Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity
The role of cyclooxygenase-2 (COX-2), a well-known pharmacological target for attenuating inflammation, in regulating obesity and its comorbidities remains unclear. We sought to determine the role of COX-2 in modulating metabolic inflammation and systemic metabolic homeostasis in obesity. Male WT an...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227525000835 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849473538805727232 |
|---|---|
| author | Jeyakumar Balakrishnan Cyrus Desouza Rishikesh Thakare Yazen Alnouti Viswanathan Saraswathi |
| author_facet | Jeyakumar Balakrishnan Cyrus Desouza Rishikesh Thakare Yazen Alnouti Viswanathan Saraswathi |
| author_sort | Jeyakumar Balakrishnan |
| collection | DOAJ |
| description | The role of cyclooxygenase-2 (COX-2), a well-known pharmacological target for attenuating inflammation, in regulating obesity and its comorbidities remains unclear. We sought to determine the role of COX-2 in modulating metabolic inflammation and systemic metabolic homeostasis in obesity. Male WT and COX-2 KO mice were fed a chow diet or a high fat diet (HF, 45% fat) for 13 weeks. While the body weight gain did not alter, the visceral adipose tissue mass was significantly higher in KO-HF mice than in WT-HF mice. Plasma triglycerides and total cholesterol levels were higher in KO-HF mice than in WT-HF mice. Total body fat mass was higher with a concomitant reduction in lean mass in KO-HF mice than in WT-HF mice. Paradoxically, hepatic steatosis was reduced in KO-HF mice. While liver triglycerides were reduced, the liver cholesterol was increased in KO-HF mice. Bile acids and markers of cholesterol biosynthesis were unaltered between WT-HF and KO-HF groups. The mRNA and/or protein levels of autophagy markers were significantly decreased in KO-HF mice compared to WT-HF mice, indicating that a reduction in autophagy may increase cholesterol levels in these mice. The liver inflammatory markers were significantly increased only in WT mice fed a HF diet but not in KO-HF fed mice compared to their respective controls. Visceral adipose tissue showed a reduction in inflammatory markers in spite of an increase in adiposity. These data suggest that despite being effective in attenuating the inflammatory processes, inhibition of COX-2 exerts undesirable consequences on metabolic homeostasis. |
| format | Article |
| id | doaj-art-6da9eca954ec4523bd089cfb50c77e0c |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-6da9eca954ec4523bd089cfb50c77e0c2025-08-20T03:24:07ZengElsevierJournal of Lipid Research0022-22752025-06-0166610082310.1016/j.jlr.2025.100823Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesityJeyakumar Balakrishnan0Cyrus Desouza1Rishikesh Thakare2Yazen Alnouti3Viswanathan Saraswathi4Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USADepartment of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USADepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USADepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USADepartment of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; For correspondence: Viswanathan SaraswathiThe role of cyclooxygenase-2 (COX-2), a well-known pharmacological target for attenuating inflammation, in regulating obesity and its comorbidities remains unclear. We sought to determine the role of COX-2 in modulating metabolic inflammation and systemic metabolic homeostasis in obesity. Male WT and COX-2 KO mice were fed a chow diet or a high fat diet (HF, 45% fat) for 13 weeks. While the body weight gain did not alter, the visceral adipose tissue mass was significantly higher in KO-HF mice than in WT-HF mice. Plasma triglycerides and total cholesterol levels were higher in KO-HF mice than in WT-HF mice. Total body fat mass was higher with a concomitant reduction in lean mass in KO-HF mice than in WT-HF mice. Paradoxically, hepatic steatosis was reduced in KO-HF mice. While liver triglycerides were reduced, the liver cholesterol was increased in KO-HF mice. Bile acids and markers of cholesterol biosynthesis were unaltered between WT-HF and KO-HF groups. The mRNA and/or protein levels of autophagy markers were significantly decreased in KO-HF mice compared to WT-HF mice, indicating that a reduction in autophagy may increase cholesterol levels in these mice. The liver inflammatory markers were significantly increased only in WT mice fed a HF diet but not in KO-HF fed mice compared to their respective controls. Visceral adipose tissue showed a reduction in inflammatory markers in spite of an increase in adiposity. These data suggest that despite being effective in attenuating the inflammatory processes, inhibition of COX-2 exerts undesirable consequences on metabolic homeostasis.http://www.sciencedirect.com/science/article/pii/S0022227525000835COX-2MASLDobesityinflammationtriglyceridescholesterol |
| spellingShingle | Jeyakumar Balakrishnan Cyrus Desouza Rishikesh Thakare Yazen Alnouti Viswanathan Saraswathi Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity Journal of Lipid Research COX-2 MASLD obesity inflammation triglycerides cholesterol |
| title | Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity |
| title_full | Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity |
| title_fullStr | Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity |
| title_full_unstemmed | Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity |
| title_short | Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity |
| title_sort | global deletion of cox 2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet induced obesity |
| topic | COX-2 MASLD obesity inflammation triglycerides cholesterol |
| url | http://www.sciencedirect.com/science/article/pii/S0022227525000835 |
| work_keys_str_mv | AT jeyakumarbalakrishnan globaldeletionofcox2attenuateshepaticinflammationbutimpairsmetabolichomeostasisindietinducedobesity AT cyrusdesouza globaldeletionofcox2attenuateshepaticinflammationbutimpairsmetabolichomeostasisindietinducedobesity AT rishikeshthakare globaldeletionofcox2attenuateshepaticinflammationbutimpairsmetabolichomeostasisindietinducedobesity AT yazenalnouti globaldeletionofcox2attenuateshepaticinflammationbutimpairsmetabolichomeostasisindietinducedobesity AT viswanathansaraswathi globaldeletionofcox2attenuateshepaticinflammationbutimpairsmetabolichomeostasisindietinducedobesity |