A High-Fat Diet Induces Cardiac Damage in Obesity-Resistant Rodents with Reduction in Metabolic Health.

BACKGROUND/AIMS: Obesity resistance is associated with the complex interaction of stringent and environmental factors that confer the ability to resist mass gain and body fat deposition, even when eating high-calorie diets. Considering that there are numerous gaps in the literature on the metabolic processes that explain Obesity resistance, specifically in relation to oxidative stress, the purpose of the study was to investigate whether obesity-resistant (OR) rats develop elevated reactive oxygen species in cardiac tissue. METHODS: Wistar rats were initially randomized into two groups: a standard diet (SD) and a high-fat diet (HFD) group. The SD and HFD groups were further divided into control (C), OR, and obese prone (OP) subgroups based on body weight. This criterion consisted of organizing the animals in each group in ascending order according to body weight (BW), and the cutoff point was identified in the animals by terciles: 1) lower BW; 2) intermediate BW; and 3) higher BW. Rats were sacrificed on the 14th week, and serum and organs were collected. Nutritional assessment, food profiles, histological analysis, comorbidities, and cardiovascular characteristics were determined. RESULTS: BW showed a significant difference between the standard diet and high-fat diet groups in the 4th week of the experimental protocol, characterizing obesity. In the 4th week, after the characterization of Obesity resistance, there was a significant difference in BW between groups C, OP, and OR. The OP and OR groups showed a significant increase in caloric intake in relation to the C group. The OP group showed a significant increase in final BW, retroperitoneal fat pad mass, sum of corporal fat deposits and reactive oxygen species, in relation to groups C and OR. The area under the glycemic curve, insulin resistance index and basal glucose were elevated in the OP group in relation to the C. OP also promoted an increase in HOMA-IR when compared with C. OR rats showed a non-significant increase in insulin and HOMA-IR in OR vs. C (p = ~0.1), but no significant differences were observed between OP vs. OR for these parameters, suggesting that both groups suffered from decreased metabolic health. Total cardiac mass, left ventricular cross-sectional area, and cholesterol levels were significantly elevated in the OP and OR groups compared with the C group. CONCLUSION: A high-fat diet induces cardiac damage in obesity-resistant rodents with reduction in metabolic health.

Effects of hypercaloric diet-induced hyperinsulinemia and hyperlipidemia on the ovarian follicular development in mice.

Long-term hypercaloric diets may adversely affect the development of ovarian follicles. We investigated the effects of high sugar (HS), high fat low sugar (HFLS), and high fat normal sugar (HFNS) diets on the ovarian follicle development in mice fed with these diets as compared to those fed with normal diet (control) for 180 days. Body weight, gonadal fat, glucose, lipid, insulin, estrous cycle, sex hormones and ovarian tissues were examined, and metabolism-related protein expression in the ovaries was evaluated by immunoblotting. The mice fed with hypercaloric diets showed hyperinsulinemia and hyperlipidemia, and exhibited heavier body and gonadal fat weights, longer estrous cycles, and fewer preantral and antral follicles than mice fed with normal diet. The sex hormone levels in the blood were similar to those in controls, except for significantly elevated estradiol levels in the HS diet group. The AMPKα phosphorylation was reduced, while AKT phosphorylation and caspase-3 levels were increased in the ovarian tissues of mice in all three hypercaloric diet groups than those in control. Taken together, the results suggest hyperinsulinemia and hyperlipidemia as possible mechanisms that impair the development of ovarian follicles in response to long-term exposure to unhealthy hypercaloric diets.

High-Fat and Combined High-Fat and Sucrose Diets Promote Cardiac Oxidative Stress Independent of Nox2 Redox Regulation and Obesity in Rats.

BACKGROUND/AIMS: Oxidative stress is associated with cardiometabolic alterations, and the involvement of excess glucose and fatty acids has been demonstrated in this process. Thus, the aim of this study was to investigate the effects of different hypercaloric diets on cardiac oxidative stress. METHODS: Wistar rats were randomized into four groups: control (C), high-sucrose (HS), high-fat (HF), and high-fat with sucrose (HFS). Nutritional assessment, food profiles, histological analysis, comorbidities, and cardiovascular characteristics were determined. Cardiac oxidative stress was analyzed by malondialdehyde (MDA) and carbonylated proteins, and the cardiac protein expression levels of type 1 angiotensin receptor (AT-1), nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), superoxide dismutase (SOD 1 e 2), glutathione peroxidase (GPX), and catalase (CAT) were determined by western blot. RESULTS: The HF group showed an increase in adiposity; however, it did not present adipocyte hypertrophy and comorbidities. Cardiac MDA and carbonylated protein levels were higher in the HF and HFS compared with the C group. The levels of oxidant and antioxidant proteins showed no difference between the groups. CONCLUSION: HF and HFS dietary interventions promoted cardiac oxidative stress, in the presence and absence of obesity, respectively. However, this process was neither mediated by the pro-oxidants AT1 and Nox2, nor by the quantitative reduction of antioxidant enzymes.

Oxidative stress in animal models of obesity caused by hypercaloric diets: A systematic review.

Obesity is a global health difficulty characterized by an excessive accumulation of fat that increases body weight. Obesity has been studied in multiple animal models, of which those in which it is induced by diet stand out. Due to the increase in this condition, other mechanisms have been addressed that are triggered by states of overweight or obesity, such as the appearance of oxidative stress. These models aim to relate obesity caused by diet and how it influences the development of oxidative stress. In this study, a systematic review of the literature of 39 articles that studied obesity due to the consumption of hypercaloric diets and the appearance of oxidative stress in different animal models was carried out. This review identified the models with the most excellent use and the characteristics of the most appropriate diets to characterize states of oxidative stress due to obesity. In addition, the advantages and disadvantages of each model used are provided, as well as the techniques used for the assessment of obesity, and oxidative stress, providing the information in such a way that there is a general overview of the existing models of the parameters that allow to adequately establish both variables studied, providing information that allows the researcher to choose the appropriate model and factors according to the interest and objectives of the present research.

High-carbohydrate and fat diet consumption causes metabolic deterioration, neuronal damage, and loss of recognition memory in rats.

The number of people diagnosed with metabolic syndrome (MetS) has increased dramatically to reach alarming proportions worldwide. The origin of MetS derives from bad eating habits and sedentary lifestyle. Most people consume foods high in carbohydrates and saturated fat. In recent years, it has been reported that alterations in insulin at the brain level could have an impact on the appearance of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dementia, depression, and other types of disorders that compromise brain function. These alterations have been associated with damage to the structure and function of neurons located in the reptilian and limbic systems, a decrease in dendritic arborization and an exacerbated inflammatory state that impaired learning and memory and increased in the state of stress and anxiety. Although the molecular mechanisms induced by MetS to cause neurodegeneration are not fully understood. The aim of this study is to know the effect of the intake of hypercaloric diets on the structure and function of neurons located in the frontal cortex, hypothalamus and hippocampus and its impact on behavior in rats with metabolic syndrome. In conclusion, the present study illustrated that chronic exposure to hypercaloric diets, with a high content of sugars and saturated fatty acids, induces a proinflammatory state and exacerbates oxidative stress in brain regions such as the hypothalamus, hippocampus, and frontal cortex, leading to dysfunction. metabolism, neuronal damage, and recognition memory loss.

Dysmetabolism and Neurodegeneration: Trick or Treat?

Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.

Differential biochemical-inflammatory patterns in the astrocyte-neuron axis of the hippocampus and frontal cortex in Wistar rats with metabolic syndrome induced by high fat or carbohydrate diets.

Metabolic syndrome (MetS) is a public health problem and a risk of developing cardiometabolic and neurodegenerative diseases. The biochemical-inflammatory impairment in brain areas related to learning and memory has not been differentiated between MetS models. We aimed to compare the effect of the MetS generated by consuming high-fat (HFD) or -carbohydrate diets (HCD) on the hippocampus and frontal cortex, related to astrocyte-neuron metabolism and neuroinflammation origin. Sixty male Wistar rats were separated into three groups: 1) control group, 2) HCD group, and 3) HFD group. After 3 months, we evaluated zoometry, a serum bioclinical profile, and in the hippocampus and frontal cortex, we performed biochemical assays (concentration of lactate, glutamate, fatty acids, and ASAT, ALAT, and LDH activity), immunoreactivity tests (GFAP, COX2, CD36, and BDNF), and immunoassays (TNF-α, IL-1ß, IL-6, and PGE2). The bioclinical parameters showed that both diets induce MetS. At the brain level, it is noteworthy that the HCD group had an increase in lactate and glutamate concentration, reactive astrogliosis, immunoreactive COX2 neurons in the CA1 subfield hippocampus and frontal cortex, and high levels of PGE2, TNF-α, IL-1ß, and IL-6, and low BDNF immunoreactivity. Meanwhile, the HFD is highlighted by increased fatty acid levels and CD36 expression in the hippocampus and frontal cortex, strong reactive astrogliosis and COX2 immunoreactivity, and the greatest inflammation with the lowest BDNF immunoreactivity. In conclusion, MetS induction by an HFD or HCD generates different biochemical, cellular, and inflammatory patterns in the hippocampus and frontal cortex.

Exposure to a hypercaloric diet produces long lasting changes in motivation.

Changes in motivation have been observed following induction of diet-induced obesity. However, to date, results have been contradictory, some authors reporting an increase in motivation to obtain palatable food, but others observing a decrease. Observed differences might be associated with the length of both the evaluation period and exposure to the diet. Therefore, the aim of this study was to evaluate changes in motivation during 20 weeks of exposure to a hypercaloric diet. Performance of the subjects in a progressive ratio schedule was evaluated before and during the exposure to a high-fat, high-sugar choice diet (HFHSc). A decrease in motivation was observed after 2 weeks of diet exposure, low levels of motivation remained throughout 20 weeks. A comparable decrease in motivation took longer (3 weeks) to develop using chow diet in the control group. Overall, our results suggest that, when changes in motivation are being evaluated, long periods of diet exposure made no further contribution, once motivation decreased, it remained low up to 18 weeks. Exposure to a HFHSc diet is a useful animal model of obesity, since it replicates some pathophysiological and psychological features of human obesity such as an increase in fasting glucose levels, body weight and the weight of adipose tissue.

A High-Fat and High-Carbohydrate Diet Promotes Reminiscent Hallmarks of an Aging Ovary in the Rabbit Model.

The primary definition of ovarian aging refers to the loss of follicles. Moreover, the aging of the microenvironment in ovaries, specifically affecting the follicles, may reveal deterioration with advancing age. Besides aging, metabolic disorders associated with hypercaloric diets may affect ovarian health and manifest characteristics associated with premature aging. In this study, we used 10-week-old chinchilla rabbits fed with a high-fat and high-carbohydrate diet (HFCD) until 25 weeks of age to explore hallmarks of reminiscent ovarian aging. The HFCD diet appeared to affect the ovarian reserve, reflected in a significant decrease in primordial follicles. Likewise, Sudan black stain detection revealed substantial differences in the deposits of lipofuscin in the interstitial glands of HFCD-fed rabbits compared to controls, constituting a "hallmark" of aging. The HFCD showed no induced changes in the expression of SOD 2 in the interstitial gland; however, surface epithelium cells were greater expressed. Besides this, the HFCD induced nuclear translocation of NF-ΚΒ p65 factor transcription in surface epithelium cells. We conclude that an HFCD induces a greater accumulation of senescence cells in the interstitial gland, promoting characteristics reminiscent of ovarian aging. However, the activation mechanism of NF-KB caused by an HFCD, which may be stress-responsive and generated by the interstitial gland, requires further study.

Long-Term Hypercaloric Diet Consumption Exacerbates Age-Induced Dysmetabolism and Carotid Body Dysfunction: Beneficial Effects of CSN Denervation.

Carotid bodies (CBs) are metabolic sensors whose dysfunction is involved in the genesis of dysmetabolic states. Ageing induces significant alterations in CB function also prompting to metabolic deregulation. On the other hand, metabolic disease can accelerate ageing processes. Taking these into account, we evaluated the effect of long-term hypercaloric diet intake and CSN resection on age-induced dysmetabolism and CB function. Experiments were performed in male Wistar rats subjected to 14 or 44 weeks of high-fat high-sucrose (HFHSu) or normal chow (NC) diet and subjected to either carotid sinus nerve (CSN) resection or a sham procedure. After surgery, the animals were kept on a diet for more than 9 weeks. Metabolic parameters, basal ventilation, and hypoxic and hypercapnic ventilatory responses were evaluated. CB type I and type II cells, HIF-1α and insulin receptor (IR), and GLP-1 receptor (GLP1-R)-positive staining were analyzed by immunofluorescence. Ageing decreased by 61% insulin sensitivity in NC animals, without altering glucose tolerance. Short-term and long-term HFHSu intake decreased insulin sensitivity by 55 and 62% and glucose tolerance by 8 and 29%, respectively. CSN resection restored insulin sensitivity and glucose tolerance. Ageing decreased spontaneous ventilation, but short-term or long-term intake of HFHSu diet and CSN resection did not modify basal ventilatory parameters. HFHSu diet increased hypoxic ventilatory responses in young and adult animals, effects attenuated by CSN resection. Ageing, hypercaloric diet, and CSN resection did not change hypercapnic ventilatory responses. Adult animals showed decreased type I cells and IR and GLP-1R staining without altering the number of type II cells and HIF-1α. HFHSu diet increased the number of type I and II cells and IR in young animals without significantly changing these values in adult animals. CSN resection restored the number of type I cells in HFHSu animals and decreased IR-positive staining in all the groups of animals, without altering type II cells, HIF-1α, or GLP-1R staining. In conclusion, long-term hypercaloric diet consumption exacerbates age-induced dysmetabolism, and both short- and long-term hypercaloric diet intakes promote significant alterations in CB function. CSN resection ameliorates these effects. We suggest that modulation of CB activity is beneficial in exacerbated stages of dysmetabolism.

Diet and Exercise Modulate GH-IGFs Axis, Proteolytic Markers and Myogenic Regulatory Factors in Juveniles of Gilthead Sea Bream (Sparus aurata).

The physiological and endocrine benefits of sustained exercise in fish were largely demonstrated, and this work examines how the swimming activity can modify the effects of two diets (high-protein, HP: 54% proteins, 15% lipids; high-energy, HE: 50% proteins, 20% lipids) on different growth performance markers in gilthead sea bream juveniles. After 6 weeks of experimentation, fish under voluntary swimming and fed with HP showed significantly higher circulating growth hormone (GH) levels and plasma GH/insulin-like growth-1 (IGF-1) ratio than fish fed with HE, but under exercise, differences disappeared. The transcriptional profile of the GH-IGFs axis molecules and myogenic regulatory factors in liver and muscle was barely affected by diet and swimming conditions. Under voluntary swimming, fish fed with HE showed significantly increased mRNA levels of capn1, capn2, capn3, capns1a, n3, and ub, decreased gene and protein expression of Ctsl and Mafbx and lower muscle texture than fish fed with HP. When fish were exposed to sustained exercise, diet-induced differences in proteases' expression and muscle texture almost disappeared. Overall, these results suggest that exercise might be a useful tool to minimize nutrient imbalances and that proteolytic genes could be good markers of the culture conditions and dietary treatments in fish.

Differential effect of high-fat, high-sucrose and combined high-fat/high-sucrose diets consumption on fat accumulation, serum leptin and cardiac hypertrophy in rats.

The consumption of high calorie-content diets is the first cause of obesity, probably the main health issue worldwide; however, the experimental evidences for evaluating the differential metabolic modifications of high-sucrose or high-fat diets are scare. We evaluated the metabolic outcomes of the obesity induced by the chronic consumption of high-sucrose (HS), high-fat (HF) or combined diets (HSHF), among the effect on the development of cardiac hypertrophy in Wistar rats. Rats from the HS, HF, and HSHS groups developed moderate obesity. Only the HS group showed increased triglycerides levels after four months. Increased leptin levels were observed in HS and HF groups without changes on cardiac hypertrophy; on the opposing, HSHF group presented hypertrophy without the changes in serum leptin. The three experimental groups showed a decreased expression of leptin receptors ObR-b. In our results, the kind of diet for the induction of obesity is relevant for the outcome of the pathological profile.

Modeling Diet-Induced Metabolic Syndrome in Rodents.

Standardized animal models represent one of the most valuable tools available to understand the mechanism underlying the metabolic syndrome (MetS) and to seek for new therapeutic strategies. However, there is considerable variability in the studies conducted with this essential purpose. This review presents an updated discussion of the most recent studies using diverse experimental conditions to induce MetS in rodents with unbalanced diets, discusses the key findings in metabolic outcomes, and critically evaluates what we have been learned from them and how to advance in the field. The study includes scientific reports sourced from the Web of Science and PubMed databases, published between January 2013 and June 2020, which used hypercaloric diets to induce metabolic disorders, and address the impact of the diet on metabolic parameters. The collected data are used as support to discuss variables such as sex, species, and age of the animals, the most favorable type of diet, and the ideal diet length to generate metabolic changes. The experimental characteristics propose herein improve the performance of a preclinical model that resembles the human MetS and will guide researchers to investigate new therapeutic alternatives with confidence and higher translational validity.

Impact of different hypercaloric diets on obesity features in rats: a metagenomics and metabolomics integrative approach.

Diet is considered a key influencing agent affecting the gut microbiome. Dysbiosis of microbial communities contributes to the development of metabolic diseases such as obesity. We aimed to characterize the physiological, microbial and metabolic changes induced by different obesogenic diets to understand the diet-specific modulation of the host-microbiota co-metabolism in rodents. For this purpose, Wistar rats were fed standard, cafeteria (CAF), low-fat (LF), high-fat (HF) and high-fat high-sucrose (HFS) diets for 10 weeks. The CAF diet strongly induced an obese phenotype accompanied by dyslipidemia, hyperleptinemia, insulin resistance and hepatic steatosis, whereas both HF and HFS diets promoted overweight. Concerning the microbiome, CAF feeding induced a rise of the Bacteroidetes-to-Firmicutes ratio, while few microbial genera were altered in the HF or HFS group. Changes in microbial activity according to dietary treatment were also reflected in the disruption of short-chain fatty acid production and bile acid metabolism, which were mainly associated with fiber intake. Urinary metabolomics revealed a significant increase in metabolites related to oxidative stress and metabolic inflammation together with an altered excretion of host-microbiota co-metabolites only in the CAF group. Moreover, several associations between metabolic patterns, physiological status and specific microbial communities were described, helping to elucidate the crucial role of the microbiota in host homeostasis. Overall, our study suggests that different hypercaloric dietary models distinctively influence gut microbiota composition and reveals robust and similar clustering patterns concerning both cecal microbiome and urinary metabolome profiles.

Differential Effects of High Sugar, High Lard or a Combination of Both on Nutritional, Hormonal and Cardiovascular Metabolic Profiles of Rodents.

BACKGROUND: Dietary interventions in rodents can induce an excess of adipose tissue and metabolic disorders that resemble human obesity. Nevertheless, these approaches are not standardized, and the phenotypes may vary distinctly among studies. The aim of this study was to investigate the effects of different dietary interventions on nutritional, metabolic, biochemical, hormonal, and cardiovascular profiles, as well as to add to development and characterization of an experimental model of obesity. METHODS: Male Wistar rats were randomized into four groups: control diet (C), high-sugar (HS), high-fat (HF), or high-sugar and high-fat (HFHS). Weekly measurements of body weight, adiposity, area under the curve (AUC) for glucose, blood pressure (BP) and serum triglycerides, total cholesterol level, and leptin were performed. RESULTS: HF and HFHS models were led to obesity by increases in adipose tissue deposition and the adiposity index. All hypercaloric diets presented systolic BP increases. In addition, the AUC for glucose was greater in HF and HFHS than in C, and only the HF group presented hyperleptinemia. CONCLUSIONS: HF and HFHS diet approaches promote obesity and comorbidities, and thus represent a useful tool for studying human obesity-related disorders. By contrast, the HS model did not prove to be a good model of obesity.