Animal Model Of Diet-induced Obesity Research Articles

Changes of fat-mass and obesity-associated protein expression in the hippocampus in animal models of high-fat diet-induced obesity and D-galactose-induced aging

Fat-mass and obesity-associated protein (Fto) is highly expressed in the brain including, the hippocampus, and its expression is significantly decreased in the brain of Alzheimer’s disease patients. In the present study, we measured Fto immunoreactivity and protein levels in the hippocampus of obese and aged mice, which were induced by high-fat diet for 12 weeks and D-galactose treatment for 10 weeks, respectively. The obesity and aging phenotypes were assessed by physiological parameters and Morris water maze test, respectively. High fat diet fed mice showed significant increases in body weight and blood glucose levels compared to that in the control or D-galactose-induced aged mice. In addition, treatment with D-galactose significantly decreased the spatial memory. Fto immunoreactivity in the control group was mainly detected in the pyramidal cells of the CA1 and CA3 regions and in the granule cells of the dentate gyrus. In the hippocampus of high-fat diet-fed mice, Fto immunoreactive structures were similarly found in the hippocampus compared to that in the control group, but Fto immunoreactivity in high-fat diet-fed mice was also found in the stratum oriens and radiatum of the CA1 and CA3 regions and the polymorphic layer of the dentate gyrus. In the hippocampus of D-galactose-induced aged mice, fewer Fto immunoreactive structures were detected in the granule cell layer of the dentate gyrus compared to the control group. Fto mRNA and protein levels based on quantitative real-time polymerase chain reaction and western blot assays were slightly increased in the hippocampus of high-fat diet-fed mice compared to that in control mice. In addition, Fto mRNA and protein levels were significantly decreased in the aged hippocampus compared to that in the control group. Fto protein levels are susceptible to the aging process, but not in the hippocampus of high-fat diet-induced obesity. The reduction of Fto in aged mice may be associated with reduced memory impairment in mice.

Weight loss normalizes enhanced expression of the oncogene survivin in visceral adipose tissue and blood leukocytes from individuals with obesity

Background/objectivesSurvivin is an oncogene associated with a decrease in apoptosis, an increase in tumor growth, and poor clinical outcome of diverse malignancies. A correlation between obesity, cancer, and survivin is reported in the literature. To date, the impact of weight loss on change in survivin levels is understudied. This study was aimed at: (1) comparing survivin levels in adipose tissue (AT) from lean and obese animal models and evaluating changes after weight loss induced by energy restriction and/or exercise; (2) comparing survivin levels in normal weighted and obese humans and evaluating changes in survivin levels after weight loss induced by a very-low-calorie ketogenic diet (VLCKD) or bariatric surgery in AT and/or blood leukocytes (PBL/PBMCs).Subjects/methodsSurvivin expression was evaluated in subcutaneous (SAT) and visceral (VAT) AT derived from animal models of monogenic (Zucker rats) and diet-induced obesity (Sprague Dawley rats and C57BL/6J mice) and after a 4-week weight-loss protocol of energy restriction and/or exercise. Plasma was used to measure the inflammatory status. Survivin expression was also evaluated in PBMCs from patients with obesity and compared with normal weight, in PBLs after VLCKD, and in SAT and/or PBLs after bariatric surgery.ResultsSurvivin expression was specifically higher in VAT from obese that lean animals, without differences in SAT. It decreased after weight loss induced by energy restriction and correlated with adiposity and inflammatory markers. In humans, the correlation between being obese and higher levels of survivin was confirmed. In obese subjects, survivin levels were reduced following weight loss after either VLCKD or bariatric surgery. Particularly, a decrease in PBMCs expression (not in SAT one) was found after surgery.ConclusionsWeight loss is effective in decreasing survivin levels. Also, PBL/PBMC should be regarded as appropriate mirror of survivin levels in VAT for the identification of an obesity-related protumoral microenvironment.

Effects of Prunus cerasus L. Seeds and Juice on Liver Steatosis in an Animal Model of Diet-Induced Obesity.

The accumulation of adipose tissue increases the risk of several diseases. The fruits-intake, containing phytochemicals, is inversely correlated with their development. This study evaluated the effects of anthocyanin-rich tart cherries in diet-induced obese (DIO) rats. DIO rats were exposed to a high-fat diet with the supplementation of tart cherry seeds powder (DS) and seed powder plus juice (DJS). After 17 weeks, the DIO rats showed an increase of body weight, glycaemia, insulin, and systolic blood pressure. In the DS and DJS groups, there was a decrease of systolic blood pressure, glycaemia, triglycerides, and thiobarbituric reactive substances in the serum. In the DJS rats, computed tomography revealed a decrease in the spleen-to-liver attenuation ratio. Indeed, sections of the DIO rats presented hepatic injury characterized by steatosis, which was lower in the supplemented groups. In the liver of the DIO compared with rats fed with a standard diet (CHOW), a down-regulation of the GRP94 protein expression and a reduction of LC3- II/LC3-I ratio were found, indicating endoplasmic reticulum stress and impaired autophagy flux. Interestingly, tart cherry supplementation enhanced both unfolded protein response (UPR) and autophagy. This study suggests that tart cherry supplementation, although it did not reduce body weight in the DIO rats, prevented its related risk factors and liver steatosis.

Effect of mitoquinone (Mito-Q) on neuropathic endpoints in an obese and type 2 diabetic rat model

This study sought to determine whether the addition of mitoquinone (Mito-Q) in the diet is an effective treatment for peripheral neuropathy in animal models of diet-induced obesity (pre-diabetes) and type 2 diabetes. Unlike other anti-oxidative stress compounds investigated as a treatment for peripheral neuropathy, Mito-Q specifically targets mitochondria. Although mito-Q has been shown to reduce oxidative stress generated by mitochondria there have been no studies performed of the effect of Mito-Q on peripheral neuropathy induced by diet-induced obesity or type 2 diabetes. Diet-induced obese (12 weeks after high fat diet) or type 2 diabetic rats (12 weeks of high fat diet and 4 weeks after the onset of hyperglycemia) were treated via the diet with Mito-Q (0.93 g/kg diet) for 12 weeks. Afterwards, glucose utilization, vascular reactivity of epineurial arterioles to acetylcholine and peripheral neuropathy related endpoints were examined. The addition of Mito-Q to the diets of obese and diabetic rats improved motor and/or sensory nerve conduction velocity, cornea and intraepidermal nerve fibre density, cornea sensitivity and thermal nociception. Surprisingly, treating obese and diabetic rats with Mito-Q did not improve glucose utilization or vascular reactivity by epineurial arterioles to acetylcholine. These studies imply that mitochondrial dysfunction contributes to peripheral neuropathy in animal models of pre-diabetes and late-stage type 2 diabetes. However, improvement in peripheral neuropathy following treatment with Mito-Q was not associated with improvement in glucose utilization or vascular reactivity of epineurial arterioles to acetylcholine.

Treatment with indigo plant (Polygonum tinctorium Lour) improves serum lipid profiles in Wistar rats fed a high-fat diet.

We investigated the effects of Polygonum tinctorium Lour (PTL), a plant commonly known as indigo, on biological parameters in an animal model of high-fat diet-induced obesity. Wistar rats fed a high-fat diet and treated with PTL showed lower serum levels of triglycerides and total cholesterol levels and a higher serum levels of HDL cholesterol than those in Wistar rats fed a high-fat diet without PTL treatment. The weight of mesenteric fat in PTL-treated rats was decreased compared to that in control rats not treated with PTL. In addition, energy metabolic rate in the dark period, but not in the light period, in PTL-treated rats was higher than that in control rats. Although a significant difference was not observed, body weight in PTL-treated rats tended to be decreased compared to that in control rats. The results show that PTL improves serum lipid profiles in Wistar rats with high-fat diet-induced obesity. J. Med. Invest. 67 : 158-162, February, 2020.

Polylactose, a Novel Prebiotic Dietary Fiber, Reduces Adiposity and Hepatic Lipid Accumulation (P20-027-19)

ObjectivesPolylactose is a novel dietary fiber, synthesized by extrusion of lactose. To evaluate its potential as a prebiotic, we determined its fermentability, effect on the microbiome, and its effects on adiposity, fatty liver, and liver cholesterol in a diet-induced obesity animal model. Methods72 male Wistar rats were fed normal fat (NF) or high fat (HF, 51% fat by kcal) diets containing various fibers (6% fiber of interest and 3% cellulose, by weight); including cellulose (NFC and HFC), polylactose (HFPL), matched lactose (HFML), matched to the residual lactose in the HFPL diet, and two established prebiotic fibers, polydextrose (HFPD) and fructooligosaccharides (HFFOS). After 10 weeks on experimental diets, organs were harvested and cecal contents collected for analysis. ResultsThere were no significant differences in final body weights among the groups, nor did average daily food intake differ significantly among the HF-fed groups. HFPL animals had greater cecal weight (empty) and lower cecal contents pH when compared to all other groups, suggesting that polylactose is much more vigorously fermented than the other prebiotic fibers. This was also indicated by an increase in taxonomical abundance of probiotic species in the cecum. Epididymal fat pad weight was significantly decreased in the HFPL animals compared to all other HF groups (P < 0.05) and did not differ from the normal fat control (NFC). Liver lipids and cholesterol were significantly reduced in HFPL fed animals when compared to HFC fed animals and were numerically lower than all other HF groups. Transcriptome analysis of the liver revealed increased lipid oxidation and decrease lipid synthesis pathway expression, providing insights into mechanisms of reduction of lipid accumulation in the liver. ConclusionsPolylactose is a vigorously fermentable fiber and elicits a beneficial change in the gut microbiome. We also demonstrate that consuming polylactose, in the context of a high fat diet, prevents the accumulation of body fat normally seen with this diet, as well as reduced lipid and cholesterol accumulation in the liver. As these effects of polylactose were greater than those of two established prebiotics, fructooligosaccharides and polydextrose, this suggests that polylactose is a potent prebiotic. Funding SourcesMidwest Dairy Association.

Adipose Tissue Protein Glycoxidation is Associated with Weight‐Loss Potential

ObjectiveThis study aimed to characterize the differences in protein oxidation biomarkers in adipose tissue (AT) as an indicator of AT metabolism and bariatric surgery weight‐loss success.MethodsA human model, in which sixty‐five individuals with obesity underwent bariatric surgery, and a diet‐induced obesity animal model, in which animals were treated for 2 months with normocaloric diets, were analyzed to determine the associations between AT protein oxidation and body weight loss. Protein oxidative biomarkers were determined by gas chromatography/mass spectrometry in AT from human volunteers before the surgery, as well as 2 months after a diet treatment in the animal model.ResultsThe levels of carboxyethyl‐lysine (CEL) and 2‐succinocystein (2SC) in both visceral and subcutaneous AT before the surgery directly correlated with greater weight loss in both human and animal models. 2SC levels in subcutaneous AT greater than 4.7 × 106 μmol/mol lysine (95% CI: 3.4 × 106 to 6.0 × 106) may predict greater weight loss after bariatric surgery (receiver operating characteristic curve area = 0.8222; P = 0.0047). Additionally, it was observed that individuals with diabetes presented lower levels of CEL and 2SC in subcutaneous AT (P = 0.0266 and P = 0.0316, respectively) compared with individuals without diabetes.ConclusionsCEL and 2SC in AT are useful biomarkers of AT metabolism and predict the individual's ability to reduce body weight after bariatric surgery.

Inward Glucose Transfer Accounts for Insulin-Dependent Increase in Brain Glucose Metabolism Associated with Diet-Induced Obesity.

There is a general agreement that there are changes in brain metabolism in insulin-resistant individuals during conditions of hyperinsulinemia. However, the impact on obesity is unclear, and the metabolic constants underlying these modifications are unknown. The aim of this study was to evaluate these changes in a large animal model of diet-induced obesity. Twenty adult miniature pigs were fed with either an obesogenic diet or a regular diet for 5 months. At that time, fat deposition was evaluated using computed tomography scanning, and 18 fluorodeoxyglucose positron emission tomography images were acquired dynamically both in the fasted state and during a euglycemic-hyperinsulinemic clamp. Glucose uptake rates and pixel-wise modeled brain volumes were calculated together with brain connectivity. Whole-body insulin sensitivity was reduced by more than 50% in the obesity group. During insulin stimulation, whole-brain insulin-induced increased glucose uptake was unaltered in lean animals but increased markedly in the animals with obesity. The increased glucose uptake reflected an increase in the inward transfer without changes in phosphorylation or outward brain transport. Connectivity was increased in the animals with obesity CONCLUSIONS: Diet-induced obesity is associated with an increase in insulin-stimulated brain glucose uptake as a consequence of a larger inward transfer. These changes occurred together with an increased connectivity in reference to regions associated with memory recollection.

HIV-based lentivirus-mediated vasoactive intestinal peptide gene delivery protects against DIO animal model of Type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM. VIP gene expression was shown by immunocytochemistry (ICC) and VIP peptide secretion was confirmed by ELISA both in HepG2 liver and MIN6 pancreatic beta cell lines. Functional properties of VIP were demonstrated by cAMP production assay and glucose-stimulated insulin secretion test (GSIS). Intraperitoneal (IP) delivery of LentiVIP vectors into mice significantly increased serum VIP concentrations compared to control mice. Most importantly, LentiVIP delivery in DIO animal model of T2DM resulted in improved insulin sensitivity, glucose tolerance and protection against STZ-induced diabetes in addition to reduction in serum triglyceride/cholesterol levels. Collectively, these data suggest LentiVIP delivery should be evaluated as an experimental therapeutic approach for the treatment of T2DM.

A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models

The protein-tyrosine phosphatase PTP1B is a negative regulator of insulin and leptin signaling and a highly validated therapeutic target for diabetes and obesity. Conventional approaches to drug development have produced potent and specific PTP1B inhibitors, but these inhibitors lack oral bioavailability, which limits their potential for drug development. Here, we report that DPM-1001, an analog of the specific PTP1B inhibitor trodusquemine (MSI-1436), is a potent, specific, and orally bioavailable inhibitor of PTP1B. DPM-1001 also chelates copper, which enhanced its potency as a PTP1B inhibitor. DPM-1001 displayed anti-diabetic properties that were associated with enhanced signaling through insulin and leptin receptors in animal models of diet-induced obesity. Therefore, DPM-1001 represents a proof of concept for a new approach to therapeutic intervention in diabetes and obesity. Although the PTPs have been considered undruggable, the findings of this study suggest that allosteric PTP inhibitors may help reinvigorate drug development efforts that focus on this important family of signal-transducing enzymes.

Wheat germ supplementation alleviates insulin resistance and cardiac mitochondrial dysfunction in an animal model of diet-induced obesity.

Obesity is strongly associated with insulin resistance (IR), along with mitochondrial dysfunction to metabolically active tissues and increased production of reactive O2 species (ROS). Foods rich in antioxidants such as wheat germ (WG), protect tissues from damage due to ROS and modulate some negative effects of obesity. This study examined the effects of WG supplementation on markers of IR, mitochondrial substrate metabolism and innate antioxidant markers in two metabolically active tissues (i.e. liver and heart) of C57BL/6 mice fed a high-fat-high-sucrose (HFS) diet. Male C57BL/6 mice, 6-week-old, were randomised into four dietary treatment groups (n 12 mice/group): control (C, 10 % fat kcal), C+10 % WG, HFS (60 % fat kcal) or HFS+10 % WG (HFS+WG). After 12 weeks of treatment, HFS+WG mice had significantly less visceral fat (-16 %, P=0·006) compared with the HFS group. WG significantly reduced serum insulin (P=0·009), the insulinotropic hormone, gastric inhibitory peptide (P=0·0003), and the surrogate measure of IR, homoeostatic model assessment of IR (P=0·006). HFS diet significantly elevated (45 %, P=0·02) cardiac complex 2 mitochondrial VO2, suggesting increased metabolic stress, whereas WG stabilised this effect to the level of control. Consequently, genes which mediate antioxidant defense and mitochondrial biogenesis (superoxide dismutase 2 (Sod2) and PPARγ coactivator 1-α (Pgc1a), respectively) were significantly reduced (P<0·05) in the heart of the HFS group, whereas WG supplementation tended to up-regulate both genes. WG significantly increased hepatic gene expression of Sod2 (P=0·048) but not Pgc1a. Together, these results showed that WG supplementation in HFS diet, reduced IR and improved cardiac mitochondrial metabolic functions.

The effects of fatty acid composition on cardiac hypertrophy and function in mouse models of diet-induced obesity

High-fat diets (HFDs) are used frequently to study the development of cardiac dysfunction in animal models of obesity and diabetes. However, impairment in systolic function, often reported as declining ejection fraction, may not consistently occur in a given time frame which could be contributable to a variety of factors within the experimental design. One major factor may be the amounts of saturated and unsaturated fatty acids (FAs) that are present in the diet. To determine whether the FA content and composition were critical determinants in the development of cardiac dysfunction in response to high-fat feeding, we fed adult, male mice Western diet (45% fat, 60% saturated), Surwit diet (60% fat, 90% saturated), milk-fat-based diet (60% fat, 60% saturated) or high-fat Western diet (HFWD, 60% fat, 32% saturated) for 12 weeks. We report that neither the amount of total fat nor the ratio of saturated to unsaturated FAs in the diets differentially affects body weight and adiposity in mice. In addition, no evidence of systolic dysfunction is present after 12 weeks. Interestingly, the HFWD, with equal parts saturated, monounsaturated and polyunsaturated FAs, induces mild cardiac hypertrophy and diastolic dysfunction after 12 weeks, which coincides with elevated serum levels of arachidonic acid. Our results suggest that the dietary FA content and composition may be a primary determinant of diastolic, but not systolic, dysfunction in animal models of diet-induced obesity.

Is the FVB/N mouse strain truly resistant to diet-induced obesity?

C57Bl/6J mice are the gold standard animal model of diet‐induced obesity. These animals become obese with higher adiposity, blood fasting glucose, triglycerides, and total cholesterol when fed a high‐fat diet (HFD). Conversely, the FVB/N mouse line is thought to be resistant to diet‐induced obesity, with low or no weight gain and adiposity in response to a HFD. In this study, we investigated whether FVB/N mice are resistant or susceptible to metabolic disorder that is promoted by a HFD. Biometric parameters and blood chemistry were analyzed in C57Bl/6J and FVB/N mice that were fed a chow diet or HFD. Glucose and insulin sensitivity were assessed by performing the glucose tolerance test and measuring serum insulin/glucose and homeostasis model assessment‐insulin resistance. Metabolism‐related gene expression was investigated by real‐time reverse transcription polymerase chain reaction. Adipocyte morphology and liver steatosis were evaluated using standard histology. FVB/N mice had higher adiposity than C57Bl/6J mice that were fed a chow diet and were glucose intolerant. FVB/N mice that were fed a HFD presented higher insulin resistance and greater liver steatosis. Epididymal white adipose tissue exhibited severe inflammation in FVB/N mice that were fed a HFD. The FVB/N mouse strain is suitable for studies of diet‐induced obesity, and the apparent lack of a HFD‐induced response may reveal several strain‐specific events that are triggered by a HFD. Further studies of the FVB/N background may shed light on the complex multifactorial symptoms of obesity and metabolic syndrome.

Nebivolol Ameliorates Cardiac NLRP3 Inflammasome Activation in a Juvenile-Adolescent Animal Model of Diet-Induced Obesity.

NLRP3 is involved in obesity-induced cardiac remodeling and dysfunction. In this study, we evaluated whether the cardiac protective effects of nebivolol relied on attenuating NLRP3 activation in a juvenile-adolescent animal model of diet-induced obesity. Weaning male Sprague-Dawley rats were fed with either a standard chow diet (ND) or a high-fat diet (HFD) for 8 weeks. The obese rats were subsequently subdivided into three groups: 1) HFD control group; 2) HFD with low-dose nebivolol (5 mg/kg/d); 3) HFD with high-dose nebivolol (10 mg/kg/d). Treatment with nebivolol prevented HFD-induced obesity associated excess cardiac lipid accumulation as well as myocardial mitochondrial dysfunction. Nebivolol attenuated pro-inflammatory cytokines secretion and NLRP3 inflammasome activation in myocardium of obese rats. In parallel, nebivolol treatment of obese animals increased cardiac β3-AR expression, reversing the reduction of endothelial nitric oxide synthase (eNOS). In vitro, nebivolol treatment of palmitate-incubated H9C2 cells suppressed autophagy, restored mitochondrial biogenesis, leading to decreased mitochondrial reactive oxygen species (mtROS) generation, and suppressed NLRP3 inflammasome activation. Meanwhile the presence of shRNA against β3-AR or against eNOS deteriorated the protective effects of nebivolol. These data suggest the beneficial effect of nebivolol on myocardial lipotoxicity contributing to inhibiting NLRP3 inflammasome activation possibly via improved mitochondrial dysfunction.

Undaria pinnatifida and Fucoxanthin Ameliorate Lipogenesis and Markers of Both Inflammation and Cardiovascular Dysfunction in an Animal Model of Diet-Induced Obesity.

Brown algae and its carotenoids have been shown to have a positive influence on obesity and its comorbidities. This study evaluated the effect of Undaria pinnatifida and fucoxanthin on biochemical, physiological and inflammation markers related to obesity and on the expression of genes engaged on white adipose tissue lipid metabolism in a murine model of diet-induced obesity. The treatments improved energy expenditure, β-oxidation and adipogenesis by upregulating PPARα, PGC1α, PPARγ and UCP-1. Adipogenesis was also confirmed by image analysis of the retroperitoneal adipose tissue, by measuring cell area, perimeter and cellular density. Additionally, the treatments, ameliorated adipose tissue accumulation, insulin resistance, blood pressure, cholesterol and triglycerides concentration in serum, and reduced lipogenesis and inflammation by downregulating acetyl-CoA carboxylase (ACC) gene expression, increasing serum concentration and expression of adiponectin as well as downregulating IL-6 expression. Both fucoxanthin and Undaria pinnatifida may be considered for treating obesity and other diseases related.

D-Allulose supplementation normalized the body weight and fat-pad mass in diet-induced obese mice via the regulation of lipid metabolism under isocaloric fed condition.

A number of findings suggest that zero-calorie d-allulose, also known as d-psicose, has beneficial effects on obesity-related metabolic disturbances. However, it is unclear whether d-allulose can normalize the metabolic status of diet-induced obesity without having an impact on the energy density. We investigated whether 5% d-allulose supplementation in a high fat diet(HFD) could normalize body fat in a diet-induced obesity animal model under isocaloric pair-fed conditions. Mice were fed an HFD with or without various sugar substitutes (d-glucose, d-fructose, erytritol, or d-allulose, n = 10 per group) for 16 wk. Body weight and fat-pad mass in the d-allulose group were dramatically lowered to that of the normal group with a simultaneous decrease in plasma leptin and resistin concentrations. d-allulose lowered plasma and hepatic lipids while elevating fecal lipids with a decrease in mRNA expression of CD36, ApoB48, FATP4, in the small intestine in mice. In the liver, activities of both fatty acid synthase and β-oxidation were downregulated by d-allulose to that of the normal group; however, in WAT, fatty acid synthase was decreased while β-oxidation activity was enhanced. Taken together, our findings suggest that 5% dietary d-allulose led to the normalization of the metabolic status of diet-induced obesity by altering lipid-regulating enzyme activities and their gene-expression level along with fecal lipids.

Abstract P3-09-03: Combined effects of soy isoflavones and a high fat diet on the mammary gland in an animal model of diet-induced obesity

Abstract Scope: Obesity is a major risk factor for the development of breast cancer whereas isoflavone (ISO) exposure is discussed to reduce this risk. Aim of this study was to investigate effects of dietary soy ISO intake on proliferation and estrogenicity of ISO in the mammary gland of obese female Wistar rats. Methods: Female Wistar rats (5 – 7 rats / group) grew up on low fat ISO-depleted diet (LF IDD) or ISO-rich diet enriched with a soy based commercial extract (LF IRD; ISO: 467 mg / kg diet). Starting postnatal day 83, ovariectomized (OVX) and intact animals received high fat diet for 12 weeks to induce obesity in the absence (HF IDD) or presence of ISO (HF IRD, ISO: 431 mg / kg diet). A special diet switch group (HF IRD switch OVX), grew up on LF IDD but switched to HF IRD after ovariectomy. This mimics the short term exposure to ISO in postmenopausal Western women who take ISO supplements. Two groups receiving LF diet either with or without ISO (LF IRD, LF IDD) lifelong served as control. From ablactation until the end of the experiment body weight and food consumption were monitored twice a week. After 12 weeks of HF diet animals were sacrificed. Body weight, visceral fat mass, and serum leptin were measured, and breast tissue was excised. Protein expression of proliferating cell nuclear antigen (PCNA) and progesterone receptor (PR) in breast tissue was analyzed by both immunohistochemistry (IHC) and Western Blot as markers for proliferation and estrogenicity of ISO, respectively. Results: Analysis of ISO plasma levels revealed 1400 nM in LF IRD group and 300 – 700 nM in HF IRD groups. HF diet increased body weight, visceral fat mass and serum leptin levels compared to LF diet. In the mammary gland HF increased expression of proliferation marker PCNA and PR as compared to LF groups. Lifelong but not short term (HF IRD switch OVX) ISO exposure reduced body weight, visceral fat mass and leptin levels in HF OVX rats. In the mammary gland lifelong ISO exposure reduced PCNA expression in both LF and HF intact animals whereas in HF OVX animals lifelong ISO exposure increased PCNA expression compared to short term ISO exposure. PR expression increased in HF IRD OVX compared to HF IDD OVX. Conclusion: The ISO plasma levels of the rats are comparable to the average ISO plasma levels as found in Asian population. Our results show that lifelong ISO intake reduces the risk to develop obesity in female rats. In the mammary gland lifelong ISO exposure decreases cell proliferation and shows estrogenicity by increasing PR expression. Effects of short term ISO exposure are less strong compared to lifelong ISO exposure. This supports the hypothesis that only lifelong but not short term ISO exposure can reduce the risk to develop breast cancer. Citation Format: Kurrat A, Diel P, Blei T, Kluxen F, Mueller D, Pichotta M, Soukup S, Kulling S, Oden C. Combined effects of soy isoflavones and a high fat diet on the mammary gland in an animal model of diet-induced obesity. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-09-03.

Balsam Poplar (Populus Balsamifera), a Traditional Eastern James Bay Cree Medicine, exerts a Limited Modulation of Intestinal Lipid Homeostasis in an Animal Model of Diet-Induced Obesity

Balsam Poplar (Populus Balsamifera), a Traditional Eastern James Bay Cree Medicine, exerts a Limited Modulation of Intestinal Lipid Homeostasis in an Animal Model of Diet-Induced Obesity

Heart morphology in Zucker-obese rat

Obesity represents the central and causal component of the metabolic syndrome (MetS), which is a growing medical challenge in western countries as a result of changes in lifestyle. Obesity is also associated with an increased incidence of arterial hypertension and of cardiovascular disease burden. In animal models of diet-induced obesity, endothelial inflammatory activation, demonstrated by changes in adhesion molecule expression, is one of the earliest manifestation of vascular and cardiac damage. The intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin (Ig) superfamily present on the surface of several other cell types, including endothelial cells. Adhesion molecules [e.g., ICAM-1, vascular cell adhesion molecule 1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1)] if in contact with an activated endothelium could represent attractive targets for delivery of drugs and imaging probes to vascular pathological sites. The present study was designed to investigate, with morphological, immunochemical and immunohistochemical techniques, changes of heart and coronary arteries in Obese Zucker rats (OZR) compared to the lean Zucker rats (LZRs). The OZRs, with a mutation in leptin receptors, is a model of Type II diabetes mellitus, characterized by the presence of obesity, hyperglycemia, hyperinsulinemia, hyperlipidemia and moderate hypertension similar to MetS. The heart of OZRs of 12, 16 and 20 weeks was processed for microanatomical analysis and ICAM-1, VCAM-1 and PECAM-1 and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) immunohistochemistry. OZRs at the different age, developed ventricular hypertrophy, characterized by increase size of cardiomyocytes but not fibrosis compared to LZRs. This phenomenon was more evident in 20-weeks-old OZRs. VCAM-1 was more expressed in the coronary arteries compared to other adhesion molecules, and increased in the OZRs of 20-weeks of age. In the same age, IL-6 expression was significantly increased. These results suggest that the obesity leads to heart tissue changes and coronary inflammation. Myocardial vascular inflammation, induced by metabolic comorbidities, could contribute to the development of heart failure. Protective strategies in obesity may be focussed versus body weight loss and countering of metabolic alterations induced by obesity.

OC-106 Activation of the bile acid receptor, farnesoid-x receptor, may reduce ileal inflammatory cytokine expression in an animal model of diet-induced obesity

<h3>Introduction</h3> A high fat (HF)/high sugar (HS), Western diet has been implicated in the pathogenesis of IBD.¹The BA receptor, farnesoid-x receptor (FXR), is central to the crosstalk between the host and its microbiota.²FXR has an immuno-modulatory role in the GI tract.^3,4We hypothesised that disruption to BA signalling, induced by a HF/HS diet associated dysbiosis, is a mechanism linking diet to the development of IBD. The aim of this study was to investigate the effect of HF/HS feeding and FXR agonism on ileal inflammation in a mouse model of obesity. <h3>Method</h3> Animal husbandry was performed under licence from the Home Office (as per ASPA 1986). C3H/He mice (n = 44) were fed standard chow or HF/HS chow (trans-fats, with fructose corn syrup). At 24 weeks, feed was supplemented with an FXR agonist (5 mg/kg or 1 mg/kg of feed) or control. At 42 weeks, body weight and visceral adipose tissue (VAT) weight was recorded and the ileum was dissected. The expression of TNFα, IFNγ and IL-6 was measured by RT-PCR (ΔΔCt method). FXR and its downstream targets, SHP and IBABP, were measured to assay for FXR activity. <i>T-</i>tests, regression analysis and Pearson correlation were calculated using Prism version 6.0e. P values were 2-tailed, a P value of &lt;0.05 was considered significant. <h3>Results</h3> Mice fed a HF/HS diet were significantly heavier, with more VAT than mice on the control diet (mean weight of 49.9 g versus mean weight of 41.6 g, p &lt; 0.01). There was a positive correlation between the amount of VAT and the ileal expression of TNFα and IFNγ (y = 1.32*X p = 0.05, y = 1.24*X p = 0.02 respectively). The FXR agonist significantly increased the expression of IBABP (fold increase of 2.0, p = 0.01). In HF/HS fed mice, supplementation with 1 mg/kg FXR agonist attenuated the increase in ileal expression of all cytokines assayed, although the observed trend failed to reach significance. <h3>Conclusion</h3> Animals fed a western lifestyle diet express more ileal inflammatory cytokine. There is a trend to suggest that supplementation with an FXR agonist reduces diet induced cytokine expression. By mediating dietary risk, FXR may be a potential therapeutic target in IBD, particularly to reduce relapses in patients with known disease. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Ananthakrishnan AN. Gastroenterol Hepatol. 2013;9(6) Swann JR, Want EJ, <i>et al</i>. PNAS 2011;108(1) Vavassori P, Mencarelli A, <i>et al</i>. J Immunol. 2009;183 Gadaleta RM, van Erpecum KJ, <i>et al</i>. Gut 2011;60