FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers

Leng, Yan; Wang, Zhifei; Tsai, Li-Kai; Leeds, Peter; Fessler, Emily; Wang, Junyu; Chuang, De‐Maw

doi:10.1038/mp.2013.192

Cited by 76 publications

(80 citation statements)

References 41 publications

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“…We also demonstrated that activation of the cell survival factor Akt-1 occurs upstream and downstream of FGF-21 and that both protein molecules are involved in the synergistic neuroprotective effects of VPA/lithium cotreatment in aging primary neurons (Leng et al, 2015). Interestingly, treatment of primary neurons with lithium produces small but significant effects on FGF21 expression, while VPA and other related HDAC inhibitors alone are ineffective in inducing FGF21.…”

Section: Introductionmentioning

confidence: 79%

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: 79%

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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“…5C). As a positive control we also tested if FGF21 activated AKT/ERK survival signaling at 37°C as previously reported in neurons (Leng et al, 2015). Paradoxically, AKT/ERK phosphorylation was decreased 24h later potentially suggesting feedback inhibition (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons

et al. 2015

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Extremely mild hypothermia to 36.0°C is not thought to appreciably differ clinically from 37.0°C. However, it is possible that 36.0°C stimulates highly sensitive hypothermic signaling mechanism(s) and alters biochemistry. To the best of our knowledge, no such ultra-sensitive pathway/mechanisms have been described. Here we show that cold stress protein RNA Binding motif 3 (RBM3) increases in neuron and astrocyte cultures maintained at 33°C or 36°C for 24 or 48h, compared to 37°C controls. Neurons cultured at 36°C also had increased global protein synthesis (GPS). Finally, we found that melatonin or fibroblast growth factor 21 (FGF21) augmented RBM3 upregulation in young neurons cooled to 36°C. Our results show that a 1°C reduction in temperature can induce pleiotropic biochemical changes by upregulating GPS in neurons which may be mediated by RBM3 and that this process can be pharmacologically mimicked and enhanced with melatonin or FGF21.

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“…FGF21 also has a strong neuroprotective role and may act on mood and other cognitive systems [103]. FGF21 appears to modulate circadian behaviors and suppress physical activity through its actions on the central nervous system [104].…”

Section: Modifiers Of Leptinmentioning

confidence: 99%

Leptin and the brain: Influences on brain development, cognitive functioning and psychiatric disorders

2015

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FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers

Cited by 76 publications

References 41 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

Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons

Leptin and the brain: Influences on brain development, cognitive functioning and psychiatric disorders

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