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Mesenteric adipose tissue hyperplasia is a hallmark of Crohn's disease (CD). Recently, we showed that mesenteric adipose-derived stromal cells (ADSCs) from CD, ulcerative colitis, and control patients synthesize and release adipokines in a disease-dependent manner. Here we examined the expression profiles of CD and control patient-derived mesenteric ADSCs and studied the effects of their extracellular mediators on colonocyte signaling in vitro and experimental colitis in vivo. ADSCs were isolated from mesenteric fat of control and CD patients. Microarray profiling and network analysis were performed in ADSCs and human colonocytes treated with conditioned media from cultured ADSCs. Mice with acute colitis received daily injections of conditioned media from patient-derived ADSCs, vehicle, or apolactoferrin. Proliferative responses were evaluated in conditioned media-treated colonocytes and mouse colonic epithelium. Total protein was isolated from cultured colonocytes after treatment with apolactoferrin for Western blot analysis of phosphorylated intracellular signaling kinases. Microarray profiling revealed differential mRNA expression in CD patient-derived ADSCs compared with controls, including lactoferrin. Administration of CD patient-derived medium or apolactoferrin increased colonocyte proliferation compared with controls. Conditioned media from CD patient-derived ADSCs or apolactoferrin attenuated colitis severity in mice and enhanced colonocyte proliferation in vivo. ADSCs from control and CD patients show disease-dependent inflammatory responses and alter colonic epithelial cell signaling in vitro and in vivo. Furthermore, we demonstrate lactoferrin production by adipose tissue, specifically mesenteric ADSCs. We suggest that mesenteric ADSC-derived lactoferrin may mediate protective effects and participate in the pathophysiology of CD by promoting colonocyte proliferation and the resolution of inflammation.

Lymphocytic colitis is a subtype of microscopic colitis characterized by normal colonoscopy findings and microscopic evidence of lymphocytic infiltration of colonic epithelial cells. The concomitant diagnosis of lymphocytic colitis and ulcerative colitis has been rarely reported. We present a 68-year-old man with a 40-year history of ulcerative colitis who was referred to our hospital for 3–4 weeks of non-bloody diarrhea with subsequent colonoscopy and biopsies confirming lymphocytic colitis.

Peripheral administration of a specific neurokinin-1 receptor (NK-1R) antagonist to mice leads to reduced weight gain and circulating levels of insulin and leptin after high-fat diet (HFD). Here, we assessed the contribution of substance P (SP) and NK-1R in diet-induced obesity using NK-1R deficient [knockout (KO)] mice and extended our previous findings to show the effects of SP-NK-1R interactions on adipose tissue-associated insulin signaling and glucose metabolic responses. NK-1R KO and wild-type (WT) littermates were fed a HFD for 3 wk, and obesity-associated responses were determined. Compared with WT, NK-1 KO mice show reduced weight gain and circulating levels of leptin and insulin in response to HFD. Adiponectin receptor mRNA levels are higher in mesenteric fat and liver in NK-1 KO animals compared with WT, after HFD. Mesenteric fat from NK-1R KO mice fed with HFD has reduced stress-activated protein kinase/c-Jun N-terminal kinase and protein kinase Cθ activation compared with WT mice. After glucose challenge, NK-1R KO mice remove glucose from the circulation more efficiently than WT and pair-fed controls, suggesting an additional peripheral effect of NK-1R-mediated signaling on glucose metabolism. Glucose uptake experiments in isolated rat adipocytes showed that SP directly inhibits insulin-mediated glucose uptake. Our results further establish a role for SP-NK-1R interactions in adipose tissue responses, specifically as they relate to obesity-associated pathologies such as glucose intolerance and insulin resistance. Our results highlight this pathway as an important therapeutic approach for type 2 diabetes.

Der Tourismus stellt eine der stärksten Branchen der griechischen Wirtschaft, nicht nur auf nationaler, sondern auch auf internationaler Ebene dar. Es wird geschätzt, dass er wesentliche Möglichkeiten zur weiteren Verbesserung und Entwicklung aufweisen kann. Außerdem ist es Tatsache, dass seit Beginn der 90er Jahre touristische Aktivitäten die größte Produktionsbranche sind, gleichzeitig aber auch das größte zum Export geeignete Produkt auf Weltniveau ist. In diesem Artikel wird die Fallstudie des Tourismus in Griechenland dargestellt, wie dieser sich durch Internetsuche abzeichnet, mit Grundlage vielseitiger nationaler und internationaler Institute, sowohl staatlicher als auch privater, die sich mit statistischer Datensammlung –und -führung befassen. Aus den daraus hervorgehenden Angaben werden die wichtigsten Besonderheiten des Tourismus in Griechenland ersichtlich, die ihn von anderen Staaten unterscheiden

© 2015 the American Physiological Society. In inflammatory bowel disease (IBD), obesity is associated with worsening of the course of disease. Here, we examined the role of obesity in the development of colitis and studied mesenteric fat-epithelial cell interactions in patients with IBD. We combined the diet-induce obesity with the trinitrobenzene sulfonic acid (TNBS) colitis mouse model to create groups with obesity, colitis, and their combination. Changes in the mesenteric fat and intestine were assessed by histology, myeloperoxidase assay, and cytokine mRNA expression by real-time PCR. Medium from human mesenteric fat and cultured preadipocytes was obtained from obese patients and those with IBD. Histological analysis showed inflammatory cell infiltrate and increased histological damage in the intestine and mesenteric fat of obese mice with colitis compared with all other groups. Obesity also increased the expression of proinflammatory cytokines including IL-1β, TNF-α, monocyte chemoattractant protein 1, and keratinocyte-derived chemokine, while it decreased the TNBS-induced increases in IL-2 and IFN-γ in mesenteric adipose and intestinal tissues. Human mesenteric fat isolated from obese patients and those with and IBD demonstrated differential release of adipokines and growth factors compared with controls. Fat-conditioned media reduced adiponectin receptor 1 (AdipoR1) expression in human NCM460 colonic epithelial cells. AdipoR1 intracolonic silencing in mice exacerbated TNBS-induced colitis. In conclusion, obesity worsens the outcome of experimental colitis, and obesity- and IBD-associated changes in adipose tissue promote differential mediator release in mesenteric fat that modulates colonocyte responses and may affect the course of colitis. Our results also suggest an important role for AdipoR1 for the fat-intestinal axis in the regulation of inflammation during colitis.

Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. Here we assessed the effects of SP on weight gain in response to HFD and determined glucose metabolism in Tac1-deficient (Tac1−/−) mice. The effect of SP on the expression of molecules that may predispose to reduced glucose uptake was also determined in isolated human mesenteric, omental, and sc preadipocytes. We show that although weight accumulation in response to HFD was similar between Tac1−/− mice and wild-type littermates, Tac1−/− mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase Cθ, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. Preincubation of human mesenteric preadipocytes with the protein kinase Cθ pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. Lastly, SP also induced insulin receptor substrate-1 phosphorylation in mature human sc adipocytes. Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.

Obesity is an important risk factor for colon cancer in humans, and numerous studies have shown that a high fat diet enhances colon cancer development. As both increased adiposity and high fat diet can promote tumorigenesis, we examined the effect of diet-induced obesity, without ongoing high fat diet, on colon tumor development. C57BL/6J male mice were fed regular chow or high fat diet for 8 weeks. Diets were either maintained or switched resulting in four experimental groups: regular chow (R), high fat diet (H), regular chow switched to high fat diet (RH), and high fat diet switched to regular chow (HR). Mice were then administered azoxymethane to induce colon tumors. Tumor incidence and multiplicity were dramatically smaller in the R group relative to all groups that received high fat diet at any point. The effect of obesity on colon tumors could not be explained by differences in aberrant crypt foci number. Moreover, diet did not alter colonic expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, interleukin-1β, and interferon-γ, which were measured immediately after azoxymethane treatment. Crypt apoptosis and proliferation, which were measured at the same time, were increased in the HR relative to all other groups. Our results suggest that factors associated with obesity - independently of ongoing high fat diet and obesity - promote tumor development because HR group animals had significantly more tumors than R group, and these mice were fed the same regular chow throughout the entire carcinogenic period. Moreover, there was no difference in the number of aberrant crypt foci between these groups, and thus the effect of obesity appears to be on subsequent stages of tumor development when early preneoplastic lesions transition into adenomas. © 2013 Tuominen et al.

Background/Aims: Obesity is an important risk factor for colon cancer in humans. Numerous studies in experimental animals demonstrated that a high fat diet enhances colon cancer development. A potential mechanism for this increased risk is that adipose tissue, a major source of adipokines, growth factors, and cytokines promotes tumor growth. Alternatively, a high-fat diet causes metabolic changes that can independently enhance tumor growth. Here we determined the independent effects of these factors on colon tumor development. Methods: C57BL/6J male mice were fed regular chow or high fat diet (HFD) for 8 weeks. Half of the animals on high fat diet were switched to regular chow, and half on regular chow were switched to the HFD with the resulting 4 groups being regular (R), HFD (H), regular switched to HFD (RH) and HFD switched to regular (HR). One week after the switch, 5 weekly doses of azoxymethane (AOM) were given to induce colon tumors. Mice were euthanized 1 day after the final dose of AOM to analyze gene expression, proliferation, and apoptosis in the colon or 25 weeks after AOM to analyze numbers of colon tumors and aberrant crypt foci (ACF). Body composition was measured by echo MRI. Results: We previously showed the significantly increased tumor multiplicities in all groups that received HFD (groups H, HR, and RH) relative to animals on regular diet (group R). In this study, an ELISA based array analysis of cytokines and growth factors in serum revealed that obesity was associated with differential expression of molecules involved in insulin-like growth factor (Igf) signaling. Relative to group R mice, group HR mice had ratios 1.5, 0.7, and 0.75 in serum concentrations of Igf-II, Igf binding protein (Igfbp) 5, and Igfbp6, respectively (p = 0.05 for each). These differences were also reflected in mRNA expression patterns in mesenteric adipose tissue, as all obese groups had significantly elevated expression of Igf-I and Igf-II and significantly depressed expression of Igfbp5 and 6. Group HR mice appeared to have a greater toxic response to AOM relative to all other groups as measured by apoptotic index and lengthening of the Ki67-positive proliferative zone in colonic crypts following AOM treatment. Conclusions: We have identified obesity itself as a tumor promoter. A mechanism for the increased tumor responses may involve heightened signaling through the Igf1-receptor due to increased expression of ligands and decreased expression of binding proteins in mesenteric adipocytes. Additionally, the greater tumor response of mice in HFD that were switched to regular diet likely involves a heightened toxic response to AOM. Supported by NIH RO-1 DK60729 (CP); A Pilot and Feasibility Study from CURE: Digestive Diseases Research Center 41301; and the Martin Blinder Fund for IBD Research