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. 2018 Jun;55(6):4702-4717.
doi: 10.1007/s12035-017-0663-7. Epub 2017 Jul 15.

FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice

Qingzhi Wang  1   2 , Jing Yuan  1   2 , Zhanyang Yu  2 , Li Lin  3 , Yinghua Jiang  2 , Zeyuan Cao  2 , Pengwei Zhuang  2 , Michael J Whalen  4 , Bo Song  1 , Xiao-Jie Wang  3 , Xiaokun Li  3 , Eng H Lo  2 , Yuming Xu  5 , Xiaoying Wang  6
Affiliations

FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice

Qingzhi Wang et al. Mol Neurobiol. 2018 Jun.

Abstract

Accumulating studies suggest that overnutrition-associated obesity may lead to development of type 2 diabetes mellitus and metabolic syndromes (MetS). MetS and its components are important risk factors of mild cognitive impairment, age-related cognitive decline, vascular dementia, and Alzheimer's disease. It has been recently proposed that development of a disease-course modification strategy toward early and effective risk factor management would be clinically significant in reducing the risk of metabolic disorder-initiated cognitive decline. In the present study, we propose that fibroblast growth factor 21 (FGF21) is a novel candidate for the disease-course modification approach. Using a high-fat diet (HFD) consumption-induced obese mouse model, we tested our hypothesis that recombinant human FGF21 (rFGF21) administration is effective for improving obesity-induced cognitive dysfunction and anxiety-like behavior, by its multiple metabolic modulation and anti-pro-inflammation actions. Our experimental findings support our hypothesis that rFGF21 is protective to HFD-induced cognitive impairment, at least in part by metabolic regulation in glucose tolerance impairment, insulin resistance, and hyperlipidemia; potent systemic pro-inflammation inhibition; and improvement of hippocampal dysfunction, particularly by inhibiting pro-neuroinflammation and neurogenesis deficit. This study suggests that FGF21 might be a novel molecular target of the disease-course-modifying strategy for early intervention of MstS-associated cognitive decline.

Keywords: Cognitive impairment; Fibroblast growth factor 21; High-fat diet; Inflammation; Metabolic disorders; Obese mice.

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Conflict of interest statement

Conflict of Interest The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
rFGF21 corrects HFD-induced cognitive impairment and anxietylike behavior in mice. a Y-maze: alternations of mice; b number of arm entries. c Novel object recognition test: recognition index (RI) in acquisition phase; d recognition index (RI) in trial phase. e Elevated plus maze: time spent in open arms (%); f numbers of open arm entries. Data are expressed as mean ± SE, n = 14 per group. *P < 0.05 versus SD; #P < 0.05 versus HFD
Fig. 2
Fig. 2
rFGF21 corrects glucose metabolic disorder and insulin resistance in HFDmice. a Bodyweight changes of mice fed with standard diet (SD), high-fat diet (HFD), HFD mice treated with rFGF21 (HFD + rFGF21). n = 14 per group. b Blood glucose concentration changes of SD-, HFD-, and rFGF21-treated mice under feeding condition. n = 14 per group. c Blood HbA1c changes of SD-, HFD-, and rFGF21-treated mice. n = 8 per group. d Blood glucose concentration changes at indicated times after intraperitoneal injection of glucose (2 mg/g), n = 4 per group. e Values of glucose tolerance test (GTT) were calculated and compared by area under the curve (AUC) of each group of mice. f Blood glucose concentration changes over the baseline level at indicated times after intraperitoneal injection of insulin (0.75 U/kg), n = 4 per group. g Values of insulin tolerance test (ITT) were calculated and compared by the percentage changes of area under the curve (AUC) over the SDmouse controls. h Serum insulin concentrations of each group of mice, n = 8 per group. Data are expressed as mean ± SE. *P < 0.05 versus SD; #P < 0.05 versus HFD
Fig. 3
Fig. 3
rFGF21 corrects hyperlipidemia in HFD mice. a Serum total cholesterol (TC) concentrations. b Serum highdensity lipoprotein (HDL) concentrations. c Serum lowdensity lipoprotein (LDL) concentrations. d Serum LDL/HDL ratios. e Serum triglyceride (TG) concentrations. Data are expressed as mean ± SE, n = 8 per group. *P < 0.05 versus SD; #P < 0.05 versus HFD
Fig. 4
Fig. 4
rFGF21 reduces systemic pro-inflammation of HFD mice. a Relative fold change of IL-1β, IL-6, and TNFα mRNA levels in white adipose tissue (WAT), n = 5 per group. b Serum TNFα concentrations, n = 8 per group. c Serum IL-1β concentrations, n = 8 per group. Data are expressed as mean ± SE. *P < 0.05 versus SD; #P < 0.05 versus HFD
Fig. 5
Fig. 5
rFGF21 can cross bloodbrain barrier (BBB) and activate FGF receptor 1 (FGFR1) in hippocampus of mice. a Baseline levels of serum FGF21 concentrations in SD and HFD mice. b CSF FGF21 concentrations at 4 h after initial rFGF21 injection. c Representative gel images of western blot analysis for FGF21, FGFR1, p-FGFR1, and β-Klotho protein expression. Actin served as an equal loading control. d Quantification of western blot analysis (fold change of SD mouse controls). Data are expressed as mean ± SE, n = 5 per group. *P < 0.05 versus SD; #P < 0.05 versus HFD
Fig. 6
Fig. 6
rFGF21 reduces microglia activation and pro-inflammatory cytokine expression in hippocampus of HFD mice. a Representative immunostaining images of ionized calcium binding adapter molecule 1 (Iba1; green), major histocompatibility complex II (MHCII; red), 4′,6- diamidino-2-phenylindole (DAPI; blue), and their merged ones in dentate gyrus (DG) of hippocampus. Scale bar = 50 μm. b Quantification of Iba1-positive microglia cell numbers in the hippocampal dentate gyrus. c Quantification of Iba1 and MHCII double-positive microglia cell numbers in the hippocampal dentate gyrus. d Relative fold change of IL-1β, IL-6, and TNFα mRNA levels in brain hippocampus. e Relative fold change of BDNF, IGF-1, and CD206 mRNA levels in brain hippocampus. f Representative gel images of western blot analysis for IL-1β, IL-6, and TNFα protein expression. Actin served as an equal loading control. g Quantification of western blot analysis (fold change of SDmouse controls). Data are expressed as mean ± SE, n = 5 pergroup. *P < 0.05 versus SD; #P < 0.05 versus HFD
Fig. 7
Fig. 7
rFGF21 modulates Akt/GSK-3β signaling in hippocampus of HFD mice. a Representative gel images of western blot analysis for Akt, p-Akt, GSK-3β, and p-GSK-3β protein expression. Actin served as an equal loading control. b Quantification ofwestern blot analysis (fold change of SD mouse controls). Data are expressed as mean ± SE, n = 6 per group. *P < 0.05 versus SD; #P < 0.05 versus HFD
Fig. 8
Fig. 8
rFGF21 promotes hippocampal neurogenesis but not synaptic plasticity of HFD mice. a Relative fold change of hippocampal synaptophysin (SYP-1) and PSD95 mRNA levels. b Representative gel images of western blot analysis for SYP-1 and PSD95 protein expression in hippocampus. Actin served as an equal loading control. c Quantification of western blot analysis (fold change of SD mouse controls). d Representative immunostaining images of newly born neuron marker doublecortin (DCX; red) in dentate gyrus (DG) of hippocampus. Scale bar = 50 μm. e Quantification of DCX positive cells in the hippocampal dentate gyrus. Data are expressed as mean ± SE, n = 6 per group. *P < 0.05 versus SD; #P < 0.05 versus HFD
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