Chen Qianjiang, Ding Ke, Li Mengfan, Ma Rui, Lin Jian, Guan Jialin, Lu Jingli
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
Int J Obes (Lond). 2025 Aug 12. doi: 10.1038/s41366-025-01873-8.
Targeting intracellular lipolysis represents a therapeutic potential for treating metabolic disorders such as obesity. Interleukin (IL)-33 has been shown to exert anti-obesity effects by reducing inflammation and restricting adipocyte hypertrophy.
In this study, male mice on a high-fat diet (HFD) were treated with IL-33 once every 2 days for 2 weeks. 3T3-L1 cells were treated with IL-33 to verify the down-stream effect of β1-AR activation on the adipose cells.
IL-33 treatment led to a reduction in adipose tissue mass and a decreased in lipid deposition in male mice with obesity, accompanied by activation of β-adrenergic receptor (β-AR) signals. Immunostaining for tyrosine hydroxylase (TH) revealed an increase of TH within the adipose tissue in male mice. Metabolomic analysis showed that IL-33 induced a distinct metabolic profile in differentiated adipocytes, with significant changes in metabolites related to lipolysis pathways. Supplementation with β1-AR inhibitor significantly inhibited IL-33-induced p-HSL and p-PKA activation. Compared to IL-33 alone, β1-AR inhibitor reduced glycerol release and increased accumulation of lipid droplets. We also illustrated the fatty acids (FAs) process by tracking FA trafficking, and found that the labeled FA localized lipid droplets (LDs) in mature adipocytes but shifted from LDs to mitochondria at 20 ng/mL IL-33.
We summarized that IL-33 regulated mature adipocyte metabolism and enhanced lipolysis in male mice via activation of the β-AR/cAMP/PKA/HSL signaling pathway. However, given that sex is a significant determinant in obesity, future studies should investigate potential sex-specific effects of IL-33 in metabolic regulation.
靶向细胞内脂解作用为治疗肥胖等代谢紊乱疾病提供了一种治疗潜力。白细胞介素（IL）-33已被证明可通过减轻炎症和限制脂肪细胞肥大发挥抗肥胖作用。
在本研究中，对高脂饮食（HFD）的雄性小鼠每2天用IL-33治疗一次，持续2周。用IL-33处理3T3-L1细胞，以验证β1-肾上腺素能受体（β-AR）激活对脂肪细胞的下游作用。
IL-33治疗导致肥胖雄性小鼠的脂肪组织质量减少和脂质沉积减少，同时伴有β-肾上腺素能受体（β-AR）信号的激活。酪氨酸羟化酶（TH）免疫染色显示雄性小鼠脂肪组织内TH增加。代谢组学分析表明，IL-33在分化的脂肪细胞中诱导了独特的代谢谱，与脂解途径相关的代谢物有显著变化。补充β1-AR抑制剂可显著抑制IL-33诱导的p-HSL和p-PKA激活。与单独使用IL-33相比，β1-AR抑制剂减少了甘油释放并增加了脂滴积累。我们还通过追踪脂肪酸（FA）转运说明了脂肪酸过程，发现标记的FA在成熟脂肪细胞中定位于脂滴，但在20 ng/mL IL-33时从脂滴转移到线粒体。
我们总结认为，IL-33通过激活β-AR/cAMP/PKA/HSL信号通路调节雄性小鼠成熟脂肪细胞代谢并增强脂解作用。然而，鉴于性别是肥胖的一个重要决定因素，未来的研究应调查IL-33在代谢调节中潜在的性别特异性作用。
