FTO inhibition mitigates high-fat diet-induced metabolic disturbances and cognitive decline in SAMP8 mice.
Study Goal
The researchers aimed to investigate the effects of FTO inhibition on cognitive function and metabolic parameters in SAMP8 mice fed a high-fat diet.
Results Summary
The study found that FTO inhibition improved metabolic disturbances (e.g., glucose tolerance, leptin levels) and cognitive function (e.g., memory, synaptic plasticity) in HFD-fed SAMP8 mice, while also modulating neuroinflammatory and oxidative stress markers.
Population
Senescence-accelerated mouse prone 8 (SAMP8) mice fed a high-fat diet.
Effective Dosage
Not specified (pharmacological treatment with FB23, an FTO inhibitor).
Duration
Not specified.
Interactions
None mentioned.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
SAMP8 mice fed a high-fat diet (HFD) | increase | body weight | SAMP8 mice | - | exhibited increased | #1 |
SAMP8 mice fed a high-fat diet (HFD) | decrease | glucose tolerance | SAMP8 mice | - | exhibited impaired | #2 |
SAMP8 mice fed a high-fat diet (HFD) | increase | serum leptin levels | SAMP8 mice | - | exhibited elevated | #3 |
pharmacological treatment with FB23, a well-established FTO inhibitor | increase | leptin production | SAMP8 mice fed an HFD | - | increased | #4 |
pharmacological treatment with FB23, a well-established FTO inhibitor | neutral | genes involved in lipid metabolism (Cpt1a, Atgl, Hsl, Fas) | epididymal white adipose tissue (eWAT) of SAMP8 mice fed an HFD | - | modulated | #5 |
pharmacological treatment with FB23, a well-established FTO inhibitor | neutral | genes involved in oxidative stress (OS) (Bip, Edem) | epididymal white adipose tissue (eWAT) of SAMP8 mice fed an HFD | - | modulated | #6 |
pharmacological treatment with FB23, a well-established FTO inhibitor | neutral | genes involved in inflammation (Mcp1, Tnfα) | epididymal white adipose tissue (eWAT) of SAMP8 mice fed an HFD | - | modulated | #7 |
FB23 | neutral | hepatic genes related to lipid metabolism (Cpt1a, Atgl, Mgl, Dgat2, Srebp, Plin2) | SAMP8 mice fed an HFD | - | modulated | #8 |
FB23 | neutral | hepatic genes related to OS (catalase, Edem) | SAMP8 mice fed an HFD | - | modulated | #9 |
FB23 | no change | hepatic steatosis | SAMP8 mice fed an HFD | - | remained unchanged | #10 |
FB23 treatment | increase | m6A RNA methylation in the brain | SAMP8 HFD mice | - | increased | #11 |
FB23 treatment | neutral | N6-methyladenosine (m6A)-regulatory enzymes | SAMP8 HFD mice | - | accompanied by changes in | #12 |
FB23 treatment | neutral | neuroinflammatory markers (Il6, Mcp1, iNOS) | SAMP8 HFD mice | - | modulation of | #13 |
FTO inhibition | decrease | activity of matrix metalloproteases (Mmp2, Mmp9) | SAMP8 HFD mice | - | reduced | #14 |
FTO inhibition | neutral | IGF1 signaling (Igf1, Pten) | SAMP8 HFD mice | - | altered | #15 |
FTO inhibition | increase | immediate early genes (Arc, Fos) | SAMP8 HFD mice | - | enhanced leptin signaling was observed through increased expression of | #16 |
FTO inhibition | increase | the transcription factor Stat3 | SAMP8 HFD mice | - | enhanced leptin signaling was observed through increased expression of | #17 |
FTO inhibition | increase | neurotrophic factors (Bdnf, Ngf) | SAMP8 HFD mice | - | improved synaptic plasticity was evident, as shown by increased levels of | #18 |
FTO inhibition | increase | restored neurite length and spine density | SAMP8 HFD mice | - | improved synaptic plasticity was evident, as shown by | #19 |
FB23 treatment | increase | cognitive impairments | SAMP8 HFD mice | - | effectively rescued | #20 |
FB23 treatment | increase | short- and long-term memory and spatial memory | SAMP8 HFD mice | - | revealed that treated mice exhibited enhanced | #21 |
FB23 treatment | decrease | anxiety-like behavior | SAMP8 HFD mice | - | showed a reduction in | #22 |
pharmacological FTO inhibition | decrease | HFD-induced metabolic disturbances | SAMP8 mice | - | ameliorated | #23 |
pharmacological FTO inhibition | decrease | HFD-induced cognitive decline | SAMP8 mice | - | ameliorated | #24 |
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.