Serendipitous Discovery of T Cell-Produced KLK1b22 as a Regulator of Systemic Metabolism.
Journal
ImmunoHorizons
ISSN: 2573-7732
Titre abrégé: Immunohorizons
Pays: United States
ID NLM: 101708159
Informations de publication
Date de publication:
01 06 2023
01 06 2023
Historique:
received:
10
03
2023
accepted:
05
06
2023
medline:
28
6
2023
pubmed:
26
6
2023
entrez:
26
6
2023
Statut:
ppublish
Résumé
In order to study mechanistic/mammalian target of rapamycin's role in T cell differentiation, we generated mice in which Rheb is selectively deleted in T cells (T-Rheb-/- C57BL/6J background). During these studies, we noted that T-Rheb-/- mice were consistently heavier but had improved glucose tolerance and insulin sensitivity as well as a marked increase in beige fat. Microarray analysis of Rheb-/- T cells revealed a marked increase in expression of kallikrein 1-related peptidase b22 (Klk1b22). Overexpression of KLK1b22 in vitro enhanced insulin receptor signaling, and systemic overexpression of KLK1b22 in C57BL/6J mice also enhances glucose tolerance. Although KLK1B22 expression was markedly elevated in the T-Rheb-/- T cells, we never observed any expression in wild-type T cells. Interestingly, in querying the mouse Immunologic Genome Project, we found that Klk1b22 expression was also increased in wild-type 129S1/SVLMJ and C3HEJ mice. Indeed, both strains of mice demonstrate exceptionally improved glucose tolerance. This prompted us to employ CRISPR-mediated knockout of KLK1b22 in 129S1/SVLMJ mice, which in fact led to reduced glucose tolerance. Overall, our studies reveal (to our knowledge) a novel role for KLK1b22 in regulating systemic metabolism and demonstrate the ability of T cell-derived KLK1b22 to regulate systemic metabolism. Notably, however, further studies have revealed that this is a serendipitous finding unrelated to Rheb.
Identifiants
pubmed: 37358498
pii: 265720
doi: 10.4049/immunohorizons.2300016
pmc: PMC10580127
doi:
Substances chimiques
Rheb protein, mouse
0
Klk1b22 protein, mouse
EC 3.4.99.-
Kallikreins
EC 3.4.21.-
Blood Glucose
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
493-507Subventions
Organisme : NIAID NIH HHS
ID : R01 AI077610
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136577
Pays : United States
Informations de copyright
Copyright © 2023 The Authors.
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