Transplant of fecal microbiota from healthy young mice relieves cognitive defects in late-stage diabetic mice by reducing metabolic disorders and neuroinflammation.

Fecal microbiota transplant (FMT) is becoming as a promising area of interest for treating refractory diseases. In this study, we investigated the effects of FMT on diabetes-associated cognitive defects in mice as well as the underlying mechanisms. Fecal microbiota was prepared from 8-week-aged healthy mice. Late-stage type 1 diabetics (T1D) mice with a 30-week history of streptozotocin-induced diabetics were treated with antibiotics for 7 days, and then were transplanted with bacterial suspension (100 µL, i.g.) once a day for 14 days. We found that FMT from healthy young mice significantly alleviated cognitive defects of late-stage T1D mice assessed in Morris water maze test. We revealed that FMT significantly reduced the relative abundance of Gram-negative bacteria in the gut microbiota and enhanced intestinal barrier integrity, mitigating LPS translocation into the bloodstream and NLRP3 inflammasome activation in the hippocampus, thereby reducing T1D-induced neuronal loss and astrocytic proliferation. FMT also reshaped the metabolic phenotypes in the hippocampus of T1D mice especially for alanine, aspartate and glutamate metabolism. Moreover, we showed that application of aspartate (0.1 mM) significantly inhibited NLRP3 inflammasome activation and IL-1ß production in BV2 cells under a HG/LPS condition. We conclude that FMT can effectively relieve T1D-associated cognitive decline via reducing the gut-brain metabolic disorders and neuroinflammation, providing a potential therapeutic approach for diabetes-related brain disorders in clinic.

FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP-activated protein kinase-Caspase 6 signal axis.

BACKGROUND AND AIMS: NAFLD represents an increasing health problem in association with obesity and diabetes with no effective pharmacotherapies. Growing evidence suggests that several FGFs play important roles in diverse aspects of liver pathophysiology. Here, we report a previously unappreciated role of FGF4 in the liver. APPROACH AND RESULTS: Expression of hepatic FGF4 is inversely associated with NAFLD pathological grades in both human patients and mouse models. Loss of hepatic Fgf4 aggravates hepatic steatosis and liver damage resulted from an obesogenic high-fat diet. By contrast, pharmacological administration of recombinant FGF4 mitigates hepatic steatosis, inflammation, liver damage, and fibrogenic markers in mouse livers induced to develop NAFLD and NASH under dietary challenges. Such beneficial effects of FGF4 are mediated predominantly by activating hepatic FGF receptor (FGFR) 4, which activates a downstream Ca2+ -Ca2+ /calmodulin-dependent protein kinase kinase beta-dependent AMP-activated protein kinase (AMPK)-Caspase 6 signal axis, leading to enhanced fatty acid oxidation, reduced hepatocellular apoptosis, and mitigation of liver damage. CONCLUSIONS: Our study identifies FGF4 as a stress-responsive regulator of liver pathophysiology that acts through an FGFR4-AMPK-Caspase 6 signal pathway, shedding light on strategies for treating NAFLD and associated liver pathologies.

A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as a major liver disease increasingly in association with non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). However, there are currently no approved therapies for treating NAFLD and NASH. Fibroblast growth factor 4 (FGF4) has recently been shown as a promising drug candidate for several metabolic diseases. METHODS: Mice fed a high-fat diet with high fructose/glucose drinking water (HF/HFG, Western-like diet) for 21 weeks were intraperitoneally injected with non-mitogenic recombinant FGF4△NT (rFGF4△NT, 1.0 mg/kg body weight) every other day for 8 weeks. Primary mouse hepatocytes cultured in medium containing high glucose/palmitic acid (HG/PA) or TNFα/cyclohexane (TNFα/CHX) were treated with 1.0 µg/ml rFGF4△NT. Changes in parameters for histopathology, lipid metabolism, inflammation, hepatocellular apoptosis and fibrosis were determined. The Caspase6 activity and AMPK pathway were assessed. RESULTS: Administration of rFGF4△NT significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4△NT treatment reduced fatty acid-induced lipid accumulation and lipotoxicity-induced hepatocyte apoptosis, which were associated with inhibition of Caspase6 cleavage and activation. Inhibition of AMP-activated protein kinase (AMPK) by Compound C or deficiency of Ampk abrogated rFGF4△NT-induced hepatoprotection in primary hepatocytes and in mice with NASH. CONCLUSION: rFGF4△NT exerts significant protective effects on NASH via an AMPK-dependent signaling pathway. Our study indicates that FGF4 analogs may have therapeutic potential for the Western-like diet induced NASH.