead to weight loss, indicating a complex underlying mechanism [5][8]. - Recent studies reveal that GIPR agonists and antagonists activate different neuronal pathways in the central nervous system, with agonists primarily affecting GABAergic neurons and antagonists relying on GLP-1R signaling [5][11]. Group 2: New Drug Developments - The dual-target weight loss drug tirzepatide, which activates both GIPR and GLP-1R, has demonstrated significant weight loss effects, surpassing the sum of individual effects [8]. - The GIPR-Ab/GLP-1 peptide antibody conjugate developed by Amgen requires the presence of both GIPR and GLP-1R in the brain to exert its anti-obesity effects, confirming the findings of the Gutgesell team [6][11]. - AMG133, a bispecific hybrid antibody that activates GLP-1R and antagonizes GIPR, is currently in Phase 2 clinical trials and shows promise in appetite suppression and weight loss [8][11]. Group 3: Implications for Future Research - The understanding of GIPR and GLP-1R mechanisms opens new avenues for developing more precise and effective weight loss therapies [11]. - The contrasting transcriptional responses induced by GIPR agonists and antagonists in the brain suggest potential for targeted therapeutic strategies in obesity management [11].