Reciprocal Inflammatory Signaling Between Intestinal Epithelial Cells and Adipocytes in the Absence of Immune Cells

Abstract

Visceral fat accumulation as observed in Crohn's disease and obesity is linked to chronic gut inflammation, suggesting that accumulation of gut adipocytes can trigger local inflammatory signaling. However, direct interactions between intestinal epithelial cells (IECs) and adipocytes have not been investigated, in part because IEC physiology is difficult to replicate in culture. In this study, we originally prepared intact, polarized, and cytokine responsive IEC monolayers from primary or induced pluripotent stem cell-derived intestinal organoids by simple and repeatable methods. When these physiological IECs were co-cultured with differentiated adipocytes in Transwell, pro-inflammatory genes were induced in both cell types, suggesting reciprocal inflammatory activation in the absence of immunocompetent cells. These inflammatory responses were blocked by nuclear factor-κB or signal transducer and activator of transcription 3 inhibition and by anti-tumor necrosis factor- or anti-interleukin-6-neutralizing antibodies. Our results highlight the utility of these monolayers for investigating IEC biology. Furthermore, this system recapitulates the intestinal epithelium–mesenteric fat signals that potentially trigger or worsen inflammatory disorders such as Crohn's disease and obesity-related enterocolitis.

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation

“…For example, various adipocytokines (e.g., adiponectin, apelin, chemerin, leptin) are secreted from adipocytes, but in obesity, the regulation of the production of these adipocytokines is aberrant due to enlarged adipocytes 46 , 47 . Furthermore, inflammation-associated pathological alterations of adipocytes in mesenteric fat have previously been reported 46 , as have reduced expression levels of adiponectin in colitis mice 44 , 45 . Our group and others have reported on the functional transition of mesenchymal fat (e.g., increase of TNF-α and reduction of adipokines) and its effects on immune and epithelial integrity in colitis 45 , 48 .…”

“…Furthermore, inflammation-associated pathological alterations of adipocytes in mesenteric fat have previously been reported 46 , as have reduced expression levels of adiponectin in colitis mice 44 , 45 . Our group and others have reported on the functional transition of mesenchymal fat (e.g., increase of TNF-α and reduction of adipokines) and its effects on immune and epithelial integrity in colitis 45 , 48 . Adiponectin has an anti-inflammatory reaction against TNF-α pathways, such as NF-κB activation 49 .…”

“…Obesity is the hallmark phenotype of Lepr db/db mice, and it may be that obesity causes delayed mucosal regeneration. However, obesity is a proinflammatory state in mice and humans, and adipose tissue produces inflammatory cytokines; therefore, these cytokines may contribute to delayed epithelial growth via another mechanism 44 , 45 .…”

“…These processes were repeated twice. Harvested colon tissues were incubated in cell recovery solution (Corning, High Wycomb, UK) 45 , 52 for 1 h on ice (Supplemental Fig. 1 ).…”

Adipocyte-Epithelial Interactions and Crohn's Disease - An Emerging Drug Target

“…Takahashi et al confirmed this coupling by immunostaining for perilipin (which identifies adipocyte droplets). Intestinal epithelial damage was marked where the intestine and mesentery were contiguous ( Takahashi et al, 2017 ).…”