JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance
Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in t...
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2025-08-01
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| author | Chunyan Zhang Jieun Song Wang Zhang Rui Huang Yi-Jia Li Zhifang Zhang Hong Xin Qianqian Zhao Wenzhao Li Saul J. Priceman Jiehui Deng Yong Liu David Ann Victoria Seewaldt Hua Yu |
| author_facet | Chunyan Zhang Jieun Song Wang Zhang Rui Huang Yi-Jia Li Zhifang Zhang Hong Xin Qianqian Zhao Wenzhao Li Saul J. Priceman Jiehui Deng Yong Liu David Ann Victoria Seewaldt Hua Yu |
| author_sort | Chunyan Zhang |
| collection | DOAJ |
| description | Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance. |
| format | Article |
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| institution | DOAJ |
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| language | English |
| publishDate | 2025-08-01 |
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| series | Cells |
| spelling | doaj-art-dacab2d99991411ea0fee8194d3665e72025-08-20T03:02:48ZengMDPI AGCells2073-44092025-08-011415119410.3390/cells14151194JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin ResistanceChunyan Zhang0Jieun Song1Wang Zhang2Rui Huang3Yi-Jia Li4Zhifang Zhang5Hong Xin6Qianqian Zhao7Wenzhao Li8Saul J. Priceman9Jiehui Deng10Yong Liu11David Ann12Victoria Seewaldt13Hua Yu14Department of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Surgery, City of Hope National Medical Center, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Diabetes and Metabolism, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Population Sciences, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USAAdipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance.https://www.mdpi.com/2073-4409/14/15/1194JAK2/STAT3obesityinsulin resistanceinflammation |
| spellingShingle | Chunyan Zhang Jieun Song Wang Zhang Rui Huang Yi-Jia Li Zhifang Zhang Hong Xin Qianqian Zhao Wenzhao Li Saul J. Priceman Jiehui Deng Yong Liu David Ann Victoria Seewaldt Hua Yu JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance Cells JAK2/STAT3 obesity insulin resistance inflammation |
| title | JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance |
| title_full | JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance |
| title_fullStr | JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance |
| title_full_unstemmed | JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance |
| title_short | JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance |
| title_sort | jak2 stat3 signaling in myeloid cells contributes to obesity induced inflammation and insulin resistance |
| topic | JAK2/STAT3 obesity insulin resistance inflammation |
| url | https://www.mdpi.com/2073-4409/14/15/1194 |
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