Dendritic cell–intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity

• Published in: JCI insight Vol. 8; no. 11
• Main Authors: van der Zande, Hendrik J.P., Brombacher, Eline C., Lambooij, Joost M., Pelgrom, Leonard R., Zawistowska-Deniziak, Anna, Patente, Thiago A., Heieis, Graham A., Otto, Frank, Ozir-Fazalalikhan, Arifa, Yazdanbakhsh, Maria, Everts, Bart, Guigas, Bruno
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08.06.2023; American Society for Clinical investigation
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Dendritic Cells - metabolism; Diabetes Mellitus, Type 2 - metabolism; Homeostasis; Immunology; Interleukin-17 - metabolism; Liver - metabolism; Metabolism; Mice; Obesity - metabolism; Protein Serine-Threonine Kinases - metabolism; Obesity; Immunology; Dendritic cells; Metabolism; T cells
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.157948

Obesity-associated metabolic inflammation 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 DCs. Here, we report that hepatic DCs from high-fat diet-fed (HFD-fed) obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11cΔLKB1) worsened HFD-driven hepatic steatosis and impaired glucose homeostasis. Loss of LKB1 in DCs was associated with increased expression of Th17-polarizing cytokines and accumulation of hepatic IL-17A+ Th cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11cΔLKB1 mice. Mechanistically, deficiency of the canonical LKB1 target AMPK in HFD-fed CD11cΔAMPKα1 mice recapitulated neither the hepatic Th17 phenotype nor the disrupted metabolic homeostasis, suggesting the involvement of other and/or additional LKB1 downstream effectors. We indeed provide evidence that the control of Th17 responses by DCs via LKB1 is actually dependent on both AMPKα1 salt-inducible kinase signaling. Altogether, our data reveal a key role for LKB1 signaling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 responses.