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

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


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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Anxiety / complications
  • Anxiety / drug therapy
  • Behavior, Animal
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / pathology
  • Cognitive Dysfunction / complications
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / pathology
  • Cytokines / metabolism
  • Diet, High-Fat
  • Fibroblast Growth Factors / pharmacology
  • Fibroblast Growth Factors / therapeutic use*
  • Glucose / metabolism
  • Hippocampus / metabolism
  • Humans
  • Hyperlipidemias / complications
  • Hyperlipidemias / drug therapy
  • Inflammation / complications
  • Inflammation / drug therapy
  • Insulin Resistance
  • Male
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Neurogenesis / drug effects
  • Neuronal Plasticity / drug effects
  • Receptors, Fibroblast Growth Factor / metabolism
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Signal Transduction


  • Anti-Inflammatory Agents
  • Cytokines
  • Receptors, Fibroblast Growth Factor
  • Recombinant Proteins
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Glucose