FTO inhibition mitigates high-fat diet-induced metabolic disturbances and cognitive decline in SAMP8 mice

Abstract

This study investigated the effects of fat mass and obesity‑associated (FTO) inhibition on cognitive function and meta‑</p><p>bolic parameters of senescence‑accelerated mouse prone 8 (SAMP8) mice fed a high‑fat diet (HFD). SAMP8 mice fed</p><p>an HFD exhibited increased body weight, impaired glucose tolerance, and elevated serum leptin levels. In epididymal</p><p>white adipose tissue (eWAT), pharmacological treatment with FB23, a well‑established FTO inhibitor, increased leptin</p><p>production and modulated genes involved in lipid metabolism (Cpt1a, Atgl, Hsl, Fas), oxidative stress (OS) (Bip, Edem),</p><p>and inflammation (Mcp1, Tnfα). Expression of hepatic genes related to lipid metabolism (Cpt1a, Atgl, Mgl, Dgat2, Srebp,</p><p>Plin2) and OS (catalase, Edem) were modulated by FB23, although hepatic steatosis remained unchanged. Remark‑</p><p>ably, FB23 treatment increased m6A RNA methylation in the brain, accompanied by changes in N6‑methyladenosine</p><p>(m6A)‑regulatory enzymes and modulation of neuroinflammatory markers (Il6, Mcp1, iNOS). FTO inhibition reduced</p><p>the activity of matrix metalloproteases (Mmp2, Mmp9) and altered IGF1 signaling (Igf1, Pten). Notably, enhanced</p><p>leptin signaling was observed through increased expression of immediate early genes (Arc, Fos) and the transcrip‑</p><p>tion factor Stat3. Improved synaptic plasticity was evident, as shown by increased levels of neurotrophic factors (Bdnf,</p><p>Ngf ) and restored neurite length and spine density. Consistent with these findings, behavioral tests demonstrated</p><p>that FB23 treatment effectively rescued cognitive impairments in SAMP8 HFD mice. The novel object recognition</p><p>test (NORT) and object location test (OLT) revealed that treated mice exhibited enhanced short‑ and long‑term</p><p>memory and spatial memory compared to the HFD control group. Additionally, the open field test showed a reduc‑</p><p>tion in anxiety‑like behavior after treatment with FB23. In conclusion, pharmacological FTO inhibition ameliorated</p><p>HFD‑induced metabolic disturbances and cognitive decline in SAMP8 mice. These results suggest that targeting FTO</p><p>may be a promising therapeutic approach to counteract obesity‑induced cognitive impairment and age‑related</p><p>neurodegeneration.