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.

Fibroblast growth factor 21 protects the liver from apoptosis in a type 1 diabetes mouse model via regulating L-lactate homeostasis.

AIMS/HYPOTHESIS: Fibroblast growth factor 21 (FGF21) is a hepatokine with pleiotropic effects on glucose and lipid metabolic homeostasis. Here, we aimed to elucidate the mechanisms underlying the protective effects of FGF21 on L-lactate homeostasis and liver lesions in a type 1 diabetes mellitus (T1DM) mice model. METHODS: Six-week-old male C57BL/6 mice were divided into control, T1DM, and FGF21 groups. We also examined hepatic apoptotic signaling and functional indices in wild-type and hydroxycarboxylic acid receptor 1 (HCA1) knockout mice with T1DM or long-term L-lactate exposure. After preincubation of high glucose- or L-lactate treated hepatic AML12 cells, L-lactate uptake, apoptosis, and monocarboxylic acid transporter 2 (MCT2) expression were investigated. RESULTS: In a mouse model of T1DM, hepatic FGF21 expression was downregulated by approximately 1.5-fold at 13 weeks after the hyperglycemic insult. In vivo administration of exogenous FGF21 (2 mg/kg) to diabetic or L-lactate-infused mice significantly prevented hepatic oxidative stress and apoptosis by activating extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways. HCA1-KO mice were less susceptible to diabetes- and L-lactate-induced hepatic apoptosis and dysfunction. In addition, inhibition of PI3K-mTOR activity revealed that FGF21 prevented L-lactate-induced Cori cycle alterations and hepatic apoptosis by upregulating MCT2 protein translation. CONCLUSIONS/INTERPRETATION: These results demonstrate that L-lactate homeostasis may be a therapeutic target for T1DM-related hepatic dysfunction. The protective effects of FGF21 on hepatic damage were associated with its ability to ameliorate MCT2-dependent Cori cycle alterations and prevent HCA1-mediated inhibition of ERK1/2, p38 MAPK, and AMPK signaling.