Fibroblast growth factor 21 protects mouse brain against d-galactose induced aging via suppression of oxidative stress response and advanced glycation end products formation

Yu, Yin-Hang; Bai, Fuliang; Wang, Wenfei; Yaonan, Liu; Yuan, Qingyan; Qu, Susu; Zhang, Tong; Tian, GY; Li, Siming; Li, Deshan; Ren, Guangxin

doi:10.1016/j.pbb.2015.03.020

Cited by 104 publications

(42 citation statements)

References 46 publications

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“…Prolonged fasting maintains glucose homeostasis through the brain-liver axis (Liang et al, 2014), while starvation induces FGF21 to act directly on the brain to lower insulin (Bookout et al, 2013) and suppress ovulation via a liver-neuroendocrine signaling pathway (Owen et al, 2013). FGF21 also has protective effects against various insults, including diabetes-induced cardiac cell death (Zhang et al, 2012a), glutamate-induced death of rat primary brain neurons (Leng et al, 2015), cardiac hypertrophy in mice (Planavila et al, 2013), sepsis toxicity in leptin-deficient ob/ob mice (Feingold et al, 2012), d-galactose-induced aging in mouse brain (Yu et al, 2015), and high glucose-induced damage and dysfunction in endothelial cells (Wang et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3

Leng

Wang

et al. 2016

IJNPPY

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Background:Fibroblast growth factor 21, a novel regulator of glucose and lipid metabolism, has robust protective properties in neurons. However, its expression and function in glia are unknown. Valproic acid, a mood stabilizer and anticonvulsant, is a histone deacetylase inhibitor and a dynamic gene regulator. We investigated whether histone deacetylase inhibition by valproic acid and other inhibitors upregulates fibroblast growth factor 21 expression and, if so, sought to identify the histone deacetylase isoform(s) involved and their role in altering glial cell morphology.Methods:C6 glioma or primary cortical glial cultures were treated with histone deacetylase inhibitors, and fibroblast growth factor 21 levels and length of cell processes were subsequently measured. Histone deacetylase 1, 2, or 3 was also knocked down to detect which isoform was involved in regulating fibroblast growth factor 21 mRNA levels. Finally, knockdown and overexpression of fibroblast growth factor 21 were performed to determine whether it played a role in regulating cell process length.Results:Treatment of C6 cells or primary glial cultures with valproic acid elevated fibroblast growth factor 21 mRNA levels, extended cell process length, and markedly increased acetylated histone-H3 levels. Other histone deacetylase inhibitors including pan- and class I-specific inhibitors, or selective knockdown of histone deacetylase 2 or 3 isoform produced similar effects. Knockdown or overexpression of fibroblast growth factor 21 significantly decreased or increased C6 cell process length, respectively.Conclusions:In glial cell line and primary glia, using pharmacological inhibition and selective gene silencing of histone deacetylases to boost fibroblast growth factor 21 mRNA levels results in elongation of cell processes. Our study provides a new mechanism via which histone deacetylase 2 and 3 participate in upregulating fibroblast growth factor 21 transcription and extending process outgrowth in glia.

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Section: Introductionmentioning

confidence: 99%

Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3

Leng

Wang

et al. 2016

IJNPPY

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“…Kuhla et al also showed that calorie-restriction, a most potent intervention to increase life time, induces ~20-folds increase of FGF21 mRNA and protein expression [48]. FGF21 also significantly protects mouse brain against d-galactose induced aging phenotypes by improving neurological performance in water maze task and step-down test [49]. More importantly, Sanchis-Gomar et al demonstrated that were serum FGF21 is independently associated with aging regardless of sex in a case-control study involving 81 old disease-free centenarians and 46 healthy elderly controls [50].…”

Section: Discussionmentioning

confidence: 97%

FGF21 represses cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 signaling pathway in an AMPK-dependent manner

Wang

Xiao

Ling-lin

et al. 2016

Experimental Cell Research

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“…D-galactose-induced aging mice, which were administrated with FGF21, had preserved cognitive function. This may be related to FGF21's ability to reduce brain cell damage in hippocampus by attenuating oxidative stress, increasing anti-oxidant activity, decreasing the enhanced total cholinesterase activity in the brain and reducing the expression of pro-inflammation cytokines such as IL-6 and TNF-α [63] [88].…”

Section: Discussionmentioning

confidence: 99%

“…In the brain of aging mice, FGF21could inhibit D-galactose-induced ROS production in a dose dependent manner [87], through preventing NF-κB nuclear translation and IκBα degradation [88]. Hence, as showed in Figure 2, FGF21 may ameliorate the oxidative stress of AD by enhancing the activities of SOD and reducing the production of ROS.…”

Section: Fgf21 and Oxidative Stressmentioning

confidence: 96%

“…This plays an essential role in the pathologic progress of AD. Recent work has shown that FGF21 participates in regulating oxidative stress [86] [87] [88]. It upregulated the expression of genes encoding proteins involved in antioxidative pathways, including mitochondrial uncoupling proteins (Ucp2 and Ucp3), superoxide dismutase-2 (Sod2), reduced ROS production in cardiomyocytes, and ameliorated cardiac tissue injury [86] [87].…”

Section: Fgf21 and Oxidative Stressmentioning

confidence: 99%

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Therapeutic Potential of FGF21 in Alzheimer’s Disease

Sun¹,

Xu²,

Wang³

et al. 2018

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Alzheimer's disease (AD) is the most common form of dementia which mostly affects persons younger than 65 years old. Mounting findings showed that amyloid-β (Aβ) peptides, oxidative stress, neuroinflammation and insulin resistance may play central role in the pathogenesis of AD. There are very many methods to slow it through affecting these aforementioned factors. However, more efficient prevention of the progression of AD is still ambiguous. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is expressed by several organs. It increases insulin sensitivity and regulates lipid metabolism and energy homeostasis. Emerging evidence demonstrates that FGF21 has potential effects in the brain involving metabolic regulation, neuroprotection and cognition. Hence, we hypothesize that FGF21 may be a protective factor in AD by attenuating Aβ generation, inflammation, oxidative stress, and insulin resistance. Our hypothesis will shed new light on the understanding of pathogenesis of AD and help to find a new way to prevent the genesis and progress of AD.

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Fibroblast growth factor 21 protects mouse brain against d-galactose induced aging via suppression of oxidative stress response and advanced glycation end products formation

Cited by 104 publications

References 46 publications

Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3

Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3

FGF21 represses cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 signaling pathway in an AMPK-dependent manner

Therapeutic Potential of FGF21 in Alzheimer’s Disease

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