KLF10 Deficiency in CD4+ T Cells Triggers Obesity, Insulin Resistance, and Fatty Liver

Wara, Akm Khyrul; Wang, Shijia; Wu, Chun; Fang, Fang; Haemmig, Stefan; Weber, Brittany; Aydogan, Ceren O.; Tesmenitsky, Yevgenia; Aliakbarian, Hassan; Hawse, John R.; Subramaniam, Malayannan; Zhao, Lei; Sage, Peter T.; Tavakkoli, Ali; Garza, Amanda E; Lynch, Lydia; Banks, Alexander S.; Feinberg, Mark W.

doi:10.1016/j.celrep.2020.108550

Cited by 35 publications

(38 citation statements)

References 84 publications

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“…To evaluate the role of KLF10 in CD4+ T cells in Ang II-induced vascular remodeling, CD4-targeted KLF10 deficient ( Klf10 fl/fl CD4 Cre+ , [TKO]) and CD4-Cre ( Klf10 +l+ CD4 Cre+ , [Cre]) control mice 13 were infused with PBS or Ang II for 28 or 42 days (Figure 2A). Aortic blood pressure increased in the Ang II treatment groups compared with PBS controls; however, no difference was found between TKO and Cre control mice in both 28 days and 42 days (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

“…Considering KLF10 is a putative regulator of TGF (transforming growth factor)-β signaling in specific disease states, 12,13 we evaluated the expression of TGF-β isoforms in plasma. There were no differences in TGF-β1 or TGF-β2 in plasma between KO and Cre control mice treated with Ang II (Figure S7A).…”

Section: Resultsmentioning

confidence: 99%

“…These findings build upon a broader role for KLF10 in CD4+ T cells in a range of chronic inflammatory disease states including atherosclerosis, insulin resistance, and fatty liver disease. 12,13…”

Section: Discussionmentioning

confidence: 99%

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Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Zhuang

Chen

Cheng

et al. 2022

Circulation Research

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BACKGROUND: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. METHODS: TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient ( Klf10 fl/fl CD4 Cre+ ; [TKO]) and CD4-Cre ( Klf10 +/+ CD4 Cre+ ; (Cre)) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing. RESULTS: TF profiling identified increased KLF10 expression in hypertensive human subjects and in CD4+ T cells in Ang II-treated mice. TKO mice showed enhanced perivascular fibrosis, but not interstitial fibrosis, in aorta, heart, and kidney in response to Ang II, accompanied by alterations in global longitudinal strain, arterial stiffness, and kidney function compared with Cre control mice. However, blood pressure was unchanged between the 2 groups. Mechanistically, KLF10 bound to the IL (interleukin)-9 promoter and interacted with HDAC1 (histone deacetylase 1) inhibit IL-9 transcription. Increased IL-9 in TKO mice induced fibroblast intracellular calcium mobilization, fibroblast activation, and differentiation and increased production of collagen and extracellular matrix, thereby promoting the progression of perivascular fibrosis and impairing target organ function. Remarkably, injection of anti-IL9 antibodies reversed perivascular fibrosis in Ang II-infused TKO mice and C57BL/6 mice. Single-cell RNA-sequencing revealed fibroblast heterogeneity with activated signatures associated with robust ECM (extracellular matrix) and perivascular fibrosis in Ang II-treated TKO mice. CONCLUSIONS: CD4+ T cell deficiency of Klf10 exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9. Klf10 or IL-9 in T cells might represent novel therapeutic targets for treatment of vascular or fibrotic diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Zhuang

Chen

Cheng

et al. 2022

Circulation Research

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“…KLF14 mRNA and protein levels in fat and muscle of high-fat db/db mice were significantly reduced after intervention; overexpression of LF14 enhanced insulin-stimulated glucose uptake and Akt activation in cells ( Yang et al, 2015 ). KLF10 is expressed in mouse CD4 T cells and can promote the activation of Akt, thereby regulating glucose and lipid metabolism ( Wara et al, 2020 ). KLF4 can induce TCL1 and activate AKT, enhancing glycolysis ( Nishimura et al, 2017 ).…”

Section: Akt-related Genetic Factors For Metabolic Syndromementioning

confidence: 99%

Akt: A Potential Drug Target for Metabolic Syndrome

et al. 2022

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The serine/threonine kinase Akt, also known as protein kinase B (PKB), is one of the key factors regulating glucose and lipid energy metabolism, and is the core focus of current research on diabetes and metabolic diseases. Akt is mostly expressed in key metabolism-related organs and it is activated in response to various stimuli, including cell stress, cell movement, and various hormones and drugs that affect cell metabolism. Genetic and pharmacological studies have shown that Akt is necessary to maintain the steady state of glucose and lipid metabolism and a variety of cellular responses. Existing evidence shows that metabolic syndrome is related to insulin resistance and lipid metabolism disorders. Based on a large number of studies on Akt-related pathways and reactions, we believe that Akt can be used as a potential drug target to effectively treat metabolic syndrome.

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“…Though predominantly focussed on adipose tissue, the role of Tregs in the regulation of metabolic homeostasis has become controversial over recent years. Seminal work revealed that adipose tissue Tregs are lost during obesity (11,43), and replenishing the Treg pool through IL-33 treatment or adoptive transfer reduced adipose tissue inflammation and improved metabolic homeostasis (44,45). However, aging-associated insulin resistance is ameliorated after depletion of adipose tissue Tregs (46), and deletion of the insulin receptor, IL-10 and the transcription factor Blimp1 from Tregs all prevented insulin resistance, in part through promoting adaptive thermogenesis (47,48).…”

Section: Deletion Of Lkb1 From Dcs Increased Hepatic Tregs and Th17 Cells In Obese Micementioning

confidence: 99%

LKB1 signalling in dendritic cells controls whole-body metabolic homeostasis by limiting T helper 17 priming

Zande

Brombacher

Lambooij

et al. 2021

Preprint

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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.

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KLF10 Deficiency in CD4+ T Cells Triggers Obesity, Insulin Resistance, and Fatty Liver

Cited by 35 publications

References 84 publications

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Akt: A Potential Drug Target for Metabolic Syndrome

LKB1 signalling in dendritic cells controls whole-body metabolic homeostasis by limiting T helper 17 priming

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