ABSTRACT Extensive scientific evidence indicating that non-optimal diet and sedentary lifestyle constitute some of the behaviors /risk factors associated with the onset of many diseases with significant societal impact, such as inflammatory bowel disease (IBD) and obesity. Diet is considered one of the main factors contributing to the diversity of gut microbiota. As TLRs/NLRs recognize bacterial products, there is a possibility that changes in bacterial composition induced by diet can promote a different response by TLRs/NLRs and thus may increase susceptibility to intestinal inflammation. Although several studies reported that Western Diet induces intestinal neoplastic lesions when fed to wild-type mice for 1 year, there are no studies regarding TLR/NLR KO mice. In order to elucidate a putative role for TLRs/NLRs in triggering events that lead to alteration of the small intestinal mucosa associated to consumption of western diet (WD), we utilized C57BL6/J wild-type (WT) mice and TLR/NLR KO mice (TLR2, 4, 9 and NOD2 KO mice) fed with standard diet (SD) or WD for 3, 6 and 12 months. Small intestinal mucosa morphology was assessed by histological analysis and RT-PCR was performed in order to quantify lymphocytes gene expression. Our results support the notion that WD promotes intestinal inflammation. They also demonstrate that individual TLRs have differential effects in the small intestine, regulating the mucosa homeostasis and inducing inflammatory responses. Our data contribute to the understanding of the factors by which the intestinal mucosal barrier is regulated in response to external stimuli, such as WD. This may be useful in developing novel strategies for managing and preventing intestinal inflammation High fat diet, consisting of 60% Kcal from fat, predisposes mice to the development of obesity and other pathological consequences. The increase of body fat and the adipose tissue inflammation are two important and interconnected aspects of obesity. Reducing inflammation may thus represent a feasible disease-prevention strategy for obesity. We evaluate the effects of X73, a commercial small-molecule anti-inflammatory drug (the structure of which we cannot disclose in this dissertation for Intellectual Property reasons) in a mouse model of diet-induced obesity (DIO).We used 10 C57BL/6J female mice fed with SD and 30 mice fed with High Fat Diet (HFD) for three months. Then, for other two months, the mice fed with HFD were separated in four groups as follows: 9 animals continued to be fed with HFD, 7 animals returned to SD, 7 animals continued to be fed with HFD and 7 returned to SD but they received 30mg/kg of X73 in their drinking water. Histological and metabolic analysis and RT-PCR on adipose tissue was performed in order to evaluate the effect of X73 on glucose metabolism and inflammatory markers. In conclusion our results demonstrate that X73 not only displays anti-adiposity effects by improving reducing adipocyte hypertrophy and reversing insulin resistance, but it also modulate adipose tissue inflammation. In the future, this project shall be extended in order to find the mechanism of action of X73 and improve the understanding of the immunological pathways and factors that initiate, regulate, and amplify the inflammatory cascade during obesity. This, we hope, will aid the optimization of clinical interventions and lifestyle changes aimed at improving human health.

DIET AND INFLAMMATION: FOCUS ON THE SMALL INTESTINE AND ADIPOSE TISSUE / C. Sardi ; tutor: C. Rumio ; coordinator: V. Ferrario. - : . DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2015 Jan 16. ((27. ciclo, Anno Accademico 2014. [10.13130/c-sardi_phd2015-01-16].

DIET AND INFLAMMATION: FOCUS ON THE SMALL INTESTINE AND ADIPOSE TISSUE

C. Sardi
2015

Abstract

ABSTRACT Extensive scientific evidence indicating that non-optimal diet and sedentary lifestyle constitute some of the behaviors /risk factors associated with the onset of many diseases with significant societal impact, such as inflammatory bowel disease (IBD) and obesity. Diet is considered one of the main factors contributing to the diversity of gut microbiota. As TLRs/NLRs recognize bacterial products, there is a possibility that changes in bacterial composition induced by diet can promote a different response by TLRs/NLRs and thus may increase susceptibility to intestinal inflammation. Although several studies reported that Western Diet induces intestinal neoplastic lesions when fed to wild-type mice for 1 year, there are no studies regarding TLR/NLR KO mice. In order to elucidate a putative role for TLRs/NLRs in triggering events that lead to alteration of the small intestinal mucosa associated to consumption of western diet (WD), we utilized C57BL6/J wild-type (WT) mice and TLR/NLR KO mice (TLR2, 4, 9 and NOD2 KO mice) fed with standard diet (SD) or WD for 3, 6 and 12 months. Small intestinal mucosa morphology was assessed by histological analysis and RT-PCR was performed in order to quantify lymphocytes gene expression. Our results support the notion that WD promotes intestinal inflammation. They also demonstrate that individual TLRs have differential effects in the small intestine, regulating the mucosa homeostasis and inducing inflammatory responses. Our data contribute to the understanding of the factors by which the intestinal mucosal barrier is regulated in response to external stimuli, such as WD. This may be useful in developing novel strategies for managing and preventing intestinal inflammation High fat diet, consisting of 60% Kcal from fat, predisposes mice to the development of obesity and other pathological consequences. The increase of body fat and the adipose tissue inflammation are two important and interconnected aspects of obesity. Reducing inflammation may thus represent a feasible disease-prevention strategy for obesity. We evaluate the effects of X73, a commercial small-molecule anti-inflammatory drug (the structure of which we cannot disclose in this dissertation for Intellectual Property reasons) in a mouse model of diet-induced obesity (DIO).We used 10 C57BL/6J female mice fed with SD and 30 mice fed with High Fat Diet (HFD) for three months. Then, for other two months, the mice fed with HFD were separated in four groups as follows: 9 animals continued to be fed with HFD, 7 animals returned to SD, 7 animals continued to be fed with HFD and 7 returned to SD but they received 30mg/kg of X73 in their drinking water. Histological and metabolic analysis and RT-PCR on adipose tissue was performed in order to evaluate the effect of X73 on glucose metabolism and inflammatory markers. In conclusion our results demonstrate that X73 not only displays anti-adiposity effects by improving reducing adipocyte hypertrophy and reversing insulin resistance, but it also modulate adipose tissue inflammation. In the future, this project shall be extended in order to find the mechanism of action of X73 and improve the understanding of the immunological pathways and factors that initiate, regulate, and amplify the inflammatory cascade during obesity. This, we hope, will aid the optimization of clinical interventions and lifestyle changes aimed at improving human health.
RUMIO, CRISTIANO
FERRARIO, VIRGILIO FERRUCCIO
diet;inflammation; TLR/NLR; small intestine; adipose tissue
Settore BIO/16 - Anatomia Umana
DIET AND INFLAMMATION: FOCUS ON THE SMALL INTESTINE AND ADIPOSE TISSUE / C. Sardi ; tutor: C. Rumio ; coordinator: V. Ferrario. - : . DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2015 Jan 16. ((27. ciclo, Anno Accademico 2014. [10.13130/c-sardi_phd2015-01-16].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/252813
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