P0133 Activation of Adipose Tissue Browning as a Potential Therapeutic Approach to Reduce Inflammation in Crohn’s Disease
Authors: Boronat-Toscano A , Monfort-Ferré D , Cepero C , Menacho M , Clua-Ferré L , Caro A , Lahoz M , Moline A , Valldosera G , Suau R , Mañas M J , Manyé J , Serena C 
Published: January 2025

Abstract

Background
Crohn's Disease (CD) is a chronic autoimmune disorder of the gastrointestinal tract, marked by a persistent pro-inflammatory environment. A hallmark feature is the formation of creeping fat (CrF), an immunologically active adipose tissue that exacerbates inflammation and disease progression (1). Anti-tumor necrosis factor (TNF) therapies, like Infliximab, are widely used to reduce intestinal inflammation in CD. Notably, we showed that Infliximab not only alleviates intestinal inflammation but also affects the behavior of CrF (2). Our previous work demonstrated that a browning process, linked with thermogenic activation in adipose tissue, occurs in CrF of CD patients (3). This process may play a role in regulating inflammation, as suggested by Zuo and colleagues (4), who showed that browning activation enhances anti-inflammatory responses in CrF.

Methods
Mesenteric adipose tissue, specifically CrF, was collected from CD patients (n=6). Subcutaneous and visceral adipose tissue samples were obtained from non-CD patients undergoing elective surgeries (hernia repairs or colectomies) (n=4). All tissue explants were treated with Infliximab at 5 mg/kg for 24 hours. Additionally, adipose-derived stem cells were isolated from CrF and subcutaneous tissue of both CD and non-CD patients. RNA was extracted from explants and stem cell cultures, and gene expression was analyzed using quantitative PCR. Focus was placed on browning markers (e.g., UCP-1, TMEM26) and cytokines, including TNF, CCL2, IL-4, and IL-10.

Results
Infliximab-treated CrF explants exhibited a significant increase in browning markers UCP1 and TMEM26 expression. Pro-inflammatory cytokines TNF and CCL2 showed a downward trend, while IL10 expression significantly increased (p = 0.006). In subcutaneous adipose tissue explants from non-CD patients, UCP1 and IL10 expression levels also rose significantly following Infliximab treatment, although no browning markers were upregulated in visceral adipose tissue. Infliximab-treated adipose-derived stem cells from both CD and non-CD patients showed a significant increase in UCP1 and IL4, along with a decrease in TNF expression (p &lt; 0.01).

Conclusion
Infliximab induces browning in both CD and non-CD patients, suggesting broader therapeutic potential. Additionally, adipose-derived stem cells from both groups showed increased browning markers and anti-inflammatory cytokines in response to Infliximab, underscoring their pivotal role in mediating the browning process and potentially modulating inflammation. These findings suggest that targeting adipose tissue browning could provide a novel therapeutic approach for managing inflammation in CD and related conditions.

References
1.Büning, C.; von Kraft, C.; Hermsdorf, M.; Gentz, E.; Wirth, E.K.; Valentini, L.; Haas, V. Visceral Adipose Tissue in Patients with Crohn’s Disease Correlates with Disease Activity, Inflammatory Markers, and Outcome. Inflamm. Bowel. Dis. 2015, 21, 2590–2597.
2.Boronat-Toscano A, Monfort-Ferré D, Menacho M, Caro A, Bosch R, Espina B, Algaba-Chueca F, Saera-Vila A, Moliné A, Marti M, Espin E, Millan M, Serena C. Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn's Disease. Int J Mol Sci. 2022 Sep 22;23(19):11170.
3.Monfort-Ferré D, Caro A, Menacho M, Martí M, Espina B, Boronat-Toscano A, Nuñez-Roa C, Seco J, Bautista M, Espín E, Megía A, Vendrell J, Fernández-Veledo S, Serena C. The Gut Microbiota Metabolite Succinate Promotes Adipose Tissue Browning in Crohn's Disease. J Crohns Colitis. 2022 Nov 1;16(10):1571-1583.
4.Zuo L, Geng Z, Song X, Li J, Wang Y, Zhang X, Ge S, Wang L, Liu G, Zhang L, Xu M, Zhao Y, Shen L, Ge Y, Wu R, Hu J. Browning of Mesenteric White Adipose Tissue in Crohn's Disease: A New Pathological Change and Therapeutic Target. J Crohns Colitis. 2023 Aug 21;17(8):1179-1192.