Irisarri Alba, Corral Ana, Perez-Salvador Núria, Bellver-Sanchis Aina, Ribalta-Vilella Marta, Bentanachs Roger, Alegret Marta, Laguna Juan Carlos, Barroso Emma, Palomer Xavier, Ortuño-Sahagún Daniel, Vázquez-Carrera Manuel, Pallàs Mercè, Herrero Laura, Griñán-Ferré Christian
pHD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain.
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain.
Mol Med. 2025 Feb 21;31(1):73. doi: 10.1186/s10020-025-01126-4.
This study investigated the effects of fat mass and obesity-associated (FTO) inhibition on cognitive function and metabolic parameters of senescence-accelerated mouse prone 8 (SAMP8) mice fed a high-fat diet (HFD). SAMP8 mice fed an HFD exhibited increased body weight, impaired glucose tolerance, and elevated serum leptin levels. In epididymal white adipose tissue (eWAT), pharmacological treatment with FB23, a well-established FTO inhibitor, increased leptin production and modulated genes involved in lipid metabolism (Cpt1a, Atgl, Hsl, Fas), oxidative stress (OS) (Bip, Edem), and inflammation (Mcp1, Tnfα). Expression of hepatic genes related to lipid metabolism (Cpt1a, Atgl, Mgl, Dgat2, Srebp, Plin2) and OS (catalase, Edem) were modulated by FB23, although hepatic steatosis remained unchanged. Remarkably, FB23 treatment increased m6A RNA methylation in the brain, accompanied by changes in N6-methyladenosine (m6A)-regulatory enzymes and modulation of neuroinflammatory markers (Il6, Mcp1, iNOS). FTO inhibition reduced the activity of matrix metalloproteases (Mmp2, Mmp9) and altered IGF1 signaling (Igf1, Pten). Notably, enhanced leptin signaling was observed through increased expression of immediate early genes (Arc, Fos) and the transcription factor Stat3. Improved synaptic plasticity was evident, as shown by increased levels of neurotrophic factors (Bdnf, Ngf) and restored neurite length and spine density. Consistent with these findings, behavioral tests demonstrated that FB23 treatment effectively rescued cognitive impairments in SAMP8 HFD mice. The novel object recognition test (NORT) and object location test (OLT) revealed that treated mice exhibited enhanced short- and long-term memory and spatial memory compared to the HFD control group. Additionally, the open field test showed a reduction in anxiety-like behavior after treatment with FB23. In conclusion, pharmacological FTO inhibition ameliorated HFD-induced metabolic disturbances and cognitive decline in SAMP8 mice. These results suggest that targeting FTO may be a promising therapeutic approach to counteract obesity-induced cognitive impairment and age-related neurodegeneration.
本研究调查了脂肪量和肥胖相关基因（FTO）抑制对高脂饮食（HFD）喂养的衰老加速小鼠8（SAMP8）的认知功能和代谢参数的影响。喂食HFD的SAMP8小鼠体重增加、葡萄糖耐量受损且血清瘦素水平升高。在附睾白色脂肪组织（eWAT）中，用成熟的FTO抑制剂FB23进行药物治疗可增加瘦素生成，并调节参与脂质代谢（Cpt1a、Atgl、Hsl、Fas）、氧化应激（OS）（Bip、Edem）和炎症（Mcp1、Tnfα）的基因。尽管肝脂肪变性保持不变，但与脂质代谢（Cpt1a、Atgl、Mgl、Dgat2、Srebp、Plin2）和OS（过氧化氢酶、Edem）相关的肝脏基因表达受到FB23的调节。值得注意的是，FB23治疗增加了大脑中的m6A RNA甲基化，同时伴有N6-甲基腺苷（m6A）调节酶的变化和神经炎症标志物（Il6、Mcp1、iNOS）的调节。FTO抑制降低了基质金属蛋白酶（Mmp2、Mmp9）的活性，并改变了IGF1信号通路（Igf1、Pten）。值得注意的是，通过立即早期基因（Arc、Fos）和转录因子Stat3表达的增加，观察到瘦素信号增强。神经生长因子（Bdnf、Ngf）水平升高以及神经突长度和树突棘密度恢复，表明突触可塑性得到改善。与这些发现一致，行为测试表明FB23治疗有效挽救了SAMP8 HFD小鼠的认知障碍。新颖物体识别测试（NORT）和物体位置测试（OLT）显示，与HFD对照组相比，治疗后的小鼠表现出增强的短期和长期记忆以及空间记忆。此外，旷场试验表明，FB23治疗后焦虑样行为减少。总之，药物性FTO抑制改善了HFD诱导的SAMP8小鼠的代谢紊乱和认知衰退。这些结果表明，靶向FTO可能是对抗肥胖诱导的认知障碍和年龄相关神经退行性变的一种有前景的治疗方法。
Zotero 插件
