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

Fibroblast growth factor-21 (FGF-21) is a new member of the FGF super-family and an important endogenous regulator of glucose and lipid metabolism. It has been proposed as a therapeutic target for diabetes and obesity. Its function in the central nervous system (CNS) remains unknown. Previous studie...

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Veröffentlicht in:Molecular psychiatry 2015-02, Vol.20 (2), p.215-223
Hauptverfasser: Leng, Y, Wang, Z, Tsai, L-K, Leeds, P, Fessler, E B, Wang, J, Chuang, D-M
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container_issue 2
container_start_page 215
container_title Molecular psychiatry
container_volume 20
creator Leng, Y
Wang, Z
Tsai, L-K
Leeds, P
Fessler, E B
Wang, J
Chuang, D-M
description Fibroblast growth factor-21 (FGF-21) is a new member of the FGF super-family and an important endogenous regulator of glucose and lipid metabolism. It has been proposed as a therapeutic target for diabetes and obesity. Its function in the central nervous system (CNS) remains unknown. Previous studies from our laboratory demonstrated that aging primary neurons are more vulnerable to glutamate-induced excitotoxicity, and that co-treatment with the mood stabilizers lithium and valproic acid (VPA) induces synergistic neuroprotective effects. This study sought to identify molecule(s) involved in these synergistic effects. We found that FGF-21 mRNA was selectively and markedly elevated by co-treatment with lithium and VPA in primary rat brain neurons. FGF-21 protein levels were also robustly increased in neuronal lysates and culture medium following lithium-VPA co-treatment. Combining glycogen synthase kinase-3 (GSK-3) inhibitors with VPA or histone deacetylase (HDAC) inhibitors with lithium synergistically increased FGF-21 mRNA levels, supporting that synergistic effects of lithium and VPA are mediated via GSK-3 and HDAC inhibition, respectively. Exogenous FGF-21 protein completely protected aging neurons from glutamate challenge. This neuroprotection was associated with enhanced Akt-1 activation and GSK-3 inhibition. Lithium-VPA co-treatment markedly prolonged lithium-induced Akt-1 activation and augmented GSK-3 inhibition. Akt-1 knockdown markedly decreased FGF-21 mRNA levels and reduced the neuroprotection induced by FGF-21 or lithium-VPA co-treatment. In addition, FGF-21 knockdown reduced lithium-VPA co-treatment-induced Akt-1 activation and neuroprotection against excitotoxicity. Together, our novel results suggest that FGF-21 is a key mediator of the effects of these mood stabilizers and a potential new therapeutic target for CNS disorders.
doi_str_mv 10.1038/mp.2013.192
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Combining glycogen synthase kinase-3 (GSK-3) inhibitors with VPA or histone deacetylase (HDAC) inhibitors with lithium synergistically increased FGF-21 mRNA levels, supporting that synergistic effects of lithium and VPA are mediated via GSK-3 and HDAC inhibition, respectively. Exogenous FGF-21 protein completely protected aging neurons from glutamate challenge. This neuroprotection was associated with enhanced Akt-1 activation and GSK-3 inhibition. Lithium-VPA co-treatment markedly prolonged lithium-induced Akt-1 activation and augmented GSK-3 inhibition. Akt-1 knockdown markedly decreased FGF-21 mRNA levels and reduced the neuroprotection induced by FGF-21 or lithium-VPA co-treatment. In addition, FGF-21 knockdown reduced lithium-VPA co-treatment-induced Akt-1 activation and neuroprotection against excitotoxicity. 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It has been proposed as a therapeutic target for diabetes and obesity. Its function in the central nervous system (CNS) remains unknown. Previous studies from our laboratory demonstrated that aging primary neurons are more vulnerable to glutamate-induced excitotoxicity, and that co-treatment with the mood stabilizers lithium and valproic acid (VPA) induces synergistic neuroprotective effects. This study sought to identify molecule(s) involved in these synergistic effects. We found that FGF-21 mRNA was selectively and markedly elevated by co-treatment with lithium and VPA in primary rat brain neurons. FGF-21 protein levels were also robustly increased in neuronal lysates and culture medium following lithium-VPA co-treatment. 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Combining glycogen synthase kinase-3 (GSK-3) inhibitors with VPA or histone deacetylase (HDAC) inhibitors with lithium synergistically increased FGF-21 mRNA levels, supporting that synergistic effects of lithium and VPA are mediated via GSK-3 and HDAC inhibition, respectively. Exogenous FGF-21 protein completely protected aging neurons from glutamate challenge. This neuroprotection was associated with enhanced Akt-1 activation and GSK-3 inhibition. Lithium-VPA co-treatment markedly prolonged lithium-induced Akt-1 activation and augmented GSK-3 inhibition. Akt-1 knockdown markedly decreased FGF-21 mRNA levels and reduced the neuroprotection induced by FGF-21 or lithium-VPA co-treatment. In addition, FGF-21 knockdown reduced lithium-VPA co-treatment-induced Akt-1 activation and neuroprotection against excitotoxicity. Together, our novel results suggest that FGF-21 is a key mediator of the effects of these mood stabilizers and a potential new therapeutic target for CNS disorders.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24468826</pmid><doi>10.1038/mp.2013.192</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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1476-5578
language eng
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source MEDLINE; Springer Nature - Complete Springer Journals
subjects 631/378/340
692/699/375
692/700/565/1436
Activation
Aging
AKT protein
AKT1 protein
Animals
Animals, Newborn
Antidepressants
Antimanic Agents - pharmacology
Behavioral Sciences
Biological Psychology
Brain-derived neurotrophic factor
Cardiovascular disease
Cells, Cultured
Central nervous system
Cerebral Cortex - cytology
Diabetes
Diabetes mellitus
Drug Synergism
Excitatory Amino Acid Agonists - toxicity
Excitotoxicity
Fibroblast growth factors
Fibroblast Growth Factors - metabolism
Fibroblast Growth Factors - pharmacology
Gene Expression Regulation - drug effects
Glucose metabolism
Glutamic Acid - toxicity
Glycogen
Glycogen synthase kinase 3
Glycogen Synthase Kinase 3 - metabolism
Glycogens
Growth factors
Health aspects
Hippocampus - cytology
Histone deacetylase
Inhibitors
Insulin resistance
Kinases
Lipid metabolism
Lithium
Lithium - pharmacology
Lysates
Male
Medicine
Medicine & Public Health
Mental health
Metabolic disorders
Mice
Mood
mRNA
Nervous system
Neurobiology
Neurons
Neurons - drug effects
Neuroprotection
Neuroprotective Agents - metabolism
Neuroprotective Agents - pharmacology
Neurosciences
Obesity
Oncogene Protein v-akt - genetics
Oncogene Protein v-akt - metabolism
original-article
Pharmacotherapy
Physiological aspects
Proteins
Psychiatry
Psychotropic drugs
Rats
Rats, Sprague-Dawley
Synergistic effect
Therapeutic applications
Transduction, Genetic
Valproic acid
Valproic Acid - pharmacology
Weight control
title FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers
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