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 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.
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Y
Y
Leng
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Z
Z
Wang
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
L-K
LK
Tsai
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
P
P
Leeds
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
E B
EB
Fessler
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
J
J
Wang
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
D-M
DM
Chuang
D000818:Animals; D000831:Animals, Newborn; D018692:Antimanic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic; D014635:Valproic Acid / Q000494:pharmacology
D018692:Antimanic Agents; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; C414620:fibroblast growth factor 21; D018698:Glutamic Acid; D014635:Valproic Acid; D005346:Fibroblast Growth Factors; D008094:Lithium; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3