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

bolic 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. Remark‑

ably, 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 transcrip‑

tion 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 reduc‑

tion 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.