Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures

Authors: SOTAK, MATUS - University Of Gothenburg; RAJAN, M - University Of Gothenburg; CLARK, MADISON - University Of Gothenburg; HARMS, MATTHEW - University Of California, Davis; RANI, ALANKRITA - University Of Gothenburg; KRAFT, JAMIE - University Of Gothenburg; TANDIO, D - University Of Gothenburg; SHEN, TONG - University Of California, Davis; BORKOWSKI, KAMIL - University Of California, Davis; FIEHN, OLIVER - University Of California, Davis; Newman, John; QUIDING-JARBRINK, MARIANNE - University Of Gothenburg; BIORSERUD, CHRISTINA - University Of Gothenburg; APELGREN, PETER - University Of Gothenburg; STAALESEN, TRUDE - University Of Gothenburg; HAGBERG, CAROLINA - University Of San Diego; BOUCHER, JEREMIE - University Of Gothenburg; WALLENIUS, VILLE - University Of Gothenburg; LANGE, STEPHAN - University Of San Diego; BORGESON, EMMA - University Of Gothenburg

Submitted to: iScience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/8/2022
Publication Date: 6/11/2022
Citation: Sotak, M., Rajan, M., Clark, M., Harms, M., Rani, A., Kraft, J.D., Tandio, D., Shen, T., Borkowski, K., Fiehn, O., Newman, J.W., Quiding-Jarbrink, M., Biorserud, C., Apelgren, P., Staalesen, T., Hagberg, C., Boucher, J., Wallenius, V., Lange, S., Borgeson, E. 2022. Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures. iScience. 25(7). Article 104602. https://doi.org/10.1016/j.isci.2022.104602.
DOI: https://doi.org/10.1016/j.isci.2022.104602

Interpretive Summary: Adipose tissue inflammation is thought to drive obesity-related cardiometabolic diseases. A novel approach to reduce adipose inflammation is to enhance endogenous inflammatory resolution mechanisms, by administrating or increasing specialized pro-resolving mediators, such as the lipoxins. Here, we demonstrate that treatment with Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) reduces inflammation in human adipocyte and adipose tissue explant cultures from morbidly obese patients. In a subgroup of patients that responded particularly treatment, lipoxins induced an anti-inflammatory macrophage phenotype and reduced the production of inflammatory cytokines. These responsive individuals showed higher levels of inflammatory cytokines in their blood and inflammatory lipid mediators in their adipose tissue. This study is the first to demonstrate that lipoxins have therapeutic potential in reducing obesity-related adipose inflammation and suggests that such treatment may require a tailored personalized-medicine approach

Technical Abstract: Adipose tissue inflammation is thought to drive obesity-related cardiometabolic diseases. A novel approach to reduce adipose inflammation is to enhance endogenous resolution mechanisms, by administrating or increasing specialized pro-resolving mediators (SPMs), such as the lipoxins. We have previously shown that lipoxins promote the resolution of obesity-induced adipose inflammation in mice, which protects against systemic disease. Here, we translate these findings to human pathophysiology. We demonstrate that treatment with Lipoxin A4 and Lipoxin B4 reduces inflammation in both 3D-cultured human adipocytes and in adipose tissue explant cultures from morbidly obese patients. Interestingly, a subgroup of patients responded particularly well to lipoxin treatment, and in these responders the pro-resolving lipids promoted an anti-inflammatory M2 macrophage phenotype and reduced the production of inflammatory cytokines. The responder cohort was characterized by elevated systemic levels of the acute phase C-reactive protein, which we demonstrated can directly increase inflammation in cultured human adipocytes. Another characteristic of the responder cohort was an altered adipose tissue lipidomics profile with elevated prostaglandin D2 levels, which has been interlinked with expression of the lipoxygenase enzymes required for SPM production. In conclusion, this study is the first to demonstrate proof-of-concept evidence that lipoxins have therapeutic potential in reducing obesity-related adipose inflammation. Furthermore, our data indicates that lipoxin-treatment in humans may require a tailored personalized-medicine approach.