Jean-Pierre Segain

Is Crohn's creeping fat an adipose tissue?

Background: In human pathology, the “creeping fat” (CF) of the mesentery is unique to Crohns disease (CD). CF is usually referred to as an ectopic extension of mesenteric adipose tissue (MAT). However, since no animal model developing CF has ever been established, very little is known about this type of fat‐depot expansion and its role in the development of the disease. Methods: We developed and standardized an experimental protocol in mice that reproducibly induces CF development when a severe colonic inflammation is obtained by intracolonic instillation of DNBS. Results: Macro‐microscopic observations revealed a fatty appearance of CF. Yet when compared to MAT from the same animals, CF contains very little triglycerides, few adipocytes, and we observed a very low expression and protein levels of both adipose markers (hormone‐sensitive lipase, perilipin) and adipocytokines (leptin, adiponectin). The decreased expression of perilipin in CF was also observed by immunohistochemistry. Conversely, the expression of proinflammatory and fibrous markers (Pref‐1) was much higher in CF than in MAT. These observations were fully consistent with those made on CF recovered from five CD patients and compared with subcutaneous and mesenteric fat from the same patients. Conclusions: Altogether, this work reports an original experimental mice model of CF. In this model we establish for the first time that CF only occurs in severe colonic inflammation and shows an inflammatory, fibrous but not an adipose pattern. (Inflamm Bowel Dis 2011)

Visceral adipose tissue and leptin increase colonic epithelial tight junction permeability via a RhoA-ROCK-dependent pathway

Proinflammatory cytokines produced by immune cells play a central role in the increased intestinal epithelial permeability during inflammation. Expansion of visceral adipose tissue (VAT) is currently considered a consequence of intestinal inflammation. Whether VAT per se plays a role in early modifications of intestinal barrier remains unknown. The aim of this study was to demonstrate the direct role of adipocytes in regulating paracellular permeability of colonic epithelial cells (CECs). We show in adult rats born with intrauterine growth retardation, a model of VAT hypertrophy, and in rats with VAT graft on the colon, that colonic permeability was increased without any inflammation. This effect was associated with altered expression of tight junction (TJ) proteins occludin and ZO‐1. In coculture experiments, adipocytes decreased transepithelial resistance (TER) of Caco‐2 CECs and induced a disorganization of ZO‐1 on TJs. Intraperitoneal administration of leptin to lean rats increased colonic epithelial permeability and altered ZO‐1 expression and organization. Treatment of HT29‐19A CECs with leptin, but not adiponectin, dose‐dependently decreased TER and altered TJ and F‐actin cytoskeleton organization through a RhoA‐ROCK‐dependent pathway. Our data show that adipocytes and leptin directly alter TJ function in CECs and suggest that VAT could impair colonic epithelial barrier.—Le Dréan, G., Haure‐Mirande, V., Ferrier, L., Bonnet, C., Hulin, P., de Coppet, P., Segain, J.‐P. Visceral adipose tissue and leptin increase colonic epithelial tight junction permeability via a RhoA‐ROCK‐dependent pathway. FASEB J. 28, 1059–1070 (2014). www.fasebj.org

Perinatal undernutrition alters intestinal alkaline phosphatase and its main transcription factors KLF4 and Cdx1 in adult offspring fed a high-fat diet

Nutrient restriction during gestation and/or suckling is associated with an increased risk of developing inflammation, obesity and metabolic diseases in adulthood. However, the underlying mechanisms, including the role of the small intestine, are unclear. We hypothesized that intestinal adaptation to the diet in adulthood is modulated by perinatal nutrition. This hypothesis was tested using a split-plot design experiment with 20 controls and 20 intrauterine growth-retarded (IUGR) rats aged 240 days and randomly assigned to be fed a standard chow or a high-fat (HF) diet for 10 days. Jejunal tissue was collected at necropsy and analyzed for anatomy, digestive enzymes, goblet cells and mRNA levels. Cecal contents and blood serum were analyzed for alkaline phosphatase (AP). IUGR rats failed to adapt to HF by increasing AP activity in jejunal tissue and cecal content as observed in controls. mRNA levels of transcription factors KLF4 and Cdx1 were blunted in jejunal epithelial cell of IUGR rats fed HF. mRNA levels of TNF-α were lower in IUGR rats. They also displayed exacerbated aminopeptidase N response and reduced jejunal goblet cell density. Villus and crypt architecture and epithelial cell proliferation increased with HF in both control and IUGR rats. Serum AP tended to be lower, and serum levamisole inhibition-resistant AP fraction was lower, in IUGR than controls with HF. Serum fatty acids and triglycerides were higher in IUGR rats and higher with HF. In conclusion, the adult intestine adapts to an HF diet differentially depending on early nutrition, jejunal AP and transcription factors being blunted in IUGR individuals fed HF.

Connecting metabolism to intestinal barrier function: The role of leptin

Structure and function of the intestinal epithelial barrier (IEB) are dependent upon the integrity of junctional protein structures sealing the apical surface between epithelial cells. Tight junctions (TJ) and the surrounding apical F-actin cytoskeleton are involved in the regulation of paracellular permeability. The regulation of actin cytoskeleton organization by RhoA/Rho-kinase (ROCK) pathway plays an important role in TJ assembly and function. There is mounting evidence that the adipocyte-derived hormone leptin exerts pleiotropic effects on the intestinal epithelium including nutrient absorption, epithelial growth, inflammation and injury. Leptin activates multiple cell signaling pathways in intestinal epithelial cells (IEC) that can explain these pleiotropic effects. However, these pathways are also involved in the primary role of leptin that is the regulation of energy and glucose metabolism homeostasis. In this commentary, we examine how the interplay between leptin signaling pathways that regulate cell metabolism could impact upon IEB function.

Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs

Butyrate can improve gut functions, whereas histone deacetylase inhibitors might alleviate neuro‐cognitive alterations. Our aim was to assess whether oral butyrate could modulate brain metabolism and plasticity and if this would relate to gut function. Sixteen pigs were subjected to sodium butyrate (SB) supplementation via beverage water or water only [control (C)]. All pigs had blood sampled after 2 and 3 wk of treatment, and were subjected to a brain positron emission tomography after 3 wk. Animals were euthanized after 4 wk to sample pancreas, intestine, and brain for gut physiology and anatomy measurements, as well as hippocampal histology, Ki67, and doublecortin (DCX) immunohistochemistry. SB compared with C treatment triggered basal brain glucose metabolism changes in the nucleus accumbens and hippocampus (P = 0.003), increased hippocampal granular cell layer volume (P = 0.006), and neurogenesis (Ki67: P = 0.026; DCX: P = 0.029). After 2 wk of treatment, plasma levels of glucose, insulin, lactate, glucagon‐like peptide 1, and peptide tyrosine tyrosine remained unchanged. After 3 wk, plasma levels of lactate were lower in SB compared with C animals (P = 0.028), with no difference for glucose and insulin. Butyrate intake impacted very little gut anatomy and function. These results demonstrate that oral SB impacted brain functions with little effects on the gut.— Val‐Laillet, D., Guérin, S., Coquery, N., Nogret, I., Formal, M., Romé, V., Le Normand, L., Meurice, P., Randuineau, G., Guilloteau, P., Malbert, C.‐H., Parnét, P., Lallés, J.‐P., Segain, J.‐P. Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs. FASEB J. 32, 2160–2171 (2018). www.fasebj.org