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

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.