J.C. Russell

Chylomicron and apoB48 metabolism in the JCR:LA corpulent rat, a model for the metabolic syndrome.

Postprandial (PP) lipaemia is a significant contributor to the development of dyslipidaemia and cardiovascular disease (CVD). It is also evident that PP lipaemia is prevalent during conditions of obesity and insulin resistance (IR) and may contribute to increased progression of CVD. Our group has assessed the potential of the obese JCR:LA-cp rat as a model of PP lipaemia in order to explore CM (chylomicron) metabolism during the onset and development of IR in the metabolic syndrome. Studies confirm that both fasting plasma and PP apoB48 (apolipoprotein B48) area under the curve are significantly elevated in the obese JCR:LA-cp phenotype as compared with lean controls. Mechanistic studies have also shown that the concentration of lymphatic CM apoB48 and CM size are significantly increased in this model. Furthermore, PP dyslipidaemia in the obese rat can be improved acutely with supplementation of n-3 polyunsaturated fatty acids. Using a different approach, we have subsequently hypothesized that the vascular remodelling that accompanies IR may explain accelerated entrapment of apoB48-containing particles. Small leucine-rich proteoglycans (including biglycan and decorin) have been observed to co-localize with apoB in human tissue. However, the potential impact of IR on vascular remodelling, particularly in the presence of obesity, remains unclear. Preliminary observations from the JCR:LA-cp model indicate that biglycan protein core content increases with age and is exacerbated by IR, suggestive of pro-atherogenic remodelling. The focus of this review is to contribute to the perspective of PP lipaemia in CVD risk associated with the metabolic syndrome through the use of animal models.

A Unique Rodent Model of Cardiometabolic Risk Associated with the Metabolic Syndrome and Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-/anovulation, and polycystic ovarian morphology and is a complex endocrine disorder that also presents with features of the metabolic syndrome, including obesity, insulin resistance, and dyslipidemia. These latter symptoms form cardiometabolic risk factors predisposing individuals to the development of type 2 diabetes and cardiovascular disease (CVD). To date, animal models to study PCOS in the context of the metabolic syndrome and CVD risk have been lacking. The aim of this study was to investigate the JCR:LA-cp rodent as an animal model of PCOS associated with the metabolic syndrome. Metabolic indices were measured at 6 and 12 wk, and reproductive parameters including ovarian morphology and estrous cyclicity were assessed at 12 wk or adulthood. At 6 wk of age, the cp/cp genotype of the JCR:LA-cp strain developed visceral obesity, insulin resistance, and dyslipidemia (hypertriglyceridemia and hypercholesterolemia) compared with control animals. Serum testosterone concentrations were not significantly different between groups at 6 wk of age. However, at 12 wk, the cp/cp genotype had higher serum testosterone concentrations, compared with control animals, and presented with oligoovulation, a decreased number of corpora lutea, and an increased number of total follicles, in particular atretic and cystic follicles. The cardiometabolic risk factors in the cp/cp animals were exacerbated at 12 wk including obesity, insulin resistance, and dyslipidemia. The results of this study demonstrate that the JCR:LA-cp rodent may be a useful PCOS-like model to study early mechanisms involved in the etiology of cardiometabolic risk factors in the context of both PCOS and the metabolic syndrome.

Synergistic effects of conjugated linoleic acid and chromium picolinate improve vascular function and renal pathophysiology in the insulin‐resistant JCR:LA‐cp rat

Aims:u2002 Conjugated linoleic acid (CLA) is a natural constituent of dairy products, specific isomers of which have recently been found to have insulin sensitizing and possible antiobesity actions. Chromium is a micronutrient which, as the picolinate (CrP), has been shown to increase insulin sensitivity in animal models, including the JCR:LA‐cp rat. We tested the hypothesis that these agents may have beneficial synergistic effects on the micro‐ and macrovasculopathy associated with hyperinsulinaemia and early type 2 diabetes.

A novel complex of arginine-silicate improves micro- and macrovascular function and inhibits glomerular sclerosis in insulin-resistant JCR:LA-cp rats

Aims/hypothesisThe metabolic syndrome, with associated vasculopathy, is a major cause of cardiovascular disease and nephropathy. Impaired nitric oxide (NO) metabolism and endothelial function is an important component of the disease process. Increasing the availability of arginine, the precursor of NO, might enhance vascular function and protect against end-stage disease.Materials and methodsInsulin-resistant JCR:LA-cp rats were treated with arginine–silicate–inositol complex or arginine–HCl at 1.0xa0g kg−1 day−1 (expressed as arginine–HCl) from 8 to 13 weeks of age. The contractile/relaxant function of thoracic aortae and coronary arteries was assessed in vitro. Kidneys were assessed for severity of glomerular sclerosis.ResultsArginine–silicate complex, but not arginine–HCl, normalised the hypercontractile response of the aorta to phenylephrine via an NO-dependent pathway. Coronary artery function, as indicated by reactive hyperaemia to warm ischaemia, was enhanced by both arginine compounds. In addition, the arginine–silicate complex increased coronary vasodilatation in response to bradykinin. Glomerular sclerosis was significantly reduced in rats treated with the arginine–silicate complex.Conclusions/interpretationTreatment with exogenous arginine, in an efficiently absorbed form, improves vascular function and reduces nephropathy in an animal model of insulin resistance and cardiovascular disease, via mechanism(s) independent of insulin concentration. Enhancement of NO metabolism through increased availability of the precursor arginine appears to offer protection against micro- and macrovascular disease associated with the metabolic syndrome and insulin resistance.

Evolution and obesity: resistance of obese-prone rats to a challenge of food restriction and wheel running

The adaptive hypothesis that an obese-prone genotype confers a fitness advantage when challenged with food restriction and food-related locomotion was tested using a rat model. Juvenile (35–40 days) and adolescent (45–50 days) JCR:LA-cp rats, obese prone (cp/cp) and lean prone (+/?), were exposed to 1.5u2009h daily meals and 22.5u2009h of voluntary wheel running, a procedure that normally leads to self-starvation. Genotype had a dramatic effect on survival of rats when exposed to the challenge of food restriction and wheel running. Although similar in initial body weight, obese-prone juveniles survived twice as long, and ran three times as far, as their lean-prone counterparts. Biochemical measures indicated that young obese-prone animals maintained blood glucose and fat mass, whereas lean-prone rats depleted these energy reserves. Corticosterone concentration indicated that obese-prone juveniles exhibited a lower stress response to the survival challenge than lean-prone rats, possibly due to lower energy demands and greater energy reserves. Collectively, the findings support the hypothesis that an obese-prone genotype provides a fitness advantage when food supply is inadequate, but is deleterious during periods of food surfeit, such as the energy-rich food environment of prosperous and developing societies worldwide.

Irbesartan-mediated reduction of renal and cardiac damage in insulin resistant JCR : LA-cp rats.

Background and purpose:u2002 Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro‐ and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin‐resistant JCRu2003:u2003LA‐cp rat that exhibits micro‐ and macrovascular disease with ischaemic myocardial lesions and renal disease.

Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats

The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non‐metabolizable glucose analogue, 2‐deoxy‐D‐glucose (2‐DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome.

Model of intestinal chylomicron over-production and Ezetimibe treatment: Impact on the retention of cholesterol in arterial vessels

The metabolic syndrome (MetS) and conditions of insulin resistance are often characterized by an increase in cardiovascular disease (CVD) risk without a concomitant increase in low-density lipoprotein cholesterol (LDL-C), suggesting that other atherogenic pathways maybe involved. Intestinally derived chylomicron remnants (CM-r) are also thought to contribute to atherogenic dyslipidemia during insulin resistance. Recent animal and human studies suggest that insulin resistance leads to an over-production of intestinal chylomicrons (CM), which can contribute to fasting and post-prandial dyslipidemia during these conditions. We and others have contributed new insights into the mucosal absorption, efflux and secretion of cholesterol and triglyceride (TG) in intestinal CM during conditions of insulin resistance. One of the pertinent discoveries has been that the intestine has the capacity to increase the secretion of CM during conditions of hyper-insulinemia (observed in the JCR:LA-cp rat model). Advances to identify cholesterol-transporter targets have highlighted the contribution of the intestine to whole body cholesterol metabolism. Ezetimibe (EZ) is a novel pharmaceutical compound that reduces intestinal cholesterol absorption. We know that ezetimibe either alone, or in combination with a HMG-CoA reductase inhibitor (such as simvastatin [SV]) can decrease both plasma LDL-C and CM-r concentrations. However, the combined effects of these compounds (EZ+SV) on post-prandial dyslipidemia and/or impact on arterial deposition of cholesterol during MetS have not been studied. The focus of this review is to highlight studies using an animal model of MetS and CM over-production (the JCR:LA-cp rat), and to summarize the effects of ezetimibe on intestinal cholesterol flux, CM metabolism and uptake of cholesterol into arterial vessels.

Differential expression of hypothalamic metabolic and inflammatory genes in response to short-term calorie restriction in juvenile obese- and lean-prone JCR rats

Background:Childhood obesity is an important early predictor of adult obesity and associated comorbidities. Common forms of obesity are underpinned by both environmental and genetic factors. However, the rising prevalence of obesity in genetically stable populations strongly suggests that contemporary lifestyle is a premier factor to the disease. In pediatric population, the current treatment/prevention options for obesity are lifestyle interventions such as caloric restriction (CR) and increase physical activity. In obese individuals, CR improves many metabolic parameters in peripheral tissues. Little is known about the effect of CR on the hypothalamus. This study aimed to assess the effect of CR on hypothalamic metabolic gene expression of young obese- and lean-prone animals.Methods:Male juvenile JCR:LA-cp obese-prone rats were freely fed (Obese-FF) or pair fed (Obese-FR) to lean-prone, free-feeding animals (Lean-FF). A group of lean-prone rats (Lean-FR) were matched for relative average degree of CR to Obese-FR rats.Results:In free-feeding conditions, obese-prone rats consumed more energy than lean-prone rats (P<0.001) and showed greater increases in body weight, fat mass, plasma glucose, insulin and lipids (P<0.01). These metabolic differences were associated with alterations of feeding-related neuropeptides expression in the hypothalamus, as well as pro-inflammatory cytokines and oxidative stress markers. When submitted to the same degree of CR, the two genotypes responded differently; hypothalamic inflammatory and oxidative stress gene expression was improved in Obese-FR, while it was worsened in Lean-FR rats.Conclusions:We demonstrate in JCR rats that the metabolic and inflammatory response of the brain to CR is genotype dependent.