Rat Model Of Diet-induced Obesity Research Articles

Compulsive-like eating of high-fat high-sugar food is associated with 'addiction-like' glutamatergic dysfunction in obesity prone rats.

Chronic overeating is a core feature of diet‐induced obesity. There is increasing evidence that in vulnerable individuals, such overeating could become compulsive, resembling an addictive disorder. The transition to compulsive substance use has been linked with changes at glutamatergic synapses in the nucleus accumbens. In this study, we investigated a potential link between such glutamatergic dysregulation and compulsive‐like eating using a rat model of diet‐induced obesity. A conditioned suppression task demonstrated that diet‐induced obese rats display eating despite negative consequences, as their consumption was insensitive to an aversive cue. Moreover, nucleus accumbens expression of GluA1 and xCT proteins was upregulated in diet‐induced obese animals. Lastly, both a computed ‘addiction score’ (based on performance across three criteria) and weight gain were positively correlated with changes in GluA1 and xCT expression in the nucleus accumbens. These data demonstrate that the propensity for diet‐induced obesity is associated with compulsive‐like eating of highly palatable food and is accompanied by ‘addiction‐like’ glutamatergic dysregulation in the nucleus accumbens, thus providing neurobiological evidence of addiction‐like pathology in this model of obesity.

Synbiotics intake improves disturbed metabolism in a rat model of high fat diet-induced obesity; A potential role of adipose tissue browning

Browning of white adipose tissue (WAT) is currently considered a potential therapeutic approach to treat or prevent diet-induced obesity. Synbiotics have protective effects against diet-induced obesity; however, its role in adipose tissue browning has been less investigated. to study the possible effect of synbiotics intake on browning of WAT in obese rats. Twenty-four adult male Wistar rats were randomly divided into four groups; normal diet (ND) control group, high fat diet (HFD) group, ND group receiving synbiotics, and HFD group receiving synbiotics. After eight weeks, all rats were sacrificed; and samples (blood, WAT, brown adipose tissue, and liver) were collected. Lipid profile, liver enzymes, fasting glucose, and fasting insulin levels were measured. The expression of browning-related genes: uncoupler protein-1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and peroxisome proliferator-activated receptors gamma (PPARγ) were measured by real-time polymerase chain reaction (PCR) in adipose tissues. Fibroblast growth factor 21 (FGF21) protein level was measured in serum, adipose and liver tissues, and FGF21 receptor expression was performed by real-time PCR in adipose tissues. ynbiotics intake was associated with improvement in lipid profile, liver enzymes, and insulin sensitivity in HFD rats. Moreover, the intake was associated with higher gene expression of brown adipocyte-specific markers. As for the FGF21 and its receptor, intriguing results were obtained that needs further in-depth studies. synbiotics might protect against diet-induced obesity through induction of thermogenic genes resulting in brown-like adipocyte phenotype in WAT.

Hypothesis: Amelioration of obesity-induced cognitive dysfunction via a lorcaserin-betahistine combination treatment.

The prolonged exposure to obesogenic diets disrupts the mesocortical dopaminergic input to the prefrontal cortex (PFC). This leads to suboptimal dopamine levels in this brain region, which affects cognition and control of food intake. Treatments that restore mesocortical dopaminergic neurotransmission may improve obesity‐associated cognitive dysfunction and modulate food intake to induce weight loss. Given the complexity and multifactorial nature of obesity, combination treatments would likely achieve sizeable and sustained body weight loss and improve obesity‐linked outcomes, such as cognitive dysfunction. Given this background, we hypothesize that concomitant activation of serotonin 5‐HT2C and histamine H1 receptors, coupled with antagonism of histamine H3 receptors, synergistically modulates mesocortical dopamine neurotransmission and ameliorates obesity‐induced cognitive dysfunction. We propose to test the hypothesis in a diet‐induced obesity (DIO) rat model by treating animals with the 5‐HT2C agonist lorcaserin and the H1 agonist and H3 antagonist betahistine. Consistent with our hypothesis, both lorcaserin and betahistine have been shown to reduce body weight in humans with obesity and animals. Both drugs have been demonstrated to improve cognitive functions by influencing dopaminergic signaling in the PFC. The proposed combination treatment addresses the paucity of studies on obesity treatments that improve cognitive function. This research may also help identify a potential targetable mechanism connecting obesity and neurocognitive outcomes.

PD16-09 THE ROLE OF GPER SIGNALING IN DEVELOPMENT OF PROSTATIC ENLARGEMENT IN HIGH FAT DIET INDUCED OBESITY RAT MODEL

You have accessJournal of UrologyCME1 May 2022PD16-09 THE ROLE OF GPER SIGNALING IN DEVELOPMENT OF PROSTATIC ENLARGEMENT IN HIGH FAT DIET INDUCED OBESITY RAT MODEL Shinsuke Mizoguchi, Kenichi Mori, Toshitaka Shin, and Hiromitsu Mimata Shinsuke MizoguchiShinsuke Mizoguchi More articles by this author , Kenichi MoriKenichi Mori More articles by this author , Toshitaka ShinToshitaka Shin More articles by this author , and Hiromitsu MimataHiromitsu Mimata More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002548.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although there has been increasing evidence that indicates positive relationship between metabolic syndrome and emergence in benign prostatic hyperplasia (BPH), the detailed pathophysiological mechanism is still unknown. Estrogen, which is increased in obese patients, is considered to be one of the key factors in development of BPH and G protein-coupled estrogen receptor (GPER) has been reported to be implicated in symptomatic BPH. To elucidate a role of GPER signaling in development of BPH, we evaluated changes in prostatic weight and inflammatory profiles in the prostate by GPER inhibition using high fat diet induced obesity rat model. METHODS: Male Wistar rats (8 weeks old) were divided into three groups; rats with normal diet group (ND, n=6), rats with high fat diet induced obesity group (HFD, n=6), and HFD treated by G15 (G15, n=6) which is GPER antagonist. The high fat diet contains 32% fat. These rats were maintained for twelve weeks followed by two weeks treatment by oral administration of placebo or G15 (0.1mg/kg) daily. Lateral lobes of prostate were harvested to assess prostatic weight, histological change and mRNA expression of GPER, IL1β, TGFβ, ERK1/2 by qPCR. RESULTS: HFD showed significantly increased body weight, visceral fat and prostatic weight as well as significant upregulation of gene expressions in GPER, IL1β, TGFβ, and ERK1/2 compared to ND. Hematoxylin and eosin (HE) staining showed inflammatory cell infiltration in prostatic tissue section from HFD. In contrast, HFD treated by G15 demonstrated significantly decreased prostatic weight in association with downregulation of IL1β, TGFβ and ERK1/2 compared to HFD with placebo. mRNA expression of GPER was not significantly changed between HFD and G15 group. CONCLUSIONS: We demonstrated improvement of prostatic enlargement and inflammation by GPER inhibition, which suggest GPER signaling has an important role in development of BPH in obese patients. Therefore, GPER inhibition could be an therapeutic target of BPH with metabolic syndrome. Source of Funding: KAKENHI 20K18094 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e272 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shinsuke Mizoguchi More articles by this author Kenichi Mori More articles by this author Toshitaka Shin More articles by this author Hiromitsu Mimata More articles by this author Expand All Advertisement PDF DownloadLoading ...

Time-Restricted Feeding Improved Vascular Endothelial Function in a High-Fat Diet-Induced Obesity Rat Model.

Obesity, where there is enhancement of stored body fat in adipose tissues, is associated with cardiovascular complications that are mainly related to atherosclerosis. Time-restricted feeding (TRF) is a form of restricted eating aimed at reducing weight in obese subjects. The present study aims to investigate changes in vascular endothelial function, endothelial nitric oxide synthase (eNOS), and protein kinase B (Akt) protein expressions with TRF in obese and normal rats. Male Sprague Dawley rats were divided into two normal and three obese groups; obesity was induced in the obese groups by feeding with a high-fat diet (HFD) for six weeks. After six weeks, rats were equally divided into five groups (n = 7 per group): Normal group (NR) which continued on a standard diet for six more weeks, normal group switched to TRF with a standard diet for six weeks (NR + TRFSD), obese group (OR) which continued on HFD for six more weeks, obese group switched to TRF of HFD (OR + TRFHFD), and obese group switched to TRF of a standard diet (OR + TRFSD). TRF was practiced for six weeks, after which the rats were sacrificed. Aortic endothelium-dependent and endothelium-independent relaxations and contractions were assessed using the organ bath. Aortic eNOS and Akt protein expressions were determined using immunoblotting. Fasting blood glucose, body weight, body mass index (BMI), serum lipid profile, Lee’s index, serum insulin levels, and sensitivity (HOMA-IR) were also measured. Endothelium-dependent relaxation was significantly impaired, while endothelium-dependent contraction increased in obese rats compared to that in normal rats. Both obese groups which underwent TRF with a HFD and standard diet improved their impairments in endothelium-dependent relaxation and reduced endothelium-dependent contraction; these were associated with increased expressions of aortic eNOS and Akt protein. Both obese groups with TRF reduced body weight, BMI, Lee’s index, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and improved insulin sensitivity. TRF improved endothelium-dependent relaxation and reduced endothelium-dependent contraction, thus attenuating endothelial dysfunction in obese rats. These were associated with increased aortic eNOS and Akt protein expressions.

Melatonin supplementation preserves testicular function by attenuating lactate production and oxidative stress in high fat diet-induced obese rat model

Metabolic syndrome, including obesity has been documented as a critical factor in male reproductive dysfunction with subsequent reduction in male fertility. The therapeutic potential of melatonin has been demonstrated against oxidative stress-induced pathologies. Therefore, the present study investigated the effects of melatonin on testicular dysfunction associated with high fat diet (FD)-induced obese rat model, and the possible involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ). Adult male Wistar rats (n = 6/group) were used: control group received vehicle (normal saline), obese group received 40% FD, melatonin-treated group received melatonin (4 mg/kg), and obese plus melatonin group received melatonin and 40% FD and the treatment lasted for 12 weeks. High fat diet caused increased body weight and testicular triglyceride, total cholesterol, malondialdehyde, γ-glutamyl transferase, lactate production and lactate/pyruvate ratio as well as decreased glutathione/glutathione peroxidase, nitric oxide and PPAR-γ and circulating testosterone. Nevertheless, all these alterations were attenuated when supplemented with melatonin. Taken together, these results demonstrates that FD-induced obesity causes testicular dysfunction. In addition, the results suggest that melatonin supplementation protects against obesity-associated testicular dysfunction and this effect is accompanied by upregulation of PPAR-γ.

Acetate-mediated-obestatin modulation attenuates adipose-hepatic dysmetabolism in high fat diet-induced obese rat model.

Approximately 650 million of world adult population is affected by obesity, which is characterized by adipose and hepatic metabolic dysfunction. Short chain fatty acids (SCFAs) have been linked to improved metabolic profile. However, the effect of SCFAs, particularly acetate on adipose-hepatic dysfunction is unclear. Therefore, the present study investigated the role of acetate on adipose-hepatic metabolic dysfunction and the possible involvement of obestatin in high fat diet-induced obese Wistar rats. Adult male Wistar rats (160-190 g) were allotted into groups (n = 6/group): Control, acetate-treated, obese and obese + acetate-treated groups received vehicle (distilled water), sodium acetate (200 mg/kg), 40% HFD and 40% HFD plus sodium acetate respectively. The administration lasted for 12 weeks. HFD caused increased body weight gain and visceral adiposity, insulin resistance, hyperinsulinemia and increased pancreatic-β cell function and plasma/hepatic triglyceride and total cholesterol as well as decreased adipose triglyceride and total cholesterol, increased plasma, adipose, and hepatic malondialdehyde, TNF-α, uric acid, lactate production and plasma/adipose but not gamma-glutamyl transferase and decreased plasma, adipose, and hepatic nitric oxide, glucose-6-phosphate dehydrogenase (G6PD), glutathione (GSH) and obestatin concentration compared to the control group. Notwithstanding, treatment with acetate attenuated the alterations. The results demonstrate that high fat diet-induced obesity is characterized with adipose and hepatic lipid dysmetabolism, which is associated with obestatin suppression. Findings also suggest that acetate provide protection against adipose and hepatic metabolic perturbations by restoring obestatin as well as G6PD/GSH-dependent antioxidant system.

A0593 - The effect of GPER inhibition on prostatic enlargement and chronic inflammation in high fat diet induced obesity rat model

A0593 - The effect of GPER inhibition on prostatic enlargement and chronic inflammation in high fat diet induced obesity rat model

Changes in mechanical properties of adipose tissue after bariatric surgery driven by extracellular matrix remodelling and neovascularization are associated with metabolic improvements

Biomechanical properties of adipose tissue (AT) are closely involved in the development of obesity-associated comorbidities. Bariatric surgery (BS) constitutes the most effective option for a sustained weight loss in addition to improving obesity-associated metabolic diseases including type 2 diabetes (T2D). We aimed to determine the impact of weight loss achieved by BS and caloric restriction (CR) on the biomechanical properties of AT. BS but not CR changed the biomechanical properties of epididymal white AT (EWAT) from a diet-induced obesity rat model, which were associated with metabolic improvements. We found decreased gene expression levels of collagens and Lox together with increased elastin and Mmps mRNA levels in EWAT after BS, which were also associated with the biomechanical properties. Moreover, an increased blood vessel density was observed in EWAT after surgery, confirmed by an upregulation of Acta2 and Antxr1 gene expression levels, which was also correlated with the biomechanical properties. Visceral AT from patients with obesity showed increased stiffness after tensile tests compared to the EWAT from the animal model. This study uncovers new insights into EWAT adaptation after BS with decreased collagen crosslink and synthesis as well as an increased degradation together with enhanced blood vessel density providing, simultaneously, higher stiffness and more ductility. Statement of SignificanceBiomechanical properties of the adipose tissue (AT) are closely involved in the development of obesity-associated comorbidities. In this study, we show for the first time that biomechanical properties of AT determined by E, UTS and strain at UTS are decreased in obesity, being increased after bariatric surgery by the promotion of ECM remodelling and neovascularization. Moreover, these changes in biomechanical properties are associated with improvements in metabolic homeostasis. Consistently, a better characterization of the plasticity and biomechanical properties of the AT after bariatric surgery opens up a new field for the development of innovative strategies for the reduction of fibrosis and inflammation in AT as well as to better understand obesity and its associated comorbidities.

Effects Of Melatonin Suplementation On Body Mass Index In A Diet-Induced Obesity Rat Model

Introduction: Оbesity has been labelled as a “non-infectious pandemic of our time”. It increases the risk of several debilitating diseases , including cardiovascular disorders, diabetes mellitus, tumors, and other pathologies. Up to date both therapeutic and preventive approaches have been largely unsuccessful. At the present time body mass index (BMI) is considered the most common anthropometric method to diagnose obesity. According to a variety of in vivo and in vitro studies, exogenous melatonin has a pronounced effect on carbohydrate and lipid metabolism. Furthermore, supplementation with melatonin improves oxidative stress and insulin resistance preventing hypertrophy of the adipose tissue and body weight gain. Aim: We evaluated the effect of melatonin supplementation on BMI and retroperitoneal fat mass in diet-induced obesity rat model. Materials and Methods: Male Wistar rats (n = 32), provided with standard rat chow and tap water freely available, were randomly divided into four groups as follows: control group – rats received standard rodent diet and tap water; melatonin group – rats received standard rodent diet and tap water, and melatonin administered per os (4 mg/kg/24h); fructose group – rats received standard rodent diet and tap water supplemented with 20% fructose; and fructose plus melatonin group – rats received standard rodent diet and tap water supplemented with 20% fructose, and melatonin administered per os (4 mg/kg/24 h). At the end of the experimental period, the animals were sacrificed, zoo metric measurements were taken and BMI was calculated . Results: St atistically significant differences were observed between the anthropometric parameters of the experimental groups. When compared with the control group, fructose-supplemented rats showed a remarkable increase in retroperitoneal fat mass and BMI. In contrast, groups supplemented with melatonin showed s ignificant reductions in these parameters. Conclusion: Melatonin supplementation reduces fructose-induced obesity. In particular, body weight, retroperitoneal fat mass and BMI were remarkably decreased in melatonin-treated groups.

Daily transient coating of the intestine leads to weight loss and improved glucose tolerance

IntroductionRoux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis. MethodsSprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry. ResultsAt 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ± 3.8 mg/dl vs. 99.1 ± 2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption. ConclusionWe demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.

Supplementation with Lactiplantibacillus plantarum IMC 510 Modifies Microbiota Composition and Prevents Body Weight Gain Induced by Cafeteria Diet in Rats.

Changes in functionality and composition of gut microbiota (GM) have been associated and may contribute to the development and maintenance of obesity and related diseases. The aim of our study was to investigate for the first time the impact of Lactiplantibacillus (L.) plantarum IMC 510 in a rat model of diet-induced obesity, specifically in the cafeteria (CAF) diet. This diet provides a strong motivation to voluntary overeat, due to the palatability and variety of selected energy-dense foods. The oral administration for 84 days of this probiotic strain, added to the CAF diet, decreased food intake and body weight gain. Accordingly, it ameliorated body mass index, liver and white adipose tissue weight, hepatic lipid accumulation, adipocyte size, serum parameters, including glycemia and low-density lipoprotein levels, in CAF fed rats, potentially through leptin control. In this scenario, L. plantarum IMC 510 showed also beneficial effects on GM, limiting the microbial imbalance established by long exposure to CAF diet and preserving the proportion of different bacterial taxa. Further research is necessary to better elucidate the relationship between GM and overweight and then the mechanism of action by which L. plantarum IMC 510 modifies weight. However, these promising results prompt a clear advantage of probiotic supplementation and identify a new potential probiotic as a novel and safe therapeutic approach in obesity prevention and management.

Moderate aerobic exercise, but not dietary prebiotic fibre, attenuates losses to mechanical property integrity of tail tendons in a rat model of diet-induced obesity

The purpose of this study was to investigate the alterations with obesity, and the effects of moderate aerobic exercise or prebiotic dietary-fibre supplementation on the mechanical and biochemical properties of the tail tendon in a rat model of high-fat/high-sucrose (HFS) diet-induced obesity. Thirty-two male Sprague-Dawley rats were randomized to chow (n = 8) or HFS (n = 24) diets. After 12-weeks, the HFS fed rats were further randomized into sedentary (HFS sedentary, n = 8), exercise (HFS + E, n = 8) or prebiotic fibre supplementation (HFS + F, n = 8) groups. After another 12-weeks, rats were sacrificed, and one tail tendon was isolated and tested. Stress-relaxation and stretch-to-failure tests were performed to determine mechanical properties (peak, steady-state, yield and failure stresses, Young’s modulus, and yield and failure strains) of the tendons. The hydroxyproline content was also analyzed. The HFS sedentary and HFS + F groups had higher final body masses and fat percentages compared to the chow and HFS + E groups. Yield strain was reduced in the HFS sedentary rats compared to the chow rats. Peak and steady-state stresses, failure strain, Young’s modulus, and hydroxyproline content were not different across groups. Although the HFS + E group showed higher failure stress, yield stress, and yield strain compared to the HFS sedentary group, HFS + F animals did not produce differences in the properties of the tail tendon compared to the HFS sedentary group. These results indicate that exposure to a HFS diet led to a reduction in the yield strain of the tail tendon and aerobic exercise, but not fibre supplementation, attenuated these diet-related alterations to tendon integrity.

Effect of Allium sativum extract in combination -with orlistat on insulin resistance and disrupted metabolic hormones in high fat diet induced obese rats

Obesity has increased in epidemic proportions globally and the current antiobesity drugs have treatment limitations which further reduce treatment benefits. The aim of this study was to evaluate the effect of Allium sativum and Orlistat on insulin resistance, fatty acid content and metabolic hormones; leptin, ghrelin and adiponectin in high-fat diet-induced obese rat model. The sprague-dawley rats used in this study were fed with standard chow as control diet, Fat emulsion as high-fat diet (HFD), HFD+ Orlistat, HFD+ A. sativum extract and HFD+ Orlistat+ A. sativum extract. Free fatty acid, serum glucose, insulin, leptin, ghrelin, adiponectin, and Homeostasis model assessment for insulin resistance (HOMA-IR) index were determined using standard methods. HFD significantly increased (P < .001) body weight, serum glucose, free fatty acid content, serum insulin, HOMA-IR and serum leptin. Furthermore, HFD reduced the serum levels of ghrelin and adiponectin when compared to control rats. The combined administration of A. sativum and orlistat resulted in a decrease in the body weight and HOMA-IR and also improved serum levels of glucose, insulin, leptin, ghrelin and adiponectin in obese rats fed with HFD. This suggests A. sativum in combination with orlistat, has the potential to ameliorate insulin resistance and metabolic hormones disrupted by obesity

Anti-Obesity and Lipid Lowering Activity of Bauhiniastatin-1 is Mediated Through PPAR-γ/AMPK Expressions in Diet-Induced Obese Rat Model

Objective: To evaluate the therapeutic efficacy and underlying molecular mechanisms of Bauhiniastatin-1 (BSTN1) to alleviate adiposity in diet-induced obese rodent model and in 3T3-L1 cells. Methods: BSTN1 was purified and confirmed through HPLC. In-vitro experiments such as MTT assay, Oil Red-O (ORO) stain, cellular lipid content, glycerol release and RT-PCR analysis were performed in 3T3-L1 cells in the presence and absence of BSTN1. In animal experiments, rats were divided into Group-I: normal pellet diet-fed, Group-II: HFD-fed, Groups-III, IV and V: HFD-fed BSTN1 (1.25, 2.5, and 5 mg/kg.b.wt./day/rat)-treated and Group-VI: HFD-fed Orlistat-treated. The rats were fed either normal diet or high fat diet (HFD) for 18 weeks and water ad-libitum. BSTN1 was orally administered from 13th week onwards to the selected HFD-fed groups. Body composition parameters, biochemical assays, histopathology examination and western blot analysis were performed to identify the predicted targets related to obesity. Molecular docking studies threw light on the binding interactions of BSTN1 against PPAR-γ, FAS and AMPK. Results: BSTN1 at 20 μM significantly (p < 0.001) inhibited adipocyte differentiation and lipid accumulation in 3T3-L1 cells. A conspicuous down-regulation in the mRNA expression levels of PPAR-γ, FAS and SREBP1 was observed but AMPK expression remained unchanged in BSTN1 treated 3T3-L1 cells. A substantial decrease in body weight gain, fat percent, total body fat, serum and liver lipid profile (except high-density lipoprotein), glucose, insulin and insulin resistance in BSTN1 treated rats was noticed in a dose dependent manner. In BSTN1 (5 mg/kg.b.wt.)-treated groups significantly (p < 0.01) elevated plasma adiponectin level but reduced leptin level as well as fall in serum AST and ALT were noticed. Further, the disturbed structural integrity and architecture of adipose and hepatic tissues due to high fat diet feeding were considerably recovered with BSTN1 treatment. Down-regulation in the protein expression level of PPAR-γ and activation of AMPK through phosphorylation was observed in BSTN1 treated rats than the untreated. Molecular docking studies revealed strong binding interactions of BSTN1 against PPAR-γ and AMPK and thus supported the experimental results. Conclusion: Taken together, the results suggest that BSTN1 could be a promising pharmacological molecule in the treatment of obesity and dyslipidemia.

Metformin alleviates monoamine oxidase-related vascular oxidative stress and endothelial dysfunction in rats with diet-induced obesity.

In the past decade, monoamine oxidase (MAO) with 2 isoforms, MAO-A and B, has emerged as an important source of mitochondrial reactive oxygen species (ROS) in cardio-metabolic pathologies. We have previously reported that MAO-related oxidative stress mediates endothelial dysfunction in rodent models of diabetes and diabetic patients; however, the role of MAO in the vascular impairment associated to obesity has not been investigated so far. Metformin (METF), the first-line drug in the therapy of type 2 diabetes mellitus, has been reported to elicit vasculoprotective effects via partially elucidated mechanisms. The present study was purported to assess the effects of METF on MAO expression, ROS production and vasomotor function of aortas isolated from rats with diet-induced obesity. After 24weeks of high calorie junk food (HCJF) diet, isolated aortic rings were prepared and treated with METF (10μM, 12h incubation). Measurements of MAO expression (quantitative PCR and immune histochemistry), ROS production (spectrometry and immune-fluorescence) and vascular reactivity (myograph studies) were performed in rat aortic rings. MAO expression was upregulated in aortic rings isolated from obese rats together with an increase in ROS production and an impairment of vascular reactivity. METF decreased MAO expression and ROS generation, reduced vascular contractility and improved the endothelium-dependent relaxation in the diseased vascular preparations. In conclusion, METF elicited vascular protective effects via the mitigation of MAO-related oxidative stress in the rat model of diet-induced obesity.

Abstract 2567: Duavee® improves metabolic health without increasing cancer risk: findings from a preclinical model of obesity and postmenopausal breast cancer

Abstract Introduction: Many women at high risk for breast cancer will not take standard selective estrogen receptor modulators (SERMs) for cancer prevention due to concern of side effects, especially vasomotor symptoms. Duavee®, a tissue selective complex of the SERM bazedoxifene (BZA; 20mg) + conjugated estrogen (CE; 0.45mg), is FDA approved for relief of hot-flashes. Preclinical and early phase human studies suggest Duavee® has potential for breast cancer prevention, with favorable change in mammographic fibroglandular volume and proliferation. Given the &amp;gt;40% incidence of obesity in postmenopausal women, and that obesity increases breast cancer risk, the current study was aimed at identifying the effects of obesity on response to Duavee® in a rodent model of obesity and postmenopausal breast cancer. Methods: This study used our well-characterized rat model of diet-induced obesity and postmenopausal ER-positive breast cancer. Rats were injected with N-methylnitrosourea (MNU, 50 mg/kg) at 7 weeks of age to induce mammary tumors and fed a high fat diet (HF; 46% kcal fat) to promote obesity. Lean and obese rat were selected based on % body fat at 16 weeks. Tumors were monitored by manual palpation weekly and measured using digital calipers. Tumor-bearing rats were ovariectomized (OVX) when a tumor reached 0.7cm3. Rats were then maintained on ad libitum HF diet or HF diet plus a daily oral dose of Duavee® (3mg BZA+ 0.07mg CE/kg body weight) for 8 weeks. Body composition was analyzed biweekly (qMR) and fat pads weighed at study end to determine regional fat distribution. Results: Like menopause in women, OVX induces weight gain in this model. Duavee® significantly blunted the OVX-induced weight gain in both lean (-65%, p&amp;lt;0.001) and obese (-88%, p&amp;lt;0.001) rats compared to controls. Similarly, Duavee®-treated rats gained less body fat after OVX vs controls (-50% lean; -97% obese, p&amp;lt;0.001). Duavee® administration was associated with reduction in glucose in obese rats after 2 weeks and in lean and obese rats after 8 weeks (-11% vs controls, p=0.03). The effects of Duavee® on regional fat deposition varied by adiposity. Obese Duavee®-treated rats had significantly lower pericardial fat (-17%, p&amp;lt;0.05) and tended to have lower mammary fat (-19%, p=0.08); lean rats had less gonadal fat (-20%, p&amp;lt;0.05), while deposition in this region was not altered by Duavee® in obese rats. At 8 weeks there was no evidence that Duavee® promoted tumor development or growth in lean or obese OVX rats. Conclusions: These data suggest that Duavee® may provide beneficial effects on body composition and metabolism in obese OVX animals without promotion of tumor growth. Further analyses will include study of direct effects of Duavee® on tumors, the tumor microenvironment, and systemic markers of insulin resistance and mammary cancer risk in our rat model of pre-and postmenopausal obesity and breast cancer. Citation Format: Karen A. Corleto, Tara N. Mahmood, Danilo Landrock, Stephen D. Hursting, Carol J. Fabian, Bruce F. Kimler, Erin D. Giles. Duavee® improves metabolic health without increasing cancer risk: findings from a preclinical model of obesity and postmenopausal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2567.

N-acetylcysteine reduces addiction-like behaviour towards high-fat high-sugar food in diet-induced obese rats.

Compulsive forms of eating displayed by some obese individuals share similarities with compulsive drug-taking behaviour, a hallmark feature of substance use disorder. This raises the possibility that drug addiction treatments may show utility in the treatment of compulsive overeating. N-Acetylcysteine (NAC) is a cysteine pro-drug which has experienced some success in clinical trials, reducing cocaine, marijuana and cigarette use, as well as compulsive behaviours such as gambling and trichotillomania. We assessed the impact of NAC on addiction-like behaviour towards highly palatable food in a rat model of diet-induced obesity. Adult male Sprague-Dawley rats were placed on a high-fat high-sugar diet for 8weeks and then assigned to diet-induced obesity-prone (DIO) or diet-induced obesity-resistant (DR) groups based on weight gain. DIO and DR rats were subjected to an operant conditioning paradigm whereby rats could lever press for high-fat high-sugar food pellets. This alternated with periods of signalled reward unavailability. Before treatment DIO rats ate more in their home cage, earned more food pellets in operant sessions, and responded more during periods that signalled reward unavailability (suggestive of compulsive-like food seeking) compared with DR rats. This persistent responding in the absence of reward displayed by DIO rats was ameliorated by daily injections of NAC (100mg/kg, i.p.) for 14days. By the end of the treatment period, lever-pressing by NAC-treated DIO rats resembled that of DR rats. These findings suggest that NAC reduces addiction-like behaviour towards food in rats and supports the potential use of this compound in compulsive overeating.

Contractility of permeabilized rat vastus intermedius muscle fibres following high-fat, high-sucrose diet consumption.

Obesity is a worldwide health concern associated with impaired physical function. It is not clear if contractile protein dysfunction contributes to the impairment of muscle function observed with obesity. The purpose of this study was to examine if diet-induced obesity affects contractile function of chemically permeabilized vastus intermedius fibres of male Sprague-Dawley rats expressing fast myosin heavy chain (MHC) IIa or slow MHC I. Rats consumed either a high-fat, high sucrose (HFHS) diet or a standard (CHOW) diet beginning as either weanlings (7-week duration: WEAN7 cohort, or 14-week duration: WEAN14 cohort) or young adults (12-week duration: ADULT12 cohort, 24-week duration: ADULT24 cohort). HFHS-fed rats had higher (P < 0.05) whole-body adiposity (derived from dual-energy X-ray absorptiometry) than CHOW-fed rats in all cohorts. Relative to CHOW diet groups, the HFHS diet was associated with impaired force production in (a) MHC I fibres in the ADULT24 cohort; and (b) MHC IIa fibres in the ADULT12 and ADULT24 cohorts combined. However, the HFHS diet did not significantly affect the Ca2+-sensitivity of force production, unloaded shortening velocity, or ratio of active force to active stiffness in any cohort. We conclude that diet-induced obesity can impair force output of permeabilized muscle fibres of adult rats. Novelty: We assessed contractile function of permeabilized skeletal muscle fibres in a rat model of diet-induced obesity. The high-fat, high-sucrose diet was associated with impaired force output of fibres expressing MHC I or MHC IIa in some cohorts of rats. Other measures of contractile function were not significantly affected by diet.

Diallyl Trisulfide Prevents Obesity and Decreases miRNA-335 Expression in Adipose Tissue in a Diet-Induced Obesity Rat Model.

Diallyl trisulfide (DATS), an organosulfur compound generates in crushed garlic, has various beneficial health effects. A growing body of evidence indicates that miRNAs are involved in the pathology of lifestyle diseases including obesity. The anti-obesogenic effect of garlic is previously reported; however, the effects of DATS on obesity, and the relationship between garlic compounds and the involvement of miRNA remains unclear. Here, the anti-obesogenic activity of DATS and the potential role of miRNA in a diet-induced obesity rat model are investigated. Oral administration of DATS suppressed body and white adipose tissue (WAT) weight gain in rats fed a high-fat diet compared with vehicle-administered rats. DATS lowered the plasma and liver triglyceride levels in obese rats, and decreased lipogenic mRNA levels including those of Srebp1c, Fasn, and Scd1 in the liver. DATS also suppressed de novo lipogenesis in the liver. Transcriptomic analyses of miRNA and mRNA in the epididymal WAT of obese rats using microarrays revealed that DATS decreased miRNA-335 expression and normalized the obesity-related mRNA transcriptomic signatures in epididymal WAT. The potent anti-obesogenic effects of DATS and its possible mechanism of action was clearly demonstrated in this study.