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

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 proneuroinflammation 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.

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

“…Previous study showed that peripherally derived FGF-21 leaked into the injured brain and facilitate remyelination in a mouse model of lysophosphatidylcholine-induced demyelination [44]. In addition, subcutaneously injection of recombinant human FGF-21 improved cognitive function via attenuating insulin resistance and inflammatory response in an obese mouse model [45]. Whether elevated expression of FGF-21 following our resistant training also contributed to the benefits seen in the brain should be further determined.…”

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

“…In a high‐fat, diet‐induced obese mouse model, recombinant human FGF21, which is used to treat obesity and diabetes, can improve cognitive dysfunction, restore synaptic plasticity, and ameliorate anxiety‐like behavior (63, 64). Along the same lines, our data showed that WD‐induced inflammatory signaling was accompanied by reduced Fgf21 gene expression in microglia and brain, as well as other organs.…”

Enhanced anti-amyloid effect of combined leptin and pioglitazone in APP/PS1 transgenic mice

“…mice We next investigated if mechanism underlying the reduction of Aβ load in the brain of APP/PS1 mice could be partially mediated by the molecular regulation of PPARγ levels, which play a master role in the regulation of the neuroinflammatory processes in AD ( Fig 5). Indeed, previous research has demonstrated that P reduces Aβ deposition in association with Akt/GSK3β activation by increasing the levels of insulin-degrading enzyme (IDE) and PPARγ expression [39]. For that reasons, in the current study, the downstream effect of treatment on PPARγ was investigated.…”