Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2

Abstract Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEB...

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Autores principales:	Eun Ae Jeong, Jaewoong Lee, Hyun Joo Shin, Jong Youl Lee, Kyung Eun Kim, Hyeong Seok An, Deok Ryong Kim, Kyu Yeong Choi, Kun Ho Lee, Gu Seob Roh
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	TonEBP Lipocalin-2 Neuroinflammation Hippocampus Diabetes Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/e9976abfada3468c8aeb352b2c71aff3
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spelling	oai:doaj.org-article:e9976abfada3468c8aeb352b2c71aff32021-12-05T12:24:01ZTonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-210.1186/s12974-021-02331-81742-2094https://doaj.org/article/e9976abfada3468c8aeb352b2c71aff32021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02331-8https://doaj.org/toc/1742-2094Abstract Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. Methods We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell’ medium/HG-treated mouse hippocampal HT22 cells. Results Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood–brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / −) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. Conclusions These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.Eun Ae JeongJaewoong LeeHyun Joo ShinJong Youl LeeKyung Eun KimHyeong Seok AnDeok Ryong KimKyu Yeong ChoiKun Ho LeeGu Seob RohBMCarticleTonEBPLipocalin-2NeuroinflammationHippocampusDiabetesNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TonEBP Lipocalin-2 Neuroinflammation Hippocampus Diabetes Neurology. Diseases of the nervous system RC346-429
spellingShingle	TonEBP Lipocalin-2 Neuroinflammation Hippocampus Diabetes Neurology. Diseases of the nervous system RC346-429 Eun Ae Jeong Jaewoong Lee Hyun Joo Shin Jong Youl Lee Kyung Eun Kim Hyeong Seok An Deok Ryong Kim Kyu Yeong Choi Kun Ho Lee Gu Seob Roh Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
description	Abstract Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. Methods We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell’ medium/HG-treated mouse hippocampal HT22 cells. Results Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood–brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / −) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. Conclusions These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.
format	article
author	Eun Ae Jeong Jaewoong Lee Hyun Joo Shin Jong Youl Lee Kyung Eun Kim Hyeong Seok An Deok Ryong Kim Kyu Yeong Choi Kun Ho Lee Gu Seob Roh
author_facet	Eun Ae Jeong Jaewoong Lee Hyun Joo Shin Jong Youl Lee Kyung Eun Kim Hyeong Seok An Deok Ryong Kim Kyu Yeong Choi Kun Ho Lee Gu Seob Roh
author_sort	Eun Ae Jeong
title	Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
title_short	Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
title_full	Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
title_fullStr	Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
title_full_unstemmed	Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
title_sort	tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
publisher	BMC
publishDate	2021
url	https://doaj.org/article/e9976abfada3468c8aeb352b2c71aff3
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Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2

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