Foxc2 coordinates inflammation and browning of white adipose by leptin-STAT3-PRDM16 signal in mice

Gan, Lu; Liu, Z; Fu, Feng; Wu, Tianjiao; Luo, Dan; Hu, Chen; Sun, Cheng

doi:10.1038/ijo.2017.208

Cited by 41 publications

(40 citation statements)

References 44 publications

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“…For the lipopolysaccharide (LPS) challenged experiment in vivo, mice were challenged via intraperitoneal (ip) injection with the indicated quantities of LPS (75 μg/kg, Sigma-Aldrich, St. Louis, MO, USA) in PBS for 24 hours. 39 For diet-induced obese mice model, mice were placed on a high-fat diet (HFD, fat provided 60% of the total energy, Trophic animal feed high-tech co., Ltd, Nantong, China) for 10 weeks, and the control mice were fed a standard diet (Chow, fat provided 10% of total energy, Trophic animal feed high-tech co., Ltd). Melatonin injection was performed from then on at a dose of 20 mg/kg/d for 14 days continually.…”

Section: Animal Studiesmentioning

confidence: 99%

Melatonin alleviates adipose inflammation through elevating α‐ketoglutarate and diverting adipose‐derived exosomes to macrophages in mice

Liu

Gan

Zhang

et al. 2017

Journal of Pineal Research

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139

108

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Obesity is associated with macrophage infiltration and metabolic inflammation, both of which promote metabolic disease progression. Melatonin is reported to possess anti-inflammatory properties by inhibiting inflammatory response of adipocytes and macrophages activation. However, the effects of melatonin on the communication between adipocytes and macrophages during adipose inflammation remain elusive.Here, we demonstrated melatonin alleviated inflammation and elevated α-ketoglutarate (αKG) level in adipose tissue of obese mice. Mitochondrial isocitrate dehydrogenase 2 (Idh2) mRNA level was also elevated by melatonin in adipocytes leading to increase αKG level. Further analysis revealed αKG was the target for melatonin inhibition of adipose inflammation. Moreover, sirtuin 1 (Sirt1) physically interacted with IDH2 and formed a complex to increase the circadian amplitude of Idh2 and αKG content in melatonin-inhibited adipose inflammation. Notably, melatonin promoted exosomes secretion from adipocyte and increased adipose-derived exosomal αKG level. Our results also confirmed that melatonin alleviated adipocyte inflammation and increased ratio of M2 to M1 macrophages by transporting of exosomal αKG to macrophages and promoting TET-mediated DNA demethylation.Furthermore, exosomal αKG attenuated signal transducers and activators of transduction-3 (STAT3)/NF-κB signal by its receptor oxoglutarate receptor 1 (OXGR1) in adipocytes. Melatonin also attenuated adipose inflammation and deceased macrophage number in chronic jet-lag mice. In summary, our results demonstrate melatonin alleviates metabolic inflammation by increasing cellular and exosomal αKG level in adipose tissue. Our data reveal a novel function of melatonin on adipocytes and macrophages communication, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory disease.

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Section: Animal Studiesmentioning

confidence: 99%

Melatonin alleviates adipose inflammation through elevating α‐ketoglutarate and diverting adipose‐derived exosomes to macrophages in mice

Liu

Gan

Zhang

et al. 2017

Journal of Pineal Research

Self Cite

139

108

View full text Add to dashboard Cite

show abstract

“…Few data are available on the activity of Foxc2 on monocyte adhesion to endothelial cells and the progression of atherosclerosis. Foxc2 has been found to promote adipocyte browning through inflammation and enhanced leptin expression in a mice model (Gan et al, 2018). We found that Foxc2 was involved in LPS-induced ICAM-1 expression and the adhesion of monocytes to cultured endothelial cells.…”

Section: Discussionmentioning

confidence: 68%

“…Increased adipocyte metabolism in Foxc2 transgenic mice results in reduced whole-body fat mass compared with wild-type littermates (Kume, 2012;Wang et al, 2018), and overexpression of Foxc2 in adipocytes prevented diet-induced insulin resistance in an experimental mouse model (Kim et al, 2005). Foxc2 has been shown to reduce inflammation and promote adipocyte browning through leptin signaling (Gan et al, 2018). As obesity and diabetes increase the risk of atherosclerosis, we suggest Foxc2 may be involved.…”

Section: Introductionmentioning

confidence: 76%

Forkhead Box C2 Attenuates Lipopolysaccharide-Induced Cell Adhesion via Suppression of Intercellular Adhesion Molecule-1 Expression in Human Umbilical Vein Endothelial Cells

Zheng

et al. 2019

DNA and Cell Biology

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Atherosclerosis is a chronic vascular inflammatory disease that involves diverse cell types and circulating regulatory factors, including intercellular adhesion molecule (ICAM)-1, a proinflammatory cytokine. Lipopolysaccharides (LPS) increase ICAM-1 expression and promote cell adhesion, but the mechanism is not clear. We found that LPS induced time-and dose-regulated upregulation of ICAM-1 expression and downregulation of forkhead box protein C2 (Foxc2) expression in human umbilical vein endothelial cells (HUVECs). Overexpression of Foxc2 significantly inhibited both LPS-induced ICAM-1 expression in HUVECs and LPS-induced adhesion of THP-1 cells to HUVECs. Foxc2 siRNA dramatically increased both LPS-induced ICAM-1 expression and LPS-induced adhesion of THP-1 human monocytes cells to HUVECs. We conclude that Foxc2 inhibited LPS-induced adhesion of THP-1 cells to HUVECs by suppressing ICAM-1 expression in HUVECs.

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“…In C57BL/6J mice treated with 30% fructose, when the JAK2/STAT3 was activated, the symptoms of NAFLD were improved . In another mouse model treated with lipopolysaccharide, inhibiting STAT3 pathway led to alleviation of adipocyte inflammation . These reports suggested that MS symptoms were associated with typical inflammation pathways NF‐κB, JNK and STAT3.…”

Section: Introductionmentioning

confidence: 99%

“…[14] In another mouse model treated with lipopolysaccharide, inhibiting STAT3 pathway led to alleviation of adipocyte inflammation. [15] These reports suggested that MS symptoms were associated with typical inflammation pathways NF-jB, JNK and STAT3. However, little is known which of the above pathways is critically important for MS development and treatment.…”

Section: Introductionmentioning

confidence: 99%

PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling

Yang

Lin

et al. 2018

Journal of Pharmacy and Pharmacology

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Objectives Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high-density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established. Methods In this study, wild-type and Ppara-null mice fed a medium fat diet (MFD) were administered gemfibrozil and fenofibrate for three months, to explore the effect and action mechanism. Key findings In Ppara-null mice, MFD treatment increased body weight, adipose tissue, serum TG, and impared glucose tolerance. These phenotypes were attenuated in two groups treated with gemfibrozil and fenofibrate. The STAT3 pathway was activated in adipose and hepatic tissues in positive control, and inhibited in groups treated with gemfibrozil and fenofibrate. The above phenotypes and inflammation were not observed in any wild-type group. In 3T3-L1 adipogenic stem cells treated with high-glucose, STAT3 knockdown greatly decreased the number of lipid droplets. Conclusions Low dose of clinical fibrates was effective against MS development independent of PPARα, and this action was mediated by STAT3 signaling inhibition in adipose tissue, and to a lesser extent in hepatic tissues.

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Foxc2 coordinates inflammation and browning of white adipose by leptin-STAT3-PRDM16 signal in mice

Abstract: Our results indicated that Foxc2 inhibited inflammation and promoted browning of WAT through positive regulation of leptin signal and the STAT3-PRDM16 complex. These findings identify a new potential means to prevent and treat obese caused metabolic syndrome of mammals.

Cited by 41 publications

References 44 publications

Melatonin alleviates adipose inflammation through elevating α‐ketoglutarate and diverting adipose‐derived exosomes to macrophages in mice

Melatonin alleviates adipose inflammation through elevating α‐ketoglutarate and diverting adipose‐derived exosomes to macrophages in mice

Forkhead Box C2 Attenuates Lipopolysaccharide-Induced Cell Adhesion via Suppression of Intercellular Adhesion Molecule-1 Expression in Human Umbilical Vein Endothelial Cells

PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling

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