The NLRP3 inhibitor NT-0796 enhances and sustains GLP-1R agonist-mediated weight loss in a murine diet-induced obesity model

IF 4.7 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Obesity Pub Date : 2025-04-30 DOI:10.1002/oby.24305
Peter Thornton, Valérie Reader, Zsofia Digby, John Doedens, Nicola Lindsay, Nicholas Clarke, Alan P. Watt
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引用次数: 0

Abstract

Objective

In order to investigate whether a central nervous system penetrant anti-inflammatory could augment or sustain obesity treatment with semaglutide (Wegovy), a glucagon-like peptide-1 receptor (GLP-1R) agonist, we tested two hypotheses in models of diet-induced obesity (DIO): 1) a centrally penetrant NLPR3 inhibitor, NT-0796, drives enhanced weight loss when combined with low-dose semaglutide, compared to monotherapy; and 2) NT-0796 monotherapy sustains weight loss induced by semaglutide.

Methods

Mice fed a standard high-fat or a polyunsaturated fatty acid diet served as models of DIO and were dosed with low-dose semaglutide, NT-0796, or combinations. Body weight, food intake, peripheral inflammatory markers, and hypothalamic glial fibrillary acidic protein expression were assessed.

Results

Combined dosing of NT-0796 with semaglutide drove greater weight loss than either monotherapy alone, and this effect was enhanced in mice consuming the polyunsaturated fatty acid diet. In addition, NT-0796 sharply limited weight regain following cessation of semaglutide therapy and normalized markers of both peripheral inflammation and hypothalamic astrogliosis to a far greater extent than either semaglutide or calorie restriction.

Conclusions

Alleviation of obesity-associated inflammation via NLRP3 inhibition 1) constitutes an effective weight-loss strategy as monotherapy in mice with DIO, 2) augments the weight-loss efficacy of a subtherapeutic dose of semaglutide, and 3) blocks recovery of lost weight following cessation of semaglutide.

Abstract Image

NLRP3抑制剂NT-0796在小鼠饮食诱导肥胖模型中增强并维持GLP-1R激动剂介导的体重减轻。
目的:为了研究中枢神经系统渗透性抗炎药是否能增强或维持胰高血糖素样肽-1受体(GLP-1R)激动剂半马鲁肽(Wegovy)的肥胖治疗,我们在饮食诱导肥胖(DIO)模型中验证了两种假设:1)与单药治疗相比,中枢渗透性NLPR3抑制剂NT-0796与低剂量半马鲁肽联合治疗能增强体重减轻;2) NT-0796单药治疗可维持西马鲁肽诱导的体重减轻。方法:以标准高脂肪或多不饱和脂肪酸饲料喂养的小鼠作为DIO模型,并给药低剂量的西马鲁肽、NT-0796或联合用药。评估体重、食物摄入量、外周炎症标志物和下丘脑胶质纤维酸性蛋白的表达。结果:NT-0796与西马鲁肽联合用药比单独用药更能减轻体重,并且在食用多不饱和脂肪酸饮食的小鼠中,这种效果得到了增强。此外,NT-0796显著限制了停止塞马鲁肽治疗后的体重反弹,并使外周炎症和下丘脑星形胶质增生的指标正常化,其程度远高于塞马鲁肽或卡路里限制。结论:通过抑制NLRP3减轻肥胖相关炎症1)对DIO小鼠进行单药治疗是一种有效的减肥策略,2)增强了亚治疗剂量的semaglutide的减肥效果,3)阻断了semaglutide停止后的体重恢复。
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来源期刊
Obesity
Obesity 医学-内分泌学与代谢
CiteScore
11.70
自引率
1.40%
发文量
261
审稿时长
2-4 weeks
期刊介绍: Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.
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