Cargando…

Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments

Background and Aims: A compromise in intestinal mucosal functions is associated with several chronic inflammatory diseases. Previously, we reported that obese humans have a reduced expression of intestinal Janus kinase-3 (Jak3), a non-receptor tyrosine kinase, and a deficiency of Jak3 in mice led to...

Descripción completa

Detalles Bibliográficos
Autores principales: Kumar, Premranjan, Mishra, Jayshree, Kumar, Narendra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9505565/
https://www.ncbi.nlm.nih.gov/pubmed/36145091
http://dx.doi.org/10.3390/nu14183715
_version_ 1784796504321425408
author Kumar, Premranjan
Mishra, Jayshree
Kumar, Narendra
author_facet Kumar, Premranjan
Mishra, Jayshree
Kumar, Narendra
author_sort Kumar, Premranjan
collection PubMed
description Background and Aims: A compromise in intestinal mucosal functions is associated with several chronic inflammatory diseases. Previously, we reported that obese humans have a reduced expression of intestinal Janus kinase-3 (Jak3), a non-receptor tyrosine kinase, and a deficiency of Jak3 in mice led to predisposition to obesity-associated metabolic syndrome. Since meta-analyses show cognitive impairment as co-morbidity of obesity, the present study demonstrates the mechanistic role of Jak3 in obesity associated cognitive impairment. Our data show that high-fat diet (HFD) suppresses Jak3 expression both in intestinal mucosa and in the brain of wild-type mice. Methodology: Recapitulating these conditions using global (Jak3-KO) and intestinal epithelial cell-specific conditional (IEC-Jak3-KO) mice and using cognitive testing, western analysis, flow cytometry, immunofluorescence microscopy and 16s rRNA sequencing, we demonstrate that HFD-induced Jak3 deficiency is responsible for cognitive impairments in mice, and these are, in part, specifically due to intestinal epithelial deficiency of Jak3. Results: We reveal that Jak3 deficiency leads to gut dysbiosis, compromised TREM-2-functions-mediated activation of microglial cells, increased TLR-4 expression and HIF1-α-mediated inflammation in the brain. Together, these lead to compromised microglial-functions-mediated increased deposition of β-amyloid (Aβ) and hyperphosphorylated Tau (pTau), which are responsible for cognitive impairments. Collectively, these data illustrate how the drivers of obesity promote cognitive impairment and demonstrate the underlying mechanism where HFD-mediated impact on IEC-Jak3 deficiency is responsible for Jak3 deficiency in the brain, reduced microglial TREM2 expression, microglial activation and compromised clearance of Aβ and pTau as the mechanism during obesity-associated cognitive impairments. Conclusion: Thus, we not only demonstrate the mechanism of obesity-associated cognitive impairments but also characterize the tissue-specific role of Jak3 in such conditions through mucosal tolerance, gut–brain axis and regulation of microglial functions.
format Online
Article
Text
id pubmed-9505565
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-95055652022-09-24 Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments Kumar, Premranjan Mishra, Jayshree Kumar, Narendra Nutrients Article Background and Aims: A compromise in intestinal mucosal functions is associated with several chronic inflammatory diseases. Previously, we reported that obese humans have a reduced expression of intestinal Janus kinase-3 (Jak3), a non-receptor tyrosine kinase, and a deficiency of Jak3 in mice led to predisposition to obesity-associated metabolic syndrome. Since meta-analyses show cognitive impairment as co-morbidity of obesity, the present study demonstrates the mechanistic role of Jak3 in obesity associated cognitive impairment. Our data show that high-fat diet (HFD) suppresses Jak3 expression both in intestinal mucosa and in the brain of wild-type mice. Methodology: Recapitulating these conditions using global (Jak3-KO) and intestinal epithelial cell-specific conditional (IEC-Jak3-KO) mice and using cognitive testing, western analysis, flow cytometry, immunofluorescence microscopy and 16s rRNA sequencing, we demonstrate that HFD-induced Jak3 deficiency is responsible for cognitive impairments in mice, and these are, in part, specifically due to intestinal epithelial deficiency of Jak3. Results: We reveal that Jak3 deficiency leads to gut dysbiosis, compromised TREM-2-functions-mediated activation of microglial cells, increased TLR-4 expression and HIF1-α-mediated inflammation in the brain. Together, these lead to compromised microglial-functions-mediated increased deposition of β-amyloid (Aβ) and hyperphosphorylated Tau (pTau), which are responsible for cognitive impairments. Collectively, these data illustrate how the drivers of obesity promote cognitive impairment and demonstrate the underlying mechanism where HFD-mediated impact on IEC-Jak3 deficiency is responsible for Jak3 deficiency in the brain, reduced microglial TREM2 expression, microglial activation and compromised clearance of Aβ and pTau as the mechanism during obesity-associated cognitive impairments. Conclusion: Thus, we not only demonstrate the mechanism of obesity-associated cognitive impairments but also characterize the tissue-specific role of Jak3 in such conditions through mucosal tolerance, gut–brain axis and regulation of microglial functions. MDPI 2022-09-09 /pmc/articles/PMC9505565/ /pubmed/36145091 http://dx.doi.org/10.3390/nu14183715 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kumar, Premranjan
Mishra, Jayshree
Kumar, Narendra
Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments
title Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments
title_full Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments
title_fullStr Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments
title_full_unstemmed Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments
title_short Mechanistic Role of Jak3 in Obesity-Associated Cognitive Impairments
title_sort mechanistic role of jak3 in obesity-associated cognitive impairments
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9505565/
https://www.ncbi.nlm.nih.gov/pubmed/36145091
http://dx.doi.org/10.3390/nu14183715
work_keys_str_mv AT kumarpremranjan mechanisticroleofjak3inobesityassociatedcognitiveimpairments
AT mishrajayshree mechanisticroleofjak3inobesityassociatedcognitiveimpairments
AT kumarnarendra mechanisticroleofjak3inobesityassociatedcognitiveimpairments