Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance
Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neu...
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doaj-8247097d318f467180201c55d6534dc42021-03-22T12:48:00ZengElsevierNeurobiology of Disease1095-953X2019-07-01127350361Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistanceHuanxian Chang0Tingting Di1Ya Wang2Xianying Zeng3Guoxi Li4Qi Wan5Wenfeng Yu6Ling Chen7State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, ChinaState Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Physiology, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Physiology, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Geratology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, ChinaDepartment of Physiology, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Neurology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, ChinaKey Laboratory of Endemic and Ethnic Diseases of Education Ministry, Guizhou Medical University, Guian New District, Guizhou 550025, China; Correspondence to: W. Yu, Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guiyang 550004, Guizhou, China.State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Physiology, Nanjing Medical University, Nanjing 211166, China; Correspondence to: L. Chen, State Key Lab of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Tianyuan East Road 818, Nanjing 211166, China.Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neurons express seipin protein. This study aimed to investigate the influence of systemic seipin knockout (seipin-sKO), neuronal seipin knockout (seipin-nKO) or adipose seipin knockout (seipin-aKO) in hippocampal tau phosphorylation and aggregation. Levels of tau phosphorylation at Thr212/Ser214 and Ser202/Thr205 and oligomer tau protein were increased in seipin-sKO mice and seipin-nKO mice with a decrease in axonal density and expression of PPARγ. Neuronal seipin deletion increased activities of GSK3β and Akt/mTOR signaling, which were corrected by the administration of PPARγ agonist rosiglitazone for 7 days. The autophagosome formation was reduced in seipin-sKO mice and seipin-nKO mice, which was rescued by the Akt and mTOR inhibitors. The administration of rosiglitazone or Akt, mTOR and GSK3β inhibitors for 7 days could correct the hyperphosphorylation and aggregation of tau. On the other hand, seipin-sKO mice appeared insulin resistance and an increase in phosphorylation of tau at Ser396 and JNK, which were corrected by treatment with rosiglitazone for 30 days rather than 7 days. Inhibition of JNK in seipin-sKO mice corrected the hyperphosphorylated tau at Ser396. The results indicate that neuronal seipin deletion causes hyperphosphorylation and aggregation of tau protein leading to axonal atrophy through reduced PPARγ to enhance GSK3β and Akt/mTOR signaling; systemic seipin deletion-induced insulin resistance causes tau hyperphosphorylation via cascading JNK pathway.http://www.sciencedirect.com/science/article/pii/S0969996119300762SeipinTau phosphorylationPeroxisome proliferator-activated receptor-γ (PPARγ)GSK3βMammalian target of rapamycin (mTOR)Insulin resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Huanxian Chang Tingting Di Ya Wang Xianying Zeng Guoxi Li Qi Wan Wenfeng Yu Ling Chen |
spellingShingle |
Huanxian Chang Tingting Di Ya Wang Xianying Zeng Guoxi Li Qi Wan Wenfeng Yu Ling Chen Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance Neurobiology of Disease Seipin Tau phosphorylation Peroxisome proliferator-activated receptor-γ (PPARγ) GSK3β Mammalian target of rapamycin (mTOR) Insulin resistance |
author_facet |
Huanxian Chang Tingting Di Ya Wang Xianying Zeng Guoxi Li Qi Wan Wenfeng Yu Ling Chen |
author_sort |
Huanxian Chang |
title |
Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance |
title_short |
Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance |
title_full |
Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance |
title_fullStr |
Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance |
title_full_unstemmed |
Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance |
title_sort |
seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal pparγ and insulin resistance |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2019-07-01 |
description |
Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neurons express seipin protein. This study aimed to investigate the influence of systemic seipin knockout (seipin-sKO), neuronal seipin knockout (seipin-nKO) or adipose seipin knockout (seipin-aKO) in hippocampal tau phosphorylation and aggregation. Levels of tau phosphorylation at Thr212/Ser214 and Ser202/Thr205 and oligomer tau protein were increased in seipin-sKO mice and seipin-nKO mice with a decrease in axonal density and expression of PPARγ. Neuronal seipin deletion increased activities of GSK3β and Akt/mTOR signaling, which were corrected by the administration of PPARγ agonist rosiglitazone for 7 days. The autophagosome formation was reduced in seipin-sKO mice and seipin-nKO mice, which was rescued by the Akt and mTOR inhibitors. The administration of rosiglitazone or Akt, mTOR and GSK3β inhibitors for 7 days could correct the hyperphosphorylation and aggregation of tau. On the other hand, seipin-sKO mice appeared insulin resistance and an increase in phosphorylation of tau at Ser396 and JNK, which were corrected by treatment with rosiglitazone for 30 days rather than 7 days. Inhibition of JNK in seipin-sKO mice corrected the hyperphosphorylated tau at Ser396. The results indicate that neuronal seipin deletion causes hyperphosphorylation and aggregation of tau protein leading to axonal atrophy through reduced PPARγ to enhance GSK3β and Akt/mTOR signaling; systemic seipin deletion-induced insulin resistance causes tau hyperphosphorylation via cascading JNK pathway. |
topic |
Seipin Tau phosphorylation Peroxisome proliferator-activated receptor-γ (PPARγ) GSK3β Mammalian target of rapamycin (mTOR) Insulin resistance |
url |
http://www.sciencedirect.com/science/article/pii/S0969996119300762 |
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