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LKB1 signalling in dendritic cells controls whole-body metabolic homeostasis by limiting T helper 17 priming
- Publication Year :
- 2021
- Publisher :
- Cold Spring Harbor Laboratory, 2021.
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Abstract
- Obesity-associated metaflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of dendritic cells (DCs). Here, we report that hepatic DCs from high-fat diet (HFD)-fed obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11cΔLKB1) worsened HFD-driven hepatic steatosis, systemic insulin resistance and glucose intolerance. Loss of LKB1 in DCs was associated with increased cellular expression of Th17-polarizing cytokines and increased hepatic CD4+ IL-17A+ Th17 cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11cΔLKB1 mice. Mechanistically, disrupted metabolic homeostasis was independent of the canonical LKB1-AMPK axis. Instead, we provide evidence for involvement of the AMPK-related salt-inducible kinase(s) in controlling Th17-polarizing cytokine expression in LKB1-deficient DCs. Altogether, our data reveal a key role for LKB1 signalling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 differentiation.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
Kinase
T cell
Priming (immunology)
chemical and pharmacologic phenomena
Type 2 diabetes
Biology
medicine.disease
Cell biology
Insulin resistance
medicine.anatomical_structure
Immune system
medicine
Phosphorylation
Steatosis
skin and connective tissue diseases
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........bd7b4fc4fe7452e3b37ed3fdd38a9a0d