Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization.
Leptin plays a pivotal role in the regulation of energy homeostasis and metabolism, primarily by acting on neurons in the hypothalamus that control food intake. However, leptin receptors are more widely expressed in the brain suggesting additional, as yet unknown, functions of leptin. Here we show that both embryonic and adult hippocampal neurons express leptin receptors coupled to activation of STAT3 and phosphatidylinositol 3-kinase-Akt signaling pathways. Leptin protects hippocampal neurons against cell death induced by neurotrophic factor withdrawal and excitotoxic and oxidative insults. The neuroprotective effect of leptin is antagonized by the JAK2-STAT3 inhibitor AG-490, STAT3 decoy DNA, and phosphatidylinositol 3-kinase/Akt inhibitors but not by an inhibitor of MAPK. Leptin induces the production of manganese superoxide dismutase and the anti-apoptotic protein Bcl-xL, and stabilizes mitochondrial membrane potential and lessens mitochondrial oxidative stress. Leptin receptor-deficient mice (db/db mice) are more vulnerable to seizure-induced hippocampal damage, and intraventricular administration of leptin protects neurons against seizures. By enhancing mitochondrial resistance to apoptosis and excitotoxicity, our findings suggest that leptin signaling serves a neurotrophic function in the developing and adult hippocampus.
Guo
Zhihong
Z
Laboratory of Neurosciences and National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
Jiang
Haiyang
H
Laboratory of Neurosciences and National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
Xu
Xiangru
X
Laboratory of Neurosciences and National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
Duan
Wenzhen
W
Laboratory of Neurosciences and National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.
Mattson
Mark P
MP
Laboratory of Neurosciences and National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224; Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. Electronic address: mattsonm@grc.nia.nih.gov.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D053612:Janus Kinases / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
D020738:Leptin; D018696:Neuroprotective Agents; D009498:Neurotoxins; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D051020:bcl-X Protein; D013482:Superoxide Dismutase; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt