CNS-PENETRANT NLRP3 INHIBITOR ACHIEVES DURABLE WEIGHT LOSS AND REVERSES HYPOTHALAMIC INFLAMMATION IN DIET-INDUCED OBESITY

作者：Jing Guo, Tomás P. Bachor, Ryan Takahashi, Micah Steffek, Gabriel A. Fitzgerald, Benjamin J. Huffman, Dylan Braun, Suk Ji Han, Thomas Sandmann, Connie Ha, Katrina W. Lexa, Yun-Ting Hsieh, Maayan Agam, Elizabeth W. Sun, Xiang Wang, Min Liu, Javier de Vicente, Brian M. Fox, Meghan K. Campbell, Stephen P. Cavnar, Tracy J. Yuen, Tanya Fischer, Anthony A. Estrada, Robert A. Craig, Ernie Yulyaningsih · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.10.06.680810 · 被引用次数：1 · 研究领域：Tryptophan and brain disorders、Adipose Tissue and Metabolism、Cancer, Stress, Anesthesia, and Immune Response

ABSTRACT The NLRP3 inflammasome is a key mediator of innate immunity that integrates inflammatory and metabolic stress signals. Increased and/or chronic activation of this critical pathway has been implicated in obesity, with hypothalamic neuroinflammation linked to dysregulation of energy balance. TN-783 is an investigational, CNS-penetrant, small-molecule NLRP3 inhibitor that potently suppressed inflammasome activation across multiple in vitro assays. In diet-induced obese (DIO) mice, only TN-783, and not the peripherally restricted NLRP3 inhibitor TN-101, produced progressive and sustained weight loss, underscoring the requirement for central target engagement. Weight loss was driven by a persistent reduction in food intake across both acute and chronic phases, without altering energy expenditure. This effect was further characterized by selective reduction of fat mass, with minimal impact on lean tissues. Mechanistically, NLRP3 inhibition attenuated DIO-induced hypothalamic neuroinflammation and partially reversed obesity-associated molecular changes based on transcriptomic and proteomic profiling of the hypothalamus. Beyond monotherapy, TN-783 enhanced the effects of the GLP-1 receptor agonist semaglutide by amplifying weight loss, reinitiating weight loss after semaglutide effect had plateaued, and maintaining the weight loss benefit after semaglutide withdrawal. Discontinuation of TN-783 resulted in reversal of both weight and feeding effects, indicating that its thera...