Fibroblast growth factor 21 alleviates diabetes-induced cognitive decline.

Diabetes mellitus (DM) causes damage to the central nervous system, resulting in cognitive impairment. Fibroblast growth factor 21 (FGF21) exhibits the potential to alleviate neurodegeneration. However, the therapeutic effect of intracerebroventricular (i.c.v) FGF21 infusion on diabetes-induced cognitive decline (DICD) and its potential mechanisms remain unclear. In this study, the impact of FGF21 on DICD was explored, and 1H nuclear magnetic resonance (NMR)-based metabolomics plus 13C NMR spectroscopy in combine with intravenous [1-13C]-glucose infusion were used to investigate the underlying metabolic mechanism. Results revealed that i.c.v FGF21 infusion effectively improved learning and memory performance of DICD mice; neuron loss and apoptosis in hippocampus and cortex were significantly blocked, suggesting a potential neuroprotective role of FGF21 in DICD. Metabolomics results revealed that FGF21 modulated DICD metabolic alterations related to glucose and neurotransmitter metabolism, which are characterized by distinct recovered enrichment of [3-13C]-lactate, [3-13C]-aspartate, [4-13C]-glutamine, [3-13C]-glutamine, [4-13C]-glutamate, and [4-13C]- γ-aminobutyric acid (GABA) from [1-13C]-glucose. Moreover, diabetes-induced neuron injury and metabolic dysfunctions might be mediated by PI3K/AKT/GSK-3ß signaling pathway inactivation in the hippocampus and cortex, which were activated by i.c.v injection of FGF21. These findings indicate that i.c.v FGF21 infusion exerts its neuroprotective effect on DICD by remodeling cerebral glucose and neurotransmitter metabolism by activating the PI3K/AKT/GSK-3ß signaling pathway.

Fibroblast growth factor 21 enhances learning and memory performance in mice by regulating hippocampal L-lactate homeostasis.

Fibroblast growth factor 21 (FGF21) is one endogenous metabolic molecule that functions as a regulator in glucose and lipid homeostasis. However, the effect of FGF21 on L-lactate homeostasis and its mechanism remains unclear until now. Forty-five Six-week-old male C57BL/6 mice were divided into three groups: control, L-lactate, and FGF21 (1.5 mg/kg) groups. At the end of the treatment, nuclear magnetic resonance-based metabolomics, and key proteins related to L-lactate homeostasis were determined respectively to evaluate the efficacy of FGF21 and its mechanisms. The results showed that, compared to the vehicle group, the L-lactate-treated mice displayed learning and memory performance impairments, as well as reduced hippocampal ATP and NADH levels, but increased oxidative stress, mitochondrial dysfunction, and apoptosis, which suggesting inhibited L-lactate-pyruvate conversion in the brain. Conversely, FGF21 treatment ameliorated the L-lactate accumulation state, accompanied by restoration of the learning and memory defects, indicating enhanced L-lactate uptake and utilization in hippocampal neurons. We demonstrated that maintaining constant L-lactate-pyruvate flux is essential for preserving neuronal bioenergetic and redox levels. FGF21 contributed to preparing the brain for situations of high availability of L-lactate, thus preventing neuronal vulnerability in metabolic reprogramming.