Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice
Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) i...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2025-04-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/100581 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850197684743307264 |
|---|---|
| author | Dan Wu Venkateswararao Eeda Zahra Maria Komal Rawal Audrey Wang Oana Herlea-Pana Ram Babu Undi Hui-Ying Lim Weidong Wang |
| author_facet | Dan Wu Venkateswararao Eeda Zahra Maria Komal Rawal Audrey Wang Oana Herlea-Pana Ram Babu Undi Hui-Ying Lim Weidong Wang |
| author_sort | Dan Wu |
| collection | DOAJ |
| description | Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional ‘M1-like’ CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the ‘M1-like’ CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and ‘M1-like’ ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity. |
| format | Article |
| id | doaj-art-7ccb9e6a7fe94c1fa7f3953b71e812cb |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-7ccb9e6a7fe94c1fa7f3953b71e812cb2025-08-20T02:13:06ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011310.7554/eLife.100581Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese miceDan Wu0https://orcid.org/0009-0002-8389-6107Venkateswararao Eeda1https://orcid.org/0000-0003-2740-047XZahra Maria2https://orcid.org/0000-0002-7279-3279Komal Rawal3https://orcid.org/0000-0001-6707-3392Audrey Wang4https://orcid.org/0009-0005-4736-5634Oana Herlea-Pana5https://orcid.org/0000-0002-3235-6795Ram Babu Undi6https://orcid.org/0000-0001-5061-7066Hui-Ying Lim7https://orcid.org/0000-0001-8084-6337Weidong Wang8https://orcid.org/0000-0003-3619-0953Department of Genetics, Heersink School of Medicine, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States; Department of Medicine, Division of Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesDepartment of Medicine, Division of Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesDepartment of Medicine, Division of Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesDepartment of Medicine, Division of Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesIndian Springs School, Pelham, United StatesDepartment of Medicine, Division of Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesDepartment of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesDepartment of Genetics, Heersink School of Medicine, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States; Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesDepartment of Genetics, Heersink School of Medicine, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States; Department of Medicine, Division of Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, United StatesOvernutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional ‘M1-like’ CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the ‘M1-like’ CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and ‘M1-like’ ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.https://elifesciences.org/articles/100581obesityadipose tissue macrophageER stressinsulin resistanceadipose remodelingIRE1 alpha |
| spellingShingle | Dan Wu Venkateswararao Eeda Zahra Maria Komal Rawal Audrey Wang Oana Herlea-Pana Ram Babu Undi Hui-Ying Lim Weidong Wang Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice eLife obesity adipose tissue macrophage ER stress insulin resistance adipose remodeling IRE1 alpha |
| title | Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice |
| title_full | Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice |
| title_fullStr | Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice |
| title_full_unstemmed | Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice |
| title_short | Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice |
| title_sort | targeting ire1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice |
| topic | obesity adipose tissue macrophage ER stress insulin resistance adipose remodeling IRE1 alpha |
| url | https://elifesciences.org/articles/100581 |
| work_keys_str_mv | AT danwu targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT venkateswararaoeeda targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT zahramaria targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT komalrawal targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT audreywang targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT oanaherleapana targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT rambabuundi targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT huiyinglim targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice AT weidongwang targetingire1aimprovesinsulinsensitivityandthermogenesisandsuppressesmetabolicallyactiveadiposetissuemacrophagesinmaleobesemice |