Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain (original) (raw)
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Animal models of metabolic syndrome and associated co-morbidities
Type 2 Diabetes (T2D) is recognized by the World Health Organization as a global epidemic affecting 284-347 million people in the world depending on the inclusion criteria used (Danaei et al. 2011; American Diabetes Association 2013). Co-morbidities associated with T2D are hypertension, cardiovascular diseases (CVD) (Castelli 1984; Wilson et al. 2005) and diabetic nephropathy (DN) (Shah et al. 2009; Shao et al. 2013). There is an unmet need for therapies curing or preventing the progression of T2D and combined pathologies (Grundy 2008). In the metabolic diseases field, transgenic or chemically-induced models (mainly rodents) were characterized that focused on one disease or disturbance (i.e. dyslipidemia, T2D, obesity) or pathway abnormalities (insulin resistance, glucose intolerance). The main limitation for the use of those models is the lack of translatability to human T2D and comorbidities. Metabolic syndrome (MS, MetS, Syndrome X) was described years ago as a combination of at ...
A new mouse model of metabolic syndrome and associated complications
Journal of Endocrinology, 2009
Metabolic syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy. A backcross was used to genetically map the Nmf15 locus. Mice were examined in the comprehensive laboratory animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Hypothalamic LEPR, SOCS1, and STAT3 phosphorylation were examined. Cardiac function was assessed by echo- and electrocardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity. The Nmf15 locus mapped to distal mouse chromosome 5 with an LOD (logarithm of odds) score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly ele...
Development of rat metabolic syndrome models: A review
Veterinary World, 2021
Metabolic syndrome (MetS) has become a global problem. With the increasing prevalence of MetS worldwide, understanding its pathogenesis and treatment modalities are essential. Animal models should allow an appropriate representation of the clinical manifestations of human conditions. Rats are the most commonly used experimental animals for the study. The development of a proper MetS model using rats will contribute to the successful application of research findings to the clinical setting. Various intervention methods are used to induce MetS through diet induction with various compositions, chemicals, or a combination of both. This review will provide a comprehensive overview of several studies on the development of rat MetS models, along with the characteristics of the clinical manifestations resulting from each study.
Metabolic Syndrome Components in Murine Models
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2010
Animal models have enriched understanding of the physiological basis of metabolic disorders and advanced identification of genetic risk factors underlying the metabolic syndrome (MetS). Murine models are especially appropriate for this type of research, and are an excellent resource not only for identifying candidate genomic regions, but also for illuminating the possible molecular mechanisms or pathways affected in individual components of MetS. In this review, we briefly discuss findings from mouse models of metabolic disorders, particularly in light of issues raised by the recent flood of human genome-wide association studies (GWAS) results. We describe how mouse models are revealing that genotype interacts with environment in important ways, indicating that the underlying genetics of MetS is highly context dependant. Further we show that epistasis, imprinting and maternal effects each contribute to the genetic architecture underlying variation in metabolic traits, and mouse models provide an opportunity to dissect these aspects of the genetic architecture that are difficult if not impossible to ascertain in humans. Finally we discuss how knowledge gained from mouse models can be used in conjunction with comparative genomic methods and bioinformatic resources to inform human MetS research.
Metabolic syndrome: comparison of the two commonly used animal models
2008
The metabolic syndrome (MS) is defined by the cluster of physiologic and metabolic abnormalities including overall and central obesity, impaired glucose tolerance, dyslipidemia (combination of low levels of high-density lipoprotein cholesterol and high levels of triglyceride), and hypertension. The categorization of this cluster as a syndrome is because of this assemblage of abnormalities is much more prevalent than would be expected by chance alone. 2 Since its introduction in 1988, the prevalence of MS has increased dramatically, and reported to be >20% among adult population in developed countries. 3,4 The prevalence of MS rises with age and is associated with high risk to develop diabetes and major cardiovascular consequences. An important explanation for the epidemic of MS is the dramatic elevation of carbohydrate consumption in the diet of western countries over the past few decades. The causal relationship between consumption of simple sugars, particularly fructose and sucrose, and MS was demonstrated in both human 9-12 and animal studies. The etiology of the MS is multifactorial with both genetic and environmental influences. 15 Genetic animal models of the MS demonstrated some specific genetic factors affecting traits of the MS as well as a possible genetic relationship between the syndrome and diabetes mellitus. Other animal models use high-carbohydrate diet to induce MS in genetically predisposed rodents. These models resemble the complexity of the human MS better than a monogenic model. The two most commonly studied models are the high-sucrose diet given to spontaneously hypertensive rats (SHRs) and high-fructose diet given to Sprague Dawley rats (SDRs). 17-19 These two models were never directly compared to characterize the differences between them. Such comparison is important for an appropriate use of a model in a way that allows ramification of the results to the clinical world. Therefore, the purpose of this study is to compare between the two models in terms of the ability to induce the MS and to characterize the syndrome according to the profile of the MS components and thus determine the optimal animal model to study the MS, its pathophysiology, and potential pharmacotherapy.
Features of the Metabolic Syndrome in the Berlin Fat Mouse as a Model for Human Obesity
Obesity Facts, 2011
Background: The Berlin Fat Mouse BFMI860 is a polygenic obesity mouse model which harbors a natural major gene defect resulting in early onset of obesity. To elucidate adult bodily responses in BFMI860 mice that develop juvenile obesity, we studied features of the metabolic syndrome at 20 weeks. Methods: We examined fat deposition patterns, adipokines, lipid profiles in serum, glucose homeostasis, and insulin sensitivity in mice that were fed either a standard maintenance (SMD) or a high-fat diet (HFD). Results: Like many obese humans, BFMI860 mice showed hyperleptinemia accompanied by hypoadiponectinemia already at SMD that was further unbalanced as a result of HFD. Furthermore, BFMI860 mice had high triglyceride concentrations. However, triglyceride clearance after an oral oil gavage was impaired on SMD but improved on HFD. The oral and intraperitoneal glucose as well as the insulin tolerance tests provided evidence for reduced insulin sensitivity under SMD and insulin resistance on HFD. BFMI860 mice can maintain normal glucose clearance over a wide range of feeding conditions according to an adaptation via increasing the insulin concentrations. Conclusions: BFMI860 mice show obesity, dyslipidemia, and insulin resistance as three major components of the metabolic syndrome. As these mice develop the described phenotype as a result of a major gene defect, they are a unique model for the investigation of genetic and pathophysiological mechanisms underlying the observed features of the metabolic syndrome and to search for potential strategies to revert the adverse effects under controlled conditions.
Experimental models of metabolic syndrome in rats
Scripta Scientifica Medica, 2015
Metabolic syndrome (MS) is a disorder comprising central obesity, dyslipidemia, raised blood pressure, insulin resistance. The aim of the present study was to develop a cheap, easy and reproducible rat model of MS. 36 male Wistar rats were divided in 3 groups: a control group (C) receiving regular rat chow diet, a high-fat (HF) group receiving lard enriched rat chow and a high-fat high-fructose (HFHF) group receiving lard and fructose enriched rat chow. HF and HFHF groups had also 10% fructose in their drinking water. The duration of the study was 8 weeks. Body weights were measured weekly. At the end of the study insulin tolerance test (ITT) was performed. Liver and fat weight index were measured after sacrifice. Lipid biochemical parameters and insulin concentration in serum were determined. Liver triglycerides (TG) were measured. The oxidative stress in serum was assessed by thiobarbituric reactive substances (TBARS). At the end of the study the animals did not differ in their body weights across the groups, but the fat index in both HF and HFHF groups was higher. Plasma TG and cholesterol were raised in both groups and the ratio cholesterol/ HDL-cholesterol was higher. Liver TG were elevated in HFHF rats. ITT revealed reduced insulin sensitivity in both experimental groups although serum insulin was elevated only in HFHF group. TBARS were increased in both HF and HFHF groups. Both models displayed most of the features of MS; the HFHF probably better reflects the 'cafeteria' diet and its unhealthy consequences.
Hypertension Research, 2008
The purpose of this study was to evaluate whether the spontaneously hypertensive rat SHRSP.Z-Lepr fa /Izm-Dmcr (SHRSP fatty) is a useful animal model to clarify molecular mechanisms that underlie metabolic syndrome. We investigated histopathologic changes in the cardiovascular organs and metabolic characteristics of SHRSP fatty rats, which are congenic rats from a cross between SHRSP and Zucker fatty (ZF) rats. The aortic wall and cardiac, carotid, and renal arteries from SHRSP and SHRSP fatty rats were thicker than those of ZF rats. The renal cortex in SHRSP and SHRSP fatty rats showed severe glomerulosclerosis. Pancreatic islands in SHRSP fatty and ZF rats showed marked hyperplasia. Steady-state plasma glucose concentrations were higher in SHRSP fatty than in ZF rats. Non-fasting triglyceride levels in SHRSP fatty rats were higher than in ZF rats. DNA synthesis in cultured vascular smooth muscle cells (VSMCs) from SHRSP fatty and SHRSP rats was significantly higher than that in VSMCs from Wistar-Kyoto (WKY) or ZF rats. Levels of platelet-derived growth factor A-chain and transforming growth factor-1 mRNAs were higher in VSMCs from SHRSP fatty and SHRSP than from ZF rats. Microarray analysis identified five genes that were significantly upregulated and four genes that were significantly downregulated in visceral adipose tissue of SHRSP fatty rats compared with levels in control strains (SHRSP and ZF rats). These findings suggest that the combination of hypertension and obesity accelerates vascular remodeling, dyslipidemia, and insulin resistance in metabolic syndrome. The phenotype of SHRSP fatty is similar to that of human metabolic syndrome, and therefore, studies of these rats may help clarify the molecular mechanisms that underlie metabolic syndrome in humans. ( Hypertens Res 2008; 31: 1021-1031)
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity, 2000
Studies, comparing several disease-prone and disease-resistant rat strains to elucidate the extent and severity of syndromes resembling human diseases are lacking. Therefore we studied the inbred rat strains BB/OK, BN/Crl, LEW/K and WKY/Crl in comparison with SHR/Mol and WOKW/K rats as models of metabolic syndrome. Body weight and body mass index (BMI) were measured in 12 males of each strain at 14 weeks. In addition blood glucose, serum triglycerides, cholesterol, insulin and leptin were determined at 12, 13 and 14 weeks of age. In contrast to SHR animals, WOKW rats develop a severe metabolic syndrome including obesity, hyperleptinemia, hyperinsulinemia and dyslipidemia. We conclude that; (i) the choice of disease-resistant inbred rat strains as 'healthy controls' for a disease-prone strain has to be carefully evaluated; (ii) in comparison with SHR, WOKW rats develop most if not all facets of the metabolic syndrome described in human and (iii) as with the human disease the ...