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Obesity Aggravates Acute Pancreatitis via Damaging Intestinal Mucosal Barrier and Changing Microbiota Composition in Rats. Sci Rep 2019; 9:69. [PMID: 30635594 PMCID: PMC6329748 DOI: 10.1038/s41598-018-36266-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 11/01/2018] [Indexed: 02/06/2023] Open
Abstract
Obesity may aggravate acute pancreatitis (AP) through damaging the intestinal mucosal barrier (IMB). The underlying mechanism remains unclear. This study was aimed to provide further data to clarify the mechanism. 48 rats were divided into 4 groups: 1) normal control (NC), chow-fed rats with sham operation, 2) no-obese rats with AP (NAP), chow-fed rats with taurocholate infusion, 3) obese control (OC), high-fat diet (HFD)-fed rats with sham operation, and 4) obese rats with AP (OAP), HFD-fed rats with taurocholate infusion. Pancreatic pathologic score (11.39 ± 1.76 vs. 14.11 ± 1.05, p = 0.005), intestinal permeability to FD4 (0.91 ± 0.25 μg/ml vs. 7.06 ± 3.67 μg/ml, p < 0.001), serum leptin (10.25 ± 5.59 ng/ml vs. 79.73 ± 38.44 ng/ml, p < 0.001) and ileal apoptosis (2.05 ± 0.73% vs. 4.53 ± 2.28%, p = 0.006) were significantly higher in OAP than in NAP group. The intestinal bacterial richness (Chao 1 and OTUs) was significantly lower in OAP than in NAP rats. The higher abundance of Proteobacteria and reduced proportions of intestinal Actinobacteria, Allobaculum and Barnesiella were detected in OAP group. Obesity may result in decreased intestinal leptin/ObR-b binding, distinct phylogenetic clusters of ileal bacterial communities, increased intestinal inflammatory injury and the insufficient intestinal epithelial cells proliferation during AP attack. Pancreatic injury was aggravated due to obesity associated dysfunction of IMB.
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Shen W, Li Y, Zou Y, Cao L, Cai X, Gong J, Xu Y, Zhu W. Mesenteric Adipose Tissue Alterations in Crohn's Disease Are Associated With the Lymphatic System. Inflamm Bowel Dis 2019; 25:283-293. [PMID: 30295909 DOI: 10.1093/ibd/izy306] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mesenteric fat wrapping and thickening are typical characteristics of Crohn's disease (CD). The purpose of this study was to explore the cause of mesenteric adipose hypertrophy and analyze the role of lymphatic vessels in mesenteric adipose tissue in CD. METHODS Twenty-three CD patients who underwent ileocolonic resection were included. In CD patients, specimens were obtained from hypertrophic mesenteric adipose tissue (htMAT) next to the diseased ileum. The mesenteric lymphatic vessels in mesenteric adipose tissue were separated under stereoscope microscope. Transmission electron microscopy and immunofluorescence were used to observe the structure of mesenteric lymphatic vessels. The NF-κB signaling pathway in mesenteric adipose tissue was detected in CD specimens using Western blotting. RESULTS Electron microscopy showed that the structure of mesenteric lymphatic vessel was discontinuous, and the microstructure of lymphatic endothelial cells appeared ruptured and incomplete. Through an immunofluorescence technique, we found that the surface of lymphatic endothelial cells lacked tight junction protein staining in CD. Also, the expression of claudin-1, occludin, and ZO-1 in the mesenteric lymphatic vessel of htMAT was significantly lower than that of control. These results indicated that the structure of the mesenteric lymphatic vessel in htMAT was mispatterned and ruptured, which could lead to lymph leakage. Leaky lymph factors could stimulate adipose tissue to proliferate. Antigens that leaked into the mesenteric adipose tissue could effectively elicit an immune response. The levels of cytokines (TNF-a, IL-1β, IL-6) was increased in the htMAT of CD patients by activated NF-κB signaling pathway. CONCLUSIONS Our findings demonstrated that the hypertrophy of mesenteric adipose tissue may result from mispatterned and ruptured lymphatic vessels. Alteration of mesenteric adipose tissue was associated with activated NF-κB signaling pathway. This study enhances support for elucidating the importance of mesenteric lymphatic vessels and adipose tissue in CD.
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Affiliation(s)
- Weisong Shen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yujie Zou
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China
| | - Lei Cao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xingchen Cai
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jianfeng Gong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yihan Xu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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Ye C, Wang R, Wang M, Huang Z, Tang C. Leptin alleviates intestinal mucosal barrier injury and inflammation in obese mice with acute pancreatitis. Int J Obes (Lond) 2018; 42:1471-1479. [PMID: 29934609 DOI: 10.1038/s41366-018-0125-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 04/16/2018] [Accepted: 04/20/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND/OBJECTIVES Obesity is an independent risk factor for severe acute pancreatitis (AP). Leptin plays an important role in energy homeostasis. It has been reported that leptin might also participate in the regulation of the intestinal mucosal barrier and inflammatory response. This study aimed to evaluate the effects of leptin on the intestinal mucosal barrier and inflammatory injury in obese mice with AP. SUBJECTS/METHODS AP was induced in leptin-deficient (ob/ob) or wild type (WT) mice by peritoneal injection of caerulein. The animals were divided into 4 groups: WT mice with or without exogenous leptin injection and ob/ob mice with or without leptin treatment. The inflammatory scoring of the pancreas and intestine were evaluated. Intestinal permeability, ileal interleukin (IL)-6 and IL-1β, proliferation, apoptosis and intestinal expression levels of claudin-1 and occludin were measured. RESULTS Pancreatic pathologic scores (8.50 ± 0.96 vs. 3.78 ± 1.35, p < 0.001), pancreatic levels of IL-6 (8.34 ± 3.21 ng/mg vs. 4.99 ± 0.53 ng/mg, p = 0.022), intestinal oedema scores (2.25 ± 0.46 vs. 1.14 ± 0.69, p = 0.001) and intestinal permeability to FD4 (0.78 ± 0.06 μg/ml vs. 0.53 ± 0.11 μg/ml, p < 0.001) were significantly higher in ob/ob mice than those in WT mice. Leptin replacement in ob/ob mice greatly improved the intestinal permeability (FD4 0.66 ± 0.03 μg/ml, vs. 0.78 ± 0.06 μg/ml, p = 0.012), increased the ileal expression of claudin-1(1.07 ± 0.08 vs. 0.83 ± 0.07 relative densitometry, p = 0.001) and reduced intestinal IL-6 and IL-1β to levels comparable to those in WT mice. The pancreatic level of IL-6 in ob/ob mice treated with leptin was also significantly decreased relative to that of untreated ob/ob mice (4.45 ± 1.71 ng/mg vs. 8.34 ± 3.21 ng/mg, p = 0.010). CONCLUSIONS Obesity may aggravate intestinal inflammation and increase intestinal permeability under the condition of acute pancreatitis. Exogenous leptin supplementation was in favour of anti-inflammation and improvement of intestinal mucosal barrier.
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Affiliation(s)
- Cheng Ye
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Mojin Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China. .,Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
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Jensen SR, Wheeler SE, Hvid H, Ahnfelt-Rønne J, Hansen BF, Nishimura E, Olsen GS, Brubaker PL. Elucidating the Biological Roles of Insulin and Its Receptor in Murine Intestinal Growth and Function. Endocrinology 2017; 158:2453-2469. [PMID: 28591779 DOI: 10.1210/en.2017-00195] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 06/01/2017] [Indexed: 12/14/2022]
Abstract
The role of the intestinal insulin receptor (IR) is not well understood. We therefore explored the effect of insulin (300 nmol/kg per day for 12 days) on the intestine in sex-matched C57Bl/6J mice. The intestinal and metabolic profiles were also characterized in male and female intestinal-epithelial IR knockout (IE-irKO) mice compared with all genetic controls on a chow diet or Western diet (WD) for 4 to 12 weeks. Insulin treatment did not affect intestinal size, intestinal resistance, or metabolic genes, but it reduced proximal-colon crypt depth and acutely increased colonic serine/threonine-specific protein kinase B (AKT) activation. Feeding with a WD increased body weight and fasting insulin level and decreased oral glucose tolerance in C57Bl/6J and IE-irKO mice. However, although the overall responses of the IE-irKO mice were not different from those of Villin-Cre (Vil-Cre):IRfl/+ and IRfl/fl controls, profound differences were found for female control Vil-Cre mice, which demonstrated reduced food intake, body weight, jejunal glucose transport, oral glucose tolerance, and fasting insulin and cholesterol levels. Vil-Cre mice also had smaller intestines compared with those of IE-irKO and IRfl/fl mice and greater insulin-mediated activation of jejunal IR and AKT. In summary, gain- and loss-of-function studies, with and without caloric overload, indicate that insulin did not exert remarkable effects on intestinal metabolic or morphologic phenotype except for a small effect on the colon. However, the transgenic control Vil-Cre mice displayed a distinct phenotype compared with other control and knockout animals, emphasizing the importance of thoroughly characterizing genetically modified mouse models.
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Affiliation(s)
- Stina Rikke Jensen
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Metabolic Disease Research, Novo Nordisk A/S, DK-2760 Måløv, Denmark
| | - Sarah E Wheeler
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Henning Hvid
- Metabolic Disease Research, Novo Nordisk A/S, DK-2760 Måløv, Denmark
| | | | - Bo Falck Hansen
- Metabolic Disease Research, Novo Nordisk A/S, DK-2760 Måløv, Denmark
| | - Erica Nishimura
- Metabolic Disease Research, Novo Nordisk A/S, DK-2760 Måløv, Denmark
| | | | - Patricia L Brubaker
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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5
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Jensen SR, Schoof EM, Wheeler SE, Hvid H, Ahnfelt-Rønne J, Hansen BF, Nishimura E, Olsen GS, Kislinger T, Brubaker PL. Quantitative Proteomics of Intestinal Mucosa From Male Mice Lacking Intestinal Epithelial Insulin Receptors. Endocrinology 2017; 158:2470-2485. [PMID: 28591806 DOI: 10.1210/en.2017-00194] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/31/2017] [Indexed: 12/16/2022]
Abstract
The goal of the present study was to determine whether loss of the insulin receptor alters the molecular landscape of the intestinal mucosa, using intestinal-epithelial insulin receptor knockout (IE-irKO) mice and both genetic (IRfl/fl and Villin-cre) controls. Quantitative proteomic analysis by liquid chromatography mass spectrometry was applied to jejunal and colonic mucosa from mice fed a normal chow diet and mice fed a Western diet (WD). Jejunal mucosa from IE-irKO mice demonstrated alterations in all intestinal cell lineages: Paneth, goblet, absorptive, and enteroendocrine cells. Only goblet and absorptive cells were affected in the colon. Also, a marked effect of WD consumption was found on the gut proteome. A substantial reduction was detected in Paneth cell proteins with antimicrobial activity, including lysozyme C-1, angiogenin-4, cryptdin-related sequence 1C-3 and -2, α-defensin 17, and intelectin-1a. The key protein expressed by goblet cells, mucin-2, was also reduced in the IE-irKO mice. Proteins involved in lipid metabolism, including aldose reductase-related protein 1, 15-hydroxyprostaglandin dehydrogenase, apolipoprotein A-II, and pyruvate dehydrogenase kinase isozyme 4, were increased in the mucosa of WD-fed IE-irKO mice compared with controls. In contrast, expression of the nutrient-responsive gut hormones, glucose-dependent insulinotropic polypeptide and neurotensin, was reduced in the jejunal mucosa of IE-irKO mice, and the expression of proteins of the P-type adenosine triphosphatases and the solute carrier-transporter family was reduced in the colon of WD-fed IE-irKO mice. In conclusion, IE-irKO mice display a distinct molecular phenotype, suggesting a biological role of insulin and its receptor in determining differentiated cell specificity in the intestinal epithelium.
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Affiliation(s)
- Stina Rikke Jensen
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Metabolic Disease Research, Novo Nordisk A/S, Måløv DK-2760, Denmark
| | - Erwin M Schoof
- Princess Margaret Hospital Cancer Centre, University Health Network, Ontario M5G 2M9, Canada
| | - Sarah E Wheeler
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Henning Hvid
- Metabolic Disease Research, Novo Nordisk A/S, Måløv DK-2760, Denmark
| | | | - Bo Falck Hansen
- Metabolic Disease Research, Novo Nordisk A/S, Måløv DK-2760, Denmark
| | - Erica Nishimura
- Metabolic Disease Research, Novo Nordisk A/S, Måløv DK-2760, Denmark
| | | | - Thomas Kislinger
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Patricia L Brubaker
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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Liu X, Chen J, Zhang J. AdipoR1-mediated miR-3908 inhibits glioblastoma tumorigenicity through downregulation of STAT2 associated with the AMPK/SIRT1 pathway. Oncol Rep 2017; 37:3387-3396. [PMID: 28440504 DOI: 10.3892/or.2017.5589] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 04/07/2017] [Indexed: 11/06/2022] Open
Abstract
A prospective method of treatment for cancer is to inhibit oncogene signaling pathways with microRNA (miRNA or miR). In the present study, whether the expression of STAT2, AdipoR1/AMPK/SIRT1 pathway of glioma is regulated by miR-3908 was explored. To confirm whether the predicted miR-3908 is matched with STAT2 and AdipoR1, 3'UTR luciferase activity of STAT2 and AdipoR1 was assessed. In the presence of the mimics or inhibitors of miR-3908, cell function of glioma cells, such as proliferation, growth, migration, invasion and apoptosis were analyzed. The expression of AdipoR1 and its downstream AMPK/SIRT1 pathway proteins or STAT2 were examined. Luciferase reporter analysis showed that miR-3908 directly target STAT2 and AdipoR1. miR-3908 suppressed expression of STAT2 or AdipoR1 and downregulated AdipoR1 pathway genes, including AMPK, p-AMPK and SIRT1. miR-3908 inhibited tumorigenicity, migration, growth and invasion in glioma cell lines U251 and U87 as well as increased apoptosis of these cells. The pathways related to tumorigenicity and tumor progression, STAT2 and AdipoR1/AMPK/SIRT1 could be restrained by miR-3908. In conclusion, restoration of miR-3908 expression induced suppression of cancer progression and glioblastoma tumorigenicity. The present study discovered novel tumorigenesis associated with miR-3908, which may represent a new target in treatment for glioblastoma.
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Affiliation(s)
- Xiangming Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Jinglong Chen
- Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
| | - Jinqian Zhang
- Department of Laboratory Medicine, The Second People's Hospital of Guangdong Province, Southern Medical University, Guangzhou, Guangdong 510317, P.R. China
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7
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Suman S, Kumar S, Fornace AJ, Datta K. Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine. Sci Rep 2016; 6:31853. [PMID: 27558773 PMCID: PMC4997262 DOI: 10.1038/srep31853] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 07/28/2016] [Indexed: 12/21/2022] Open
Abstract
Travel into outer space is fraught with risk of exposure to energetic heavy ion radiation such as 56Fe ions, which due to its high linear energy transfer (high-LET) characteristics deposits higher energy per unit volume of tissue traversed and thus more damaging to cells relative to low-LET radiation such as γ rays. However, estimates of human health risk from energetic heavy ion exposure are hampered due to lack of tissue specific in vivo molecular data. We investigated long-term effects of 56Fe radiation on adipokines and insulin-like growth factor 1 (IGF1) signaling axis in mouse intestine and colon. Six- to eight-week-old C57BL/6J mice were exposed to 1.6 Gy of 56Fe ions. Serum and tissues were collected up to twelve months post-irradiation. Serum was analyzed for leptin, adiponectin, IGF1, and IGF binding protein 3. Receptor expressions and downstream signaling pathway alterations were studied in tissues. Irradiation increased leptin and IGF1 levels in serum, and IGF1R and leptin receptor expression in tissues. When considered along with upregulated Jak2/Stat3 pathways and cell proliferation, our data supports the notion that space radiation exposure is a risk to endocrine alterations with implications for chronic pathophysiologic changes in gastrointestinal tract.
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Affiliation(s)
- Shubhankar Suman
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Santosh Kumar
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Albert J Fornace
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.,Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Kamal Datta
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
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Otani K, Ishihara S, Yamaguchi H, Murono K, Yasuda K, Nishikawa T, Tanaka T, Kiyomatsu T, Hata K, Kawai K, Nozawa H, Watanabe T. Adiponectin and colorectal cancer. Surg Today 2016; 47:151-158. [PMID: 27061803 DOI: 10.1007/s00595-016-1334-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 02/16/2016] [Indexed: 12/21/2022]
Abstract
Colorectal cancer is an obesity-related malignancy. Adiponectin is an adipokine produced exclusively by adipose tissue, and its concentration in the serum is reduced in obesity. A low serum level of adiponectin is associated with an increased risk of various types of malignancies including colorectal cancer. These facts suggest that the epidemiological link between obesity and cancer may have a significant association with adiponectin. Although numerous studies of colorectal cancer have been reported, the results are conflicting about the anti-cancer effect of adiponectin, and how adiponectin affects carcinogenesis or cancer development remains controversial. Because adiponectin has multiple systemic effects and exists as a high serum concentration protein, the main role of adiponectin should be regulation of homeostasis, and it would not likely act as an anti-cancerous hormone. However, as epidemiological evidence shows, a low adiponectin level may be a basic risk factor for colorectal cancer. We speculate that when the colonic epithelium is stimulated or damaged by another carcinogen under the condition of a low adiponectin level, carcinogenesis is promoted and cancer development is facilitated. In this report, we summarize recent findings of the correlation between adiponectin and colorectal cancer and investigate the effect of adiponectin on colorectal cancer.
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Affiliation(s)
- Kensuke Otani
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hironori Yamaguchi
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Koji Murono
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Koji Yasuda
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Takeshi Nishikawa
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Toshiaki Tanaka
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tomomichi Kiyomatsu
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Keisuke Hata
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kazushige Kawai
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Toshiaki Watanabe
- Department of Surgical Oncology, The University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan
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Park J, Kim I, Jung KJ, Kim S, Jee SH, Yoon SK. Gene-gene interaction analysis identifies a new genetic risk factor for colorectal cancer. J Biomed Sci 2015; 22:73. [PMID: 26362652 PMCID: PMC4566297 DOI: 10.1186/s12929-015-0180-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 08/23/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Adiponectin levels have been shown to be associated with colorectal cancer (CRC). Furthermore, a newly identified adiponectin receptor, T-cadherin, has been associated with plasma adiponectin levels. Therefore, we investigated the potential for a genetic association between T-cadherin and CRC risk. RESULT We conducted a case-control study using the Korean Cancer Prevention study-II cohort, which is composed of 325 CRC patients and 977 normal individuals. Study results revealed that rs3865188 in the 5' flanking region of the T-cadherin gene (CDH13) was significantly associated with CRC (p = 0.0474). The odds ratio (OR) for the TT genotype as compared to the TA + AA genotype was 1.577 (p = 0.0144). In addition, the interaction between CDH13 and the adiponectin gene (APN) for CRC risk was investigated using a logistic regression analysis. Among six APN single nucleotide polymorphisms (rs182052, rs17366568, rs2241767, rs3821799, rs3774261, and rs6773957), an interaction with the rs3865188 was found for four (rs2241767, rs3821799, rs3774261, and rs6773957). The group with combined genotypes of TT for rs3865188 and GG for rs377426 displayed the highest risk for CRC development as compared to those with the other genotype combinations. The OR for the TT/GG genotype as compared to the AA/AA genotype was 4.108 (p = 0.004). Furthermore, the plasma adiponectin level showed a correlation with the gene-gene interaction, and the group with the highest risk for CRC had the lowest adiponectin level (median, 4.8 μg/mL for the TT/GG genotype vs.7.835 μg/mL for the AA/AA genotype, p = 0.0017). CONCLUSIONS The present study identified a new genetic factor for CRC risk and an interaction between CDH13 and APN in CRC risk. These genetic factors may be useful for predicting CRC risk.
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Affiliation(s)
- Jongkeun Park
- Department of Medical Lifesciences, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Republic of Korea
| | - Injung Kim
- Department of Medical Lifesciences, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Republic of Korea
| | - Keum Ji Jung
- Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Soriul Kim
- Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Sun Ha Jee
- Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Sungjoo Kim Yoon
- Department of Medical Lifesciences, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Republic of Korea.
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10
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Boura P, Loukides S, Grapsa D, Achimastos A, Syrigos K. The diverse roles of adiponectin in non-small-cell lung cancer: current data and future perspectives. Future Oncol 2015; 11:2193-203. [DOI: 10.2217/fon.15.96] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, there is growing research interest for the biological role of adipose tissue-derived bioactive factors, mainly including adipokines, in various forms of cancer. Adiponectin (APN) is the most abundant circulating adipokine, and a key mediator of several cancer-related processes, such as cell proliferation, apoptosis, regulation of tumor cell invasion and angiogenesis. In this review we summarize and critically discuss the published literature on the diverse roles of APN in non-small-cell lung cancer, including its implication in lung cancer development, its use as a diagnostic and prognostic biomarker, and its correlation with cancer-related cachexia. The main challenges and future perspectives, mainly with regard to the potential development of APN-targeted therapeutic agents in cancer therapeutics, are also briefly presented and discussed.
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Affiliation(s)
- Paraskevi Boura
- Oncology Unit GPP, ‘Sotiria’ General Hospital, Athens School of Medicine, Mesogion 152, 11527, Athens, Greece
| | - Stylianos Loukides
- Oncology Unit GPP, ‘Sotiria’ General Hospital, Athens School of Medicine, Mesogion 152, 11527, Athens, Greece
| | - Dimitra Grapsa
- Oncology Unit GPP, ‘Sotiria’ General Hospital, Athens School of Medicine, Mesogion 152, 11527, Athens, Greece
| | - Apostolos Achimastos
- Oncology Unit GPP, ‘Sotiria’ General Hospital, Athens School of Medicine, Mesogion 152, 11527, Athens, Greece
| | - Konstantinos Syrigos
- Oncology Unit GPP, ‘Sotiria’ General Hospital, Athens School of Medicine, Mesogion 152, 11527, Athens, Greece
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11
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Abstract
Epidemiological studies show that both the incidence of inflammatory bowel disease (IBD) and the proportion of people with obesity and/or obesity-associated metabolic syndrome increased markedly in developed countries during the past half century. Obesity is also associated with the development of more active IBD and requirement for hospitalization and with a decrease in the time span between diagnosis and surgery. Patients with IBD, especially Crohn's disease, present fat-wrapping or "creeping fat," which corresponds to ectopic adipose tissue extending from the mesenteric attachment and covering the majority of the small and large intestinal surface. Mesenteric adipose tissue in patients with IBD presents several morphological and functional alterations, e.g., it is more infiltrated with immune cells such as macrophages and T cells. All these lines of evidence clearly show an association between obesity, adipose tissue, and functional bowel disorders. In this review, we will show that the mesenteric adipose tissue and creeping fat are not innocent by standers but actively contribute to the intestinal and systemic inflammatory responses in patients with IBD. More specifically, we will review evidence showing that adipose tissue in IBD is associated with major alterations in the secretion of cytokines and adipokines involved in inflammatory process, in adipose tissue mesenchymal stem cells and adipogenesis, and in the interaction between adipose tissue and other intestinal components (immune, lymphatic, neuroendocrine, and intestinal epithelial systems). Collectively, these studies underline the importance of adipose tissue for the identification of novel therapeutic approaches for IBD.
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12
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Suman S, Kallakury BVS, Fornace AJ, Datta K. Protracted upregulation of leptin and IGF1 is associated with activation of PI3K/Akt and JAK2 pathway in mouse intestine after ionizing radiation exposure. Int J Biol Sci 2015; 11:274-83. [PMID: 25678846 PMCID: PMC4323367 DOI: 10.7150/ijbs.10684] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/25/2014] [Indexed: 01/15/2023] Open
Abstract
Ionizing radiation is a known risk factor for gastrointestinal (GI) pathologies including cancer. Hormones and related signaling crosstalk, which could contribute to radiation-induced persistent pathophysiologic changes in the small intestine and colon, remain to be explored. The current study assessed perturbation of GI homeostasis-related hormones and signaling pathways at the systemic as well as at the tissue level in small intestine and colon. Mice (6-8 week old C57BL/6J) were exposed to 2 Gy γ radiation, serum and tissue samples were collected, and insulin like growth factor 1 (IGF-1) and leptin signaling were assessed two or twelve months after radiation exposure. Serum levels of IGF-1, IGF binding protein 3 (IGFBP3), leptin, and adiponectin were altered at these times after irradiation. Radiation was associated with increased IGF1 receptor (IGF1R) and obesity (leptin) receptor (Ob-R), decreased adiponectin receptor 1 (Adipo-R1) and 2 (Adipo-R2), and increased Ki-67 levels in small intestine and colon at both time points. Immunoblot analysis further showed increased IGF1R and Ob-R, and decreased Adipo-R2. Additionally, upregulation of PI3K/Akt and JAK2 signaling, which are downstream of IGF1 and leptin, was also observed in irradiated samples at both time points. These results when considered along with increased cell proliferation in the small intestine and colon demonstrate for the first time that ionizing radiation can persistently increase IGF1 and leptin and activate downstream proliferative pathways, which may contribute to GI functional alterations and carcinogenesis.
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Affiliation(s)
- Shubhankar Suman
- 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA
| | - Bhaskar V S Kallakury
- 2. Department of Pathology, Georgetown University Medical Center, Washington DC, USA
| | - Albert J Fornace
- 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA. ; 3. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Kamal Datta
- 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA
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Le Dréan G, Segain JP. Connecting metabolism to intestinal barrier function: The role of leptin. Tissue Barriers 2014; 2:e970940. [PMID: 25610758 DOI: 10.4161/21688362.2014.970940] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 09/25/2014] [Indexed: 12/16/2022] Open
Abstract
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.
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Key Words
- AMPK
- AMPK, AMP-activated protein kinase
- IEB, intestinal epithelial barrier
- IEC, intestinal epithelial cells
- JAK, Janus kinase
- JAK/STAT
- LepR-b, leptin receptor
- MEF, mouse embryonic fibroblast
- MLC, myosin light chain
- ROCK, Rho-kinase
- RhoA/ROCK
- STAT, signal transducer and activator of transcription
- TJ, tight junctions
- VAT, visceral adipose tissue
- barrier repair
- intestinal epithelial barrier
- leptin
- metabolism
- tight-junction
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Affiliation(s)
- Gwenola Le Dréan
- Université de Nantes; Institut des Maladies de l'Appareil Digestif (IMAD); Centre de Recherche en Nutrition Humaine du Grand Ouest (CRNH) ; Nantes, France ; CHU Hôtel-Dieu, Place Alexis Ricordeau ; Nantes, France
| | - Jean-Pierre Segain
- Université de Nantes; Institut des Maladies de l'Appareil Digestif (IMAD); Centre de Recherche en Nutrition Humaine du Grand Ouest (CRNH) ; Nantes, France ; CHU Hôtel-Dieu, Place Alexis Ricordeau ; Nantes, France
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14
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Riondino S, Roselli M, Palmirotta R, Della-Morte D, Ferroni P, Guadagni F. Obesity and colorectal cancer: Role of adipokines in tumor initiation and progression. World J Gastroenterol 2014; 20:5177-5190. [PMID: 24833848 PMCID: PMC4017033 DOI: 10.3748/wjg.v20.i18.5177] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of “adiposopathy”, defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC.
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15
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Alemán JO, Eusebi LH, Ricciardiello L, Patidar K, Sanyal AJ, Holt PR. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology 2014; 146:357-373. [PMID: 24315827 PMCID: PMC3978703 DOI: 10.1053/j.gastro.2013.11.051] [Citation(s) in RCA: 144] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/30/2013] [Accepted: 11/14/2013] [Indexed: 02/06/2023]
Abstract
Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.
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Affiliation(s)
| | - Leonardo H. Eusebi
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, and Center for Applied Biomedical Research (CRBA), University of Bologna, Italy
| | - Kavish Patidar
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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16
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An updated meta-analysis of the association between ADIPOQ rs2241766 polymorphism and colorectal cancer. Tumour Biol 2013; 35:2491-6. [PMID: 24293390 DOI: 10.1007/s13277-013-1329-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Accepted: 10/14/2013] [Indexed: 12/21/2022] Open
Abstract
Adiponectin (ADIPOQ) is a cytokine produced by adipose tissue involved in carcinogenesis. ADIPOQ SNP rs2241766 has been extensively studied in colorectal cancer (CRC) community with contentious and conflicting conclusions. The objective of this study was to comprehensively assess the association between SNP rs2241766 and CRC risk. PubMed, Embase, CNKI, as well as the references of the retrieved articles were searched to identify the eligible studies for this meta-analysis. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the association. We also examined the heterogeneity and publication bias and performed sensitivity analyses. Seven studies with 2,414 cases and 2,796 controls together did not show any significant association between SNP rs2241766 and CRC risk. Subgroup analyses by ethnicity and sample size also failed to provide statistically significant evidence. This meta-analysis demonstrates that ADIPOQ SNP rs2241766 may not represent as an effect modifier for the risk of CRC.
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17
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Le Dréan G, Haure-Mirande V, Ferrier L, Bonnet C, Hulin P, de Coppet P, Segain JP. Visceral adipose tissue and leptin increase colonic epithelial tight junction permeability via a RhoA-ROCK-dependent pathway. FASEB J 2013; 28:1059-70. [PMID: 24243887 DOI: 10.1096/fj.13-234203] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- Gwenola Le Dréan
- 2UMR 1280 INRA-University of Nantes, CHU Hôtel Dieu, Pl. Alexis Ricordeau 44093 Nantes, France.
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18
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Yun KE, Chang Y, Jung HS, Kim CW, Kwon MJ, Park SK, Sung E, Shin H, Park HS, Ryu S. Impact of body mass index on the risk of colorectal adenoma in a metabolically healthy population. Cancer Res 2013; 73:4020-7. [PMID: 23687341 DOI: 10.1158/0008-5472.can-12-3477] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Metabolically healthy obese (MHO) states exist that seem to be protected from cardiovascular risks. Although obesity is a risk factor for colorectal adenoma (CRA), there has yet to be any study of the risks of CRA in MHO individuals. In this study, we compared CRA prevalence in MHO individuals versus metabolically healthy individuals who were normal in weight. This cross-sectional study involved 18,085 Korean adults (39.1 ± 6.7 years) who had a health checkup including a colonoscopy. High-risk CRA was defined as any adenoma over 1 cm, 3 or more adenomas, adenoma with a villous component, or high-grade dysplasia. Multinomial logistic regression models were used to measure the associations between body mass index (BMI) and the risk of low-risk and high-risk CRA. Low-risk and high-risk CRA were present in 9.3% and 1.4% of the study population, respectively. After adjusting for age, sex, smoking, drinking, exercise, family history of colorectal cancer, education, and use of analgesic and aspirin, compared with normal healthy individuals, the prevalence of low-risk and high-risk CRA was increased in MHO individuals [OR = 1.44; 95% confidence interval (CI), 1.23-1.69 and OR = 1.62; 95% CI, 1.09-2.41, respectively]. In fully adjusted models, the prevalence of low-risk and high-risk CRA was associated with increasing categories of BMI in a dose-response manner (P for trend < 0.001 and 0.01, respectively). Thus, excess body weight, even in the absence of a metabolic unhealthy state, was found to be positively associated with increased presence of CRAs.
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Affiliation(s)
- Kyung Eun Yun
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Korea
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19
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Abstract
The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiologic studies have highlighted associations between increased serum leptin levels and increased tumor growth, whereas adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field.
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Affiliation(s)
- Michael N Vansaun
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
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20
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Rodrigues VS, Milanski M, Fagundes JJ, Torsoni AS, Ayrizono MLS, Nunez CEC, Dias CB, Meirelles LR, Dalal S, Coy CSR, Velloso LA, Leal RF. Serum levels and mesenteric fat tissue expression of adiponectin and leptin in patients with Crohn's disease. Clin Exp Immunol 2013; 170:358-64. [PMID: 23121676 DOI: 10.1111/j.1365-2249.2012.04660.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Crohn's disease (CD) is characterized by inflammation and an aetiology that is still unknown. Hypertrophy of mesenteric fat is a reflection of disease activity, as this fat covers the entire length of the affected area. Adipocytes synthesize leptin and adiponectin, adipocytokines responsible for pro- and anti-inflammatory effects. Therefore, we evaluated serum levels of adiponectin and leptin, as well as mesenteral expression of adiponectin in active CD and those in remission. Sixteen patients with ileocaecal CD followed at the Outpatient Clinic, Coloproctology Unit of University of Campinas Clinical Hospital, participated in the study. Analysis of serum adiponectin and leptin by enzyme-linked immunosorbent assay was performed in patients with active CD (ACD group), remission CD (RCD group) and in six healthy controls. Ten patients with active ileocaecal CD (FCD group) and eight patients with non-inflammatory disease selected for surgery were also studied. The specimens were snap-frozen and the expression of adiponectin was determined by immunoblot of protein extracts. Serum C-reactive protein levels were higher in the ACD group when compared to the others and no difference of body mass index was observed between the groups. Serum adiponectin was lower in the ACD group when compared to control, but no differences were seen when comparing the ACD and RCD groups. Mesenteric adiponectin expression was lower in the FCD group when compared to the FC group. Serum leptin was similar in all groups. The lower levels of serum and mesenteric adiponectin in active CD suggest a defective regulation of anti-inflammatory pathways in CD pathogenesis.
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Affiliation(s)
- V S Rodrigues
- Coloproctology Unit, Surgery Department, University of Campinas (UNICAMP), Sao Paulo, Brazil
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21
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Padidar S, Farquharson AJ, Williams LM, Kearney R, Arthur JR, Drew JE. High-fat diet alters gene expression in the liver and colon: links to increased development of aberrant crypt foci. Dig Dis Sci 2012; 57:1866-74. [PMID: 22373862 DOI: 10.1007/s10620-012-2092-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Accepted: 02/07/2012] [Indexed: 12/19/2022]
Abstract
BACKGROUND Obesity is associated with an increased risk of colon cancer. High-fat diets that lead to obesity may be a contributing factor, but the mechanisms are unknown. AIMS This study examines susceptibility to azoxymethane (AOM)-induced precancerous lesions in mice in response to consumption of either a low or a high-fat diet and associated molecular changes in the liver and colon. METHODS Gene markers of xenobiotic metabolism, leptin-regulated inflammatory cytokines and proliferation were assessed in liver and colon in response to high-fat feeding to determine links with increased sensitivity to AOM. RESULTS High-fat feeding increased development of AOM-induced precancerous lesions and was associated with increased CYP2E1 gene expression in the liver, but not the colon. Leptin receptors and the colon stem cell marker (Lgr5) were down-regulated in the proximal colon, with a corresponding up-regulation of the inflammatory cytokine (IL6) in response to high-fat feeding. Notably in the distal colon, where aberrant crypt foci develop in response to AOM, the proliferative stem cell marker, Lgr5, was significantly up-regulated with high-fat feeding. CONCLUSIONS The current study provides evidence that high-fat diets can alter regulation of molecular markers of xenobiotic metabolism that may expose the colon to carcinogens, in parallel with activation of β-catenin-regulated targets regulating colon epithelial cells. High-fat diets associated with obesity may alter multiple molecular factors that act synergistically to increase the risk of colon cancer associated with obesity.
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Affiliation(s)
- Sara Padidar
- Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, Scotland, UK
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22
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Farquharson AJ, Steele RJ, Carey FA, Drew JE. Novel multiplex method to assess insulin, leptin and adiponectin regulation of inflammatory cytokines associated with colon cancer. Mol Biol Rep 2011; 39:5727-36. [DOI: 10.1007/s11033-011-1382-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 12/13/2011] [Indexed: 12/16/2022]
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Leptin and fasting regulate rat gastric glucose-regulated protein 58. INTERNATIONAL JOURNAL OF PEPTIDES 2011; 2011:969818. [PMID: 22121381 PMCID: PMC3205658 DOI: 10.1155/2011/969818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Revised: 08/19/2011] [Accepted: 08/19/2011] [Indexed: 12/30/2022]
Abstract
The stomach secretes a wide range of peptides with essential metabolic functions, and thereby plays an important role in the regulation of energy homeostasis. Disulfide isomerase glucose-regulated protein 58 (GRp58) is a molecular chaperone member of the endoplasmic reticulum (ER) stress signaling pathway, which is a marker for human gastric cancer. Since GRp58 seems to be regulated by a phosphorylation/dephosphorylation pattern shift, we used the 2DE gel methodology and peptide mass fingerprinting-protein identification by means of MALDI-TOF mass spectrometry. We show that gastric mucosa GRp58 is dephosphorylated by fasting, and this effect is blunted when fasted rats are treated with leptin. Furthermore, we assessed the gene expression of GRp58 under different physiological settings known to be associated with energy homeostasis (fasting, leptin treatment and leptin deficiency). We found that intraperitoneal administration of leptin increases whereas leptin deficiency decreases GRp58 mRNA levels. However, GRp58 expression remains unchanged after fasting, indicating that leptin actions on GRp58 are no direct sensitivity to fasting. Dissection of the molecular pathways mediating the interactions between ER stress-related factors and nutrient availability, as well as their target genes, may open a new avenue for the study of obesity and other metabolic disorders.
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Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin. Proc Nutr Soc 2011; 71:175-80. [PMID: 22014041 DOI: 10.1017/s0029665111003259] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer.
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25
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Drew J. Janice Drew’s work on diet and cancer. World J Gastrointest Pathophysiol 2011; 2:61-4. [PMID: 21860839 PMCID: PMC3158879 DOI: 10.4291/wjgp.v2.i4.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 08/06/2011] [Accepted: 08/13/2011] [Indexed: 02/06/2023] Open
Abstract
Obesity and associated reduced consumption of plant derived foods are linked to increased risk of colon cancer as well as a number of other organ specific cancers. Inflammatory processes are a contributing factor but the precise mechanisms remain elusive. Obesity and cancer incidence are increasing worldwide, presenting bleak prospects for reducing, or preventing, obesity related cancers. The incidence of these preventable cancers can be achieved with greater understanding of the molecular mechanisms linking diet and carcinogenesis. Janice Drew has developed a research program over recent years to investigate molecular mechanisms related to consumption of anti-inflammatory metabolites generated from consumption of plant based diets, the impact of high fat diets and associated altered metabolism and obesity on regulation of colon inflammatory responses and processes regulating the colon epithelium. Comprehensive strategies have been developed incorporating transcriptomics, including the novel gene expression technology, the GenomeLab System and proteomics, together with biochemical analyses of plasma and tissue samples to assess correlated changes in oxidative stress, inflammation and pathology. The approaches developed have achieved success in establishing antioxidant and anti-inflammatory activity of dietary antioxidants and associated genes and pathways that interact to modulate redox status in the colon. Cellular processes and genes altered in response to obesity and high fat diets have provided evidence of molecular mechanisms that are implicated in obesity related cancer.
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26
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Byeon JS, Jeong JY, Kim MJ, Lee SM, Nam WH, Myung SJ, Kim JG, Yang SK, Kim JH, Suh DJ. Adiponectin and adiponectin receptor in relation to colorectal cancer progression. Int J Cancer 2011; 127:2758-67. [PMID: 21351255 DOI: 10.1002/ijc.25301] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Although obesity is a risk factor for colorectal cancer, the underlying mechanism is not clear. Adiponectin is an adipokine that binds to 2 types of receptors, AdipoR1 and AdipoR2. The plasma concentrations of adiponectin are reduced in obese individuals and adiponectin has been reported to have anticarcinogenic properties. Furthermore, AdipoR1 and AdipoR2 have been reported to be expressed in several malignancies. However, little is known about the expression of AdipoR1 and AdipoR2 in colorectal cancer and its clinicopathological implications. In addition, the relationship between adiponectin and colorectal cancer has not yet been determined. Here, we sought to investigate adiponectin and adiponectin receptors in relation to colorectal cancer. AdipoR1 and AdipoR2 immunostaining was detected in 72 and 68% of human colorectal cancer tissue, respectively. AdipoR1 and AdipoR2 expression levels were inversely related to T stage. The lowest AdipoR1 and AdipoR2 expression were detected in poorly differentiated adenocarcinoma. RT-PCR also showed the expression of AdipoR1 and AdipoR2 in HCT116 and SW620. MTT assay and TUNEL assay demonstrated the tendency of growth inhibition and apoptosis induction in both cell lines after full-length adiponectin treatment although statistically insignificant. Microarray analysis revealed several gene responses to full-length adiponectin, including upregulation of ENDOGL1 and MT1G. In conclusion, AdipoR1 and AdipoR2 may be intimately related to the progression of colorectal cancer. Further studies may be warranted to assess adiponectin and its receptors as a novel target for inhibition of colorectal cancer growth.
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Affiliation(s)
- Jeong-Sik Byeon
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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27
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Tiaka EK, Manolakis AC, Kapsoritakis AN, Potamianos SP. The implication of adiponectin and resistin in gastrointestinal diseases. Cytokine Growth Factor Rev 2011; 22:109-19. [PMID: 21531165 DOI: 10.1016/j.cytogfr.2011.04.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Adiponectin and resistin, members of the adipokine family, are multi-task hormones involved in several disorders, including those of the alimentary tract. In the present review, eligible studies focusing on the role of adiponectin and resistin in gastrointestinal diseases are manifested together and classified according to anatomic criteria. In addition, similarities and common patterns have been recognized, ultimately revealing an inverse association: the down-regulation of adiponectin and up-regulation of resistin - both in vitro and in vivo - in gastrointestinal disorders, irrespective of their diverse nature - inflammatory, autoimmune or malignant - or anatomic position - esophageal, gastric, of the small intestine, colonic. Finally, a potential role for both adipokines in alimentary tract-related carcinogenesis has been identified, possibly representing a missing link between obesity and cancer.
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Affiliation(s)
- Elisavet K Tiaka
- Department of Gastroenterology, University of Thessaly, University Hospital of Larissa, School of Medicine, Greece
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28
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Park SY, Kim JS, Seo YR, Sung MK. Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice. Int J Obes (Lond) 2011; 36:273-80. [PMID: 21544082 DOI: 10.1038/ijo.2011.83] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Studies have indicated that obesity is associated with a higher risk of colorectal cancer. This study was performed to determine the effect of diet-induced obesity on the formation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumors and to identify adiposity-related mechanisms. METHODS Male A/J mice were placed on either a high-fat diet (HFD; 45% of total calories from fat) or a normal diet (ND; 15% of calories from fat) for 12 weeks. To induce colon tumors, AOM was administered at a dose of 10 mg/kg body weight, followed by two cycles of DSS supply. RESULTS Study results indicated that the HFD group had twofold higher numbers of colonic tumors, as compared with the ND group. The HFD group also had significantly increased body weight and epididymal fat weight, which were associated with increases of serum insulin, insulin-like growth factor-1, leptin, epididymal fat pad leptin mRNA and colonic leptin receptor (Ob-R) mRNA. Animals on HFD showed higher expressions of Ob-R, insulin receptor, phosphorylated Akt, phosphorylated extracellular signal-regulated kinases, Bcl-xL and Cyclin D1 proteins in the colon. CONCLUSION The results suggest that HFD-induced obesity facilitates colon tumor formation, possibly by regulating downstream targets of circulating adiposity-related factors via receptor-mediated signaling of the phosphatidylinositol 3-kinase/Akt pathway.
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Affiliation(s)
- S-Y Park
- Department of Food and Nutrition, Sookmyung Women's University, Seoul, Korea
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29
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Padidar S, Farquharson AJ, Williams LM, Hoggard N, Reid MD, Duncan GJ, Drew JE. Impact of obesity and leptin on protein expression profiles in mouse colon. Dig Dis Sci 2011; 56:1028-36. [PMID: 20824498 DOI: 10.1007/s10620-010-1394-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Accepted: 08/11/2010] [Indexed: 01/04/2023]
Abstract
BACKGROUND Elevated leptin levels in obesity are associated with increased risk of colon pathology, implicating leptin signaling in colon disease. However, leptin-regulated processes in the colon are currently uncharacterized. Previously, we demonstrated that leptin receptors are expressed on colon epithelium and that increased adiposity and elevated plasma leptin in rats are associated with perturbed metabolism in colon tissue. Thus, we hypothesize that obesity disrupts expression of proteins regulated by leptin in the colon. METHODS A proteomic analysis was conducted to investigate firstly, differences in the colon of mice lacking leptin and leptin signaling (ob/ob and db/db, respectively) by comparing protein expression profiles with wild-type mice. Secondly, responses to leptin challenge in wild-type mice and ob/ob mice were compared to identify leptin-regulated proteins and associated cellular processes. RESULTS Forty proteins were identified with significantly altered expression patterns associated with differences in leptin status in comparisons between all groups of mice. These proteins are associated with calcium binding, cell cycle, cell proliferation, electron transport chain, energy metabolism, protein folding and transport, redox regulation, structural proteins, and proteins involved in transport and regulation of mucus production. CONCLUSIONS This study provides evidence that obesity and leptin significantly alter protein profiles of a number of proteins linked to cellular processes in colon tissues that may be linked to the increased risk of colon pathology associated with obesity.
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Affiliation(s)
- Sara Padidar
- Molecular Nutrition Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, Scotland, UK
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30
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Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 2010; 61:301-16. [PMID: 19824817 DOI: 10.1146/annurev.med.080708.082713] [Citation(s) in RCA: 422] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Body mass index, as an approximation of body adiposity, is associated with increased risk of several common and less common malignancies in a sex- and site-specific manner. These findings implicate sex- and cancer site-specific biological mechanisms underpinning these associations, and it is unlikely that there is a "one system fits all" mechanism. Three main candidate systems have been proposed-insulin and the insulin-like growth factor-I axis, sex steroids, and adipokines-but there are shortfalls to these hypotheses. In this review, three novel candidate mechanisms are proposed: obesity-induced hypoxia, shared genetic susceptibility, and migrating adipose stromal cells. While public health policies aimed at curbing the underlying causes of the obesity epidemic are being implemented, there is a parallel need to better understand the biological processes linking obesity and cancer as a prerequisite to the development of new approaches to prevention and treatment.
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Affiliation(s)
- Darren L Roberts
- Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, The Christie NHS Foundation Trust, Manchester, UK
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31
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Hoda RM, Scharl M, Keely SJ, McCole DF, Barrett KE. Apical leptin induces chloride secretion by intestinal epithelial cells and in a rat model of acute chemotherapy-induced colitis. Am J Physiol Gastrointest Liver Physiol 2010; 298:G714-21. [PMID: 20203064 PMCID: PMC2867420 DOI: 10.1152/ajpgi.00320.2009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The purpose of this study was to investigate whether luminal leptin alters ion transport properties of the intestinal epithelium under acute inflammatory conditions. Monolayers of human intestinal T(84) epithelial cells and a rat model of chemotherapy-induced enterocolitis were used. Cells were treated with leptin and mounted in Ussing chambers to measure basal and secretagogue-induced changes in transepithelial short-circuit current (I(sc)). Furthermore, the role of MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating responses to leptin was investigated. Acute colitis in Sprague-Dawley rats was induced by intraperitoneal injection of 40 mg/kg methotrexate. Leptin (100 ng/ml) induced a time-dependent increase in basal I(sc) in T(84) intestinal epithelial cells (P < 0.01). Moreover, pretreatment of T(84) cells with leptin for up to 1 h significantly potentiated carbachol- and forskolin-induced increases in I(sc). Pretreatment with an inhibitor of MAPK abolished the effect of leptin on basal, carbachol- and forskolin-induced chloride secretion (P < 0.05). However, the PI3K inhibitor, wortmannin, only blunted the effect of leptin on forskolin-induced increases in I(sc). Furthermore, leptin treatment evoked both ERK1/2 and Akt1 phosphorylation in T(84) cells. In the rat model, luminal leptin induced significant increases in I(sc) across segments of proximal and, to a lesser extent, distal colon (P < 0.05). We conclude that luminal leptin is likely an intestinal chloride secretagogue, particularly when present at elevated concentrations and/or in the setting of inflammation. Our findings may provide a mechanistic explanation, at least in part, for the clinical condition of secretory diarrhea both in hyperleptinemic obese patients and in patients with chemotherapy-induced intestinal inflammation.
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Affiliation(s)
- Raschid M. Hoda
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California
| | - Michael Scharl
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California
| | - Stephen J. Keely
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California
| | - Declan F. McCole
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California
| | - Kim E. Barrett
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California
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32
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Kaklamani VG, Wisinski KB, Sadim M, Gulden C, Do A, Offit K, Baron JA, Ahsan H, Mantzoros C, Pasche B. Variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes and colorectal cancer risk. JAMA 2008; 300:1523-31. [PMID: 18827209 PMCID: PMC2628475 DOI: 10.1001/jama.300.13.1523] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
CONTEXT Current epidemiological evidence suggests an association between obesity, hyperinsulinemia, and colorectal cancer risk. Adiponectin is a hormone secreted by the adipose tissue, and serum levels are inversely correlated with obesity and hyperinsulinemia. While there is evidence of an association between circulating adiponectin levels and colorectal cancer risk, no association between genes of the adiponectin pathway and colorectal cancer have been reported to date. OBJECTIVE To determine the association of 10 haplotype-tagging single-nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with colorectal cancer risk. DESIGN, SETTING, AND PATIENTS Two case-control studies including patients with a diagnosis of colorectal cancer and controls were recruited between 2000 and 2007. Case-control study 1 included a total of 441 patients with a diagnosis of colorectal cancer and 658 controls; both groups were of Ashkenazi Jewish ancestry and from New York, New York. Case-control study 2 included 199 patients with a diagnosis of colorectal cancer and 199 controls from Chicago, Illinois, matched 1:1 for sex, age, and ethnicity. MAIN OUTCOME MEASURES ADIPOQ and ADIPOR1 SNP frequency among cases and controls. RESULTS In study 1, after adjustment for age, sex, and SNPs from the same gene, 3 ADIPOQ SNPs and 1 ADIPOR1 SNP were associated with colorectal cancer risk: rs266729 (adjusted odds ratio [AOR], 0.72; 95% confidence interval [CI], 0.55-0.95) and rs822396 (AOR, 0.37; 95% CI, 0.14-1.00) were associated with decreased risk whereas rs822395 (AOR, 1.76; 95% CI, 1.09-2.84) and rs1342387 (AOR, 1.79; 95% CI, 1.18-2.72) were associated with increased risk. In study 2, after adjustment for age, sex, race, and SNPs from the same gene, the ADIPOQ SNP rs266729 was associated with a decreased colorectal cancer risk of similar magnitude as in study 1 (AOR, 0.52; 95% CI, 0.34-0.78). Combined analysis of both studies shows an association of rs266729 with decreased colorectal cancer risk (AOR, 0.73; 95% CI, 0.53-0.99). CONCLUSION The SNP rs266729, which tags the 5' flanking region of the ADIPOQ gene, is associated with decreased colorectal cancer risk.
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Affiliation(s)
- Virginia G Kaklamani
- Cancer Genetics Program, Division of Hematology and Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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Gravaghi C, Bo J, Laperle KMD, Quimby F, Kucherlapati R, Edelmann W, Lamprecht SA. Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice. Int J Obes (Lond) 2008; 32:1716-9. [PMID: 18725892 DOI: 10.1038/ijo.2008.149] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Epidemiological evidence indicates a link between obesity and human colon cancer. A putative association between obesity and colon tumorigenesis has been explored experimentally using chemical carcinogens administered to obese rodents. The main objective of this study was to generate a new mouse line that displays both obesity and intestinal tumorigenesis. To this end, we have generated C57BLKS-mLepr(db/db); Apc(1638N/+) mice combining both db and Apc mutations. The db mutation results in obesity and type 2 diabetes, the Apc mutation is a key initiating event of intestinal neoplasia. All mice were euthanized at 6 months of age and all regions of the gastrointestinal tract examined for tumors. The results show that the combination of Apc(1638N/+) and db mutations not only enhanced mutant Apc-driven small intestinal tumorigenesis but also induced gastric and colonic tumors. Homozygous db mice did not develop gastrointestinal neoplasia. These findings indicate that obesity associated with type 2 diabetes promotes gastrointestinal tumorigenesis in Apc-deficient mice and provides evidence of a mechanistic link between obesity and colorectal neoplasia.
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Affiliation(s)
- C Gravaghi
- Division of Gastroenterology and Hepatology, Department of Medicine, Strang Cancer Research Laboratory, Weill Medical College of Cornell University, New York, NY, USA
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Koch TCL, Briviba K, Watzl B, Bub A, Barth SW. Obesity-related promotion of aberrant crypt foci in DMH-treated obese Zucker rats correlates with dyslipidemia rather than hyperinsulinemia. Eur J Nutr 2008; 47:161-70. [PMID: 18480976 DOI: 10.1007/s00394-008-0711-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Accepted: 04/28/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND Obesity and energy restriction modulate the development of precancerous aberrant crypt foci (ACF) in animal models of colon cancer. AIM Investigation of the major obesity-associated determinants for ACF-development and underlying mechanisms leading to ACF-modulation, such as changes in DNA damage or colonocytes hyperproliferation. METHODS Lean and obese Zucker rats fed ad libitum (a.l.) or obese pair fed (p.f.) were induced with 1,2-dimethylhydrazine (DMH) for colon cancer. Multiple regression analyses were performed to identify major metabolic factors correlated with ACF number and size (aberrant crypts/ACF). DNA damage is analyzed by the comet-assay, epithelial proliferation by immunohistochemistry. RESULTS Aberrant crypt foci number was significantly elevated in Zucker obese a.l. (205.7+/-65.4 vs. lean 9.5+/-6.3, P<0.05) and is reduced by pair feeding in Zucker obese rats (81.4+/-28.5 vs. obese a.l., P<0.05). Compared to lean the ACF size was higher in Zucker obese a.l. (2.1+/-0.3 vs. lean 1.3+/-0.2., P<0.05) but is not reduced by pair feeding (1.7+/-0.2; P>0.05). While ACF number and size were modulated by genotype and/or pair feeding the DMH-induced DNA damage and hyperproliferation in colonocytes did not differ significantly between groups. Regression analysis showed that plasma parameters associated with lipid-metabolism (triglycerides, cholesterol, malondialdehyde) significantly correlated with the ACF number and size while parameters linked to carbohydrate-metabolism (glucose, insulin) were weaker determinants. CONCLUSION Obesity or pair feeding-associated modulation of ACF correlate with parameters related to lipid-metabolism but is not accompanied by changes in DNA damage and proliferation.
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Affiliation(s)
- Tatiana C L Koch
- Department of Nutritional Physiology and Biochemistry, Max Rubner-Institute, Haid-und-Neu-Strasse 9, 76131 Karlsruhe, Germany
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