Egg white hydrolysate enhances insulin sensitivity in high-fat diet-induced insulin-resistant rats via Akt activation.

Agents that block the renin-angiotensin system (RAS) improve glucoregulation in the metabolic syndrome disorder. We evaluated the effects of egg white hydrolysate (EWH), previously shown to modulate the protein abundance of RAS component in vivo, on glucose homeostasis in diet-induced insulin-resistant rats. Sprague-Dawley rats were fed a high-fat diet (HFD) for 6 weeks to induce insulin resistance. They were then randomly divided into four groups receiving HFD or HFD supplemented with different concentrations of EWH (1, 2 and 4 %) for another 6 weeks in the first trial. In the second trial, insulin-resistant rats were divided into two groups receiving only HFD or HFD+4 % EWH for 6 weeks. Glucose homeostasis was assessed by oral glucose tolerance and insulin tolerance tests. Insulin signalling and protein abundance of RAS components, gluconeogenesis enzymes and PPARγ were evaluated in muscle, fat and liver. Adipocyte morphology and inflammatory markers were evaluated. In vivo administration of EWH increased insulin sensitivity, improved oral glucose tolerance (P < 0·0001) and reduced systemic inflammation (P < 0·05). EWH potentiated insulin-induced Akt phosphorylation in muscle (P = 0·0341) and adipose tissue (P = 0·0276), but minimal differences in the protein abundance of tissue RAS components between the EWH and control groups were observed. EWH treatment also reduced adipocyte size (P = 0·0383) and increased PPARγ2 protein abundance (P = 0·0237). EWH treatment yielded positive effects on the inflammatory profile, glucose tolerance, insulin sensitivity and adipocyte differentiation in HFD-induced insulin resistance rats. The involvement of local RAS activity requires further investigation.

Sequential Feeding of Lipid Supplement Enriches Beef Adipose Tissues with 18:3n-3 Biohydrogenation Intermediates.

The present study was designed to determine if feeding steers extruded flaxseed and hay (25 and 75%; DM basis) together as a total mixed ration (TMR), or sequentially (non-TMR) would result in different enrichments of polyunsaturated fatty acids (PUFA) and their biohydrogenation intermediates (BHI) in beef adipose tissues [subcutaneous (SC) vs perirenal (PR) fat]. Forty-eight Angus cross steers (325 ± 16 kg) were stratified by weight to six pens, and pens were randomized to either TMR or non-TMR and fed ad libitum for an average of 242 days. The concentrations of α-linolenic acid increased by 18 mol% in both SC and PR in non-TMR steers compared to TMR steers (P < 0.01). trans 18:1 isomers were more concentrated in PR than SC (14.4 vs 9.5 mol%; P < 0.01) and increased by 10 mol% in both fat depots for non-TMR (P < 0.01). Other BHI including non-methylene-interrupted 18:2 (atypical dienes), conjugated linoleic acids and conjugated linolenic acids (CLnA) were affected by diet × tissue interactions (P < 0.01). The CLnA and CLA contents were higher in both fat depots when feeding the non-TMR, but the effect of diet was more pronounced in PR than in SC (P < 0.01). Atypical dienes were highest in PR from non-TMR and lowest in TMR fed steers (4.3 and 3.6 mol%) with SC contents being intermediate. The sequential feeding of lipid supplement can thus profoundly affect the enrichment of PUFA and their BHI in beef fat and their differentially enrichment is also fat depot dependant.

Effects of feeding steers extruded flaxseed on its own before hay or mixed with hay on animal performance, carcass quality, and meat and hamburger fatty acid composition.

The objective of the present experiment was to determine if carcass quality and fatty acid profiles of longissimus thoracis (LT) and hamburger would be affected by feeding steers extruded flaxseed on its own followed by hay (non-TMR) compared to when hay and extruded flaxseed were fed together (TMR). Forty-eight steers in six pens were assigned to TMR or non-TMR for an average of 242days. Dry matter intake was lower for non-TMR versus TMR steers (10.56 vs. 11.42kg/d; P=0.02), but final live weight (610±0.50kg) and average daily gain (1.18±0.02kg/d) did not differ. Compared to TMR, feeding non-TMR enriched LT and hamburger with α-linolenic acid (ALA; 18:3n-3) by 14%, vaccenic acid (VA; t11-18:1) by 44%, rumenic acid (RA; c9,t11-18:2) by 40%, and conjugated linolenic acid (CLnA) by 58%. Overall, feeding extruded flaxseed separately from hay in a non-TMR was more effective at enhancing deposition of ALA, VA, RA and CLnA in beef.

Koch's postulates, microbial dysbiosis and inflammatory bowel disease.

Over the past 20 years, a growing amount of evidence supports the role of microbes and an imbalanced microbiota in inflammatory bowel disease (IBD). While many reviews have been written on the microbiota in IBD, few have considered how they fulfil the Koch's postulates. In this review, we consider how the Koch's postulates might be modified so that they can be fulfilled for polymicrobial diseases, and we discuss the progress made to date in fulfilling them.

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.

Types of oilseed and adipose tissue influence the composition and relationships of polyunsaturated fatty acid biohydrogenation products in steers fed a grass hay diet.

The current study evaluated the composition and relationships of polyunsaturated fatty acid biohydrogenation products (PUFA-BHP) from the perirenal (PRF) and subcutaneous fat (SCF) of yearling steers fed a 70 % grass hay diet with concentrates containing either sunflower-seed (SS) or flaxseed (FS). Analysis of variance indicated several groups or families of structurally related FA, and individual FA within these were affected by a number of novel oilseed by fat depot interactions (P < 0.05). Feeding diets containing SS increased the proportions of non-conjugated 18:2 BHP (i.e., atypical dienes, AD) and conjugated linoleic acids (CLA) with the first double bond from carbon 7 to 9, trans-18:1 isomers with double bonds from carbon 6 to 12, and these PUFA-BHP had greater proportions in SCF compared to PRF (P < 0.05). Enrichment of conjugated linolenic acids, AD and CLA isomers with the first double bond in position 11 or 12, and t-18:1 isomers with double bonds from carbon 13 to 16 were achieved by feeding diets containing FS, with PRF having greater proportions than SCF (P < 0.05). Principal component analysis visually confirmed interaction effects on these groups/families of FA, and further confirmed or suggested a number of relationships between PUFA-BHP. Feeding SS or FS in a grass hay diet and exploiting adipose tissue differences, therefore, present unique opportunities to differentially enrich a number of PUFA-BHP which seem to have positive health potential in humans (i.e., t11-18:1, c9,t11-18:2 and c9,t11,c15-18:3).

Effects of feeding flaxseed or sunflower-seed in high-forage diets on beef production, quality and fatty acid composition.

Yearling steers were fed 70:30 forage:concentrate diets for 205 d, with either grass hay (GH) or red clover silage (RC) as the forage source, and concentrates containing either sunflower-seed (SS) or flaxseed (FS), each providing 5.4% oil to diets. Feeding diets containing SS versus FS significantly improved growth and carcass attributes (P<0.05), significantly reduced meat off-flavor intensity (P<0.05), and significantly increased intramuscular proportions of vaccenic (t11-18:1), rumenic (c9,t11-CLA) and n-6 fatty acids (FA, P<0.05). Feeding diets containing FS versus SS produced significantly darker and redder meat with greater proportions of atypical dienes (P<0.05). A significant forage × oilseed type interaction (P<0.05) was found for n-3 FA, α-linolenic acid, and conjugated linolenic acid, with their greatest intramuscular proportions found when feeding the RC-FS diet. Feeding GH versus RC also significantly improved growth and carcass attributes, sensory tenderness (P<0.05) and significantly influenced intramuscular FA composition (P<0.05), but overall, forage effects on FA profiles were limited compared to effects of oilseed.

Elevated remnant lipoproteins may increase subclinical CVD risk in pre-pubertal children with obesity: a case-control study.

OBJECTIVES: Current clinical guidelines to assess paediatric cardiovascular disease (CVD) risk heavily rely on cholesterol parameters that are generally normal for obese children. Remnant lipoproteins have emerged as a critical CVD risk factor particularly in adults with normolipidemia. We assessed remnant lipoprotein concentration (measured by apolipoprotein [apo] B48) and its relationship with other traditional CVD risk biomarkers in pre-pubertal children with obesity. METHODS: Pre-pubertal children (n = 78) with obesity (n = 39, 9.9 ± 0.3 years old) as well as sex-matched normal-weight controls (n = 39, 9.8 ± 0.3 years) were assessed for anthropometry, blood pressure and fasting plasma biochemical parameters for remnant lipoprotein, lipid and glucose/insulin metabolism, and inflammatory status. RESULTS: Children with obesity had striking 2-fold higher apoB48-containing remnant lipoproteins concentrations relative to normal-weight peers; the magnitude of elevation in the remnant lipoproteins is comparable to the levels previously reported for adults with established CVD and type-2 diabetes. Fasting apoB48 was positively correlated with fasting triglyceride concentration in children with obesity (r = 0.51, P < 0.001) and their normal-weight peers (r = 0.45, P < 0.01). Traditional CVD biomarkers including low-density lipoprotein cholesterol showed no difference between groups and remained within the normal range for a paediatric population. CONCLUSION: Elevated apoB48-containing remnant lipoprotein is a stronger biomarker for paediatric CVD risk compared to traditional cholesterol parameters and may be associated with early adaptation of the intestine during obesity. Further investigation of abnormalities associated with the secretion and/or clearance of atherogenic remnant lipoproteins during the postprandial state may yield insight into our understanding of and therapeutic targets for managing risk for CVD in children with obesity.

Glucagon and a glucagon-GLP-1 dual-agonist increases cardiac performance with different metabolic effects in insulin-resistant hearts.

BACKGROUND AND PURPOSE: The prevalence of heart disease continues to rise, particularly in subjects with insulin resistance (IR), and improved therapies for these patients is an important challenge. In this study we evaluated cardiac function and energy metabolism in IR JCR:LA-cp rat hearts before and after treatment with an inotropic compound (glucagon), a glucagon-like peptide-1 (GLP-1) receptor agonist (ZP131) or a glucagon-GLP-1 dual-agonist (ZP2495). EXPERIMENTAL APPROACH: Hearts from IR and lean JCR:LA rats were isolated and perfused in the working heart mode for measurement of cardiac function and metabolism before and after addition of vehicle, glucagon, ZP131 or ZP2495. Subsequently, cardiac levels of nucleotides and short-chain CoA esters were measured by HPLC. KEY RESULTS: Hearts from IR rats showed decreased rates of glycolysis and glucose oxidation, plus increased palmitate oxidation rates, although cardiac function and energy state (measured by ATP/AMP ratios) was normal compared with control rats. Glucagon increased glucose oxidation and glycolytic rates in control and IR hearts, but the increase was not enough to avoid AMP and ADP accumulation in IR hearts. ZP131 had no significant metabolic or functional effects in either IR or control hearts. In contrast, ZP2495 increased glucose oxidation and glycolytic rates in IR hearts to a similar extent to that of glucagon but with no concomitant accumulation of AMP or ADP. CONCLUSION AND IMPLICATIONS: Whereas glucagon compromised the energetic state of IR hearts, glucagon-GLP-1 dual-agonist ZP2495 appeared to preserve it. Therefore, a glucagon-GLP-1 dual-agonist may be beneficial compared with glucagon alone in the treatment of severe heart failure or cardiogenic shock in subjects with IR.

Increased risk of cardiovascular disease in Type 1 diabetes: arterial exposure to remnant lipoproteins leads to enhanced deposition of cholesterol and binding to glycated extracellular matrix proteoglycans.

AIMS: To determine fasting and postprandial metabolism of apolipoprotein B48 (apoB48) remnant lipoproteins in subjects with Type 1 diabetes and the relationship to progressive cardiovascular disease, and to investigate the impact of remnant lipoprotein cholesterol accumulation associated with arterial wall biglycan using a rodent model of Type 1 diabetes. METHODS: Normolipidaemic subjects (n = 9) with long-standing Type 1 diabetes (and advanced cardiovascular disease) and seven healthy control subjects were studied. Fasting and postprandial apoB48 concentration was determined following a sequential meal challenge. A rodent model of streptozotocin-induced diabetes was used to investigate the ex vivo retention of fluorescent-conjugated remnants. Binding of remnant lipoproteins to human recombinant biglycan was assessed in vitro. RESULTS: A significantly higher concentration of fasting plasma apoB48 remnants was observed in patients with Type 1 diabetes compared with control subjects. Patients with Type 1 diabetes exhibited a greater total plasma apoB48 area under the curve (AUC) and an increased incremental AUC following a second sequential meal compared with control subjects. The arterial retention of remnants ex vivo and associated cholesterol was increased sevenfold in Type 1 diabetes rats relative to controls. Remnants were shown to bind with significant affinity to human biglycan in vitro and a further 2.3-fold increased binding capacity was observed with glycated biglycan. Remnants were shown to colocalize with both arterial biglycan and glycated matrix proteins in the Type 1 diabetes rodent model. CONCLUSION: Impaired metabolism of remnant lipoproteins associated with enhanced binding to proteoglycans appears to contribute to the arterial cholesterol deposition in Type 1 diabetes. Our findings support the hypothesis that impaired remnant metabolism may contribute to accelerated progression of atherosclerosis in the hyperglycaemic and insulin-deficient state.

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.

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 1.5 h daily meals and 22.5 h 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.

Dietary supplementation of n-3 PUFA reduces weight gain and improves postprandial lipaemia and the associated inflammatory response in the obese JCR:LA-cp rat.

BACKGROUND: Postprandial dyslipidaemia occurs in obesity and insulin resistance (IR), and is associated with an increased risk of developing cardiovascular disease. We have recently established that the JCR:LA-cp rodent model develops postprandial dyslipidaemia concomitant with complications of the metabolic syndrome. Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) are proposed to modulate plasma lipids, serum hormone levels, lipoprotein metabolism and the inflammatory state; however, results remain inconsistent during conditions of IR. AIM: To assess the acute metabolic and inflammatory effects of dietary fish oil supplementation on existing postprandial dyslipidaemia in the JCR:LA-cp model. METHODS: JCR:LA-cp rats (14 weeks of age) were fed either a control, isocaloric, lipid balanced diet (15% w/w total fat, 1.0% cholesterol, P:S ratio 0.4), a lipid balanced diet with 5% n-3 PUFA [fish oil derived eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] or a lipid balanced diet with 10% n-3 PUFA for 3 weeks. Fasting plasma lipid, cytokine levels, postprandial chylomicron (apoB48) metabolism and the postprandial inflammatory response [haptoglobin and lipopolysaccharide binding protein (LBP)] were assessed following a standardized 'oral fat challenge'. RESULTS: n-3 PUFA treatment resulted in a significant improvement (i.e. decrease) in the postprandial response for triglyceride (45%) (p < 0.05), apoB48 (45%) (p < 0.03) and LBP (33%) (p < 0.05) compared to controls (measured as area under the clearance curve). In contrast, we observed a significant elevation in postprandial haptoglobin (165%) (p < 0.001) in obese rats supplemented with 10% n-3 PUFA. Treatment with 5% n-3 PUFA in the JCR:LA-cp obese animals resulted in a complementary decrease in total body weight gain (6%) (p < 0.001) and an increase (i.e. improvement) in adiponectin (33%) (p < 0.05) compared to controls, without a concomitant reduction in food intake. CONCLUSION: Acute dietary n-3 PUFA dietary supplementation can improve fasting as well as postprandial lipid metabolism and components of the associated inflammatory response in the JCR:LA-cp rat. Further, moderate dose n-3 PUFA supplementation may reduce corresponding body weight during conditions of hypercholesterolaemia and/or modulate inflammation associated with obesity and the metabolic syndrome.

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

BACKGROUND AND PURPOSE: 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 JCR : LA-cp rat that exhibits micro- and macrovascular disease with ischaemic myocardial lesions and renal disease. EXPERIMENTAL APPROACH: Obese male rats were treated with irbesartan (30 mg.kg(-1).day(-1), incorporated into chow) from 12 to 25 weeks of age. KEY RESULTS: Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA-cp rats was marginally improved, at the expense of increased plasma insulin levels ( approximately 50%). Fasting plasma triglycerides were marginally reduced ( approximately 25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium-dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%). CONCLUSIONS AND IMPLICATIONS: Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end-stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.

Methods to assess impaired post-prandial metabolism and the impact for early detection of cardiovascular disease risk.

Post-prandial lipaemia has emerged as a key contributor to cardiovascular disease (CVD) risk and progression. Specifically, delayed clearance of chylomicrons (CM) and their remnants increase the delivery of triglyceride and cholesteryl ester to the vessel wall and can accelerate the progression of atherosclerosis, which may be particularly pertinent to individuals with insulin resistance and/or obesity. As the number of studies linking post-prandial metabolism and chronic disease increases, interest has grown in the use of parameters reflecting CM metabolism as a possible indicator of early CVD risk. This, in turn has raised the question of what method might be most appropriate to detect CM and their remnants in plasma accurately. However, the handful of techniques able to measure CM metabolism (triglyceride-rich lipoprotein fractions; remnant-lipoprotein cholesterol; retinyl esters, CM-like emulsion; sodium dodecyl sulphate-polyacrylamide gel electrophoresis; immunoblotting, enzyme-linked immunoabsorbent assays; C(13) breath test; capillary finger prick) differ in their specificity, cost and applicability in research and in the clinical setting. In this review, we explore the scientific and clinical implications of CM methodology to better understand early risk assessment of CVD. We raise ongoing issues of the need to appreciate differential separation of very low-density lipoprotein and CM fractions, as well as to identify the technical basis for imprecision between assays for apolipoprotein B48. We also highlight emerging issues with respect to the practicality of measuring post-prandial metabolism in large clinical studies and offer opinions on the appropriateness of existing techniques in this field.

Effects of feeding fish oil on mesenteric lymph node cytokine responses in obese leptin receptor-deficient JCR:LA-cp rats.

OBJECTIVE: berrant immune responses have been identified in obesity; however, immune cells of lymph nodes residing in the inflammatory environment of visceral adipose tissue have been largely overlooked. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can reduce inflammation and modify T-cell function and therefore may improve immune function in obesity. Thus, we determined the effects of feeding fish oil (FO) containing EPA and DHA on mesenteric lymph node (MLN) immune cell function. METHODS: In this study, 14-week-old obese, leptin receptor-deficient JCR:LA-cp rats (cp/cp) (n=10 per group) were randomized to one of three nutritionally adequate diets for 3 weeks: control (ctl, 0% EPA+DHA), low FO (LFO, 0.8% w/w EPA+DHA) or high FO (HFO, 1.4% w/w EPA+DHA). Lean JCR:LA-cp (Cp/cp or Cp/Cp) rats (n=5) were fed ctl diet. MLN cell phospholipid (PL) fatty acid composition, phenotypes and cytokine production were measured. RESULTS: Obese ctl rats produced more IL-1beta, IL-4 and IL-10, despite a higher proportion of (n-3) polyunsaturated fatty acids (PUFAs) and a lower (n-6):(n-3) PUFA ratio in MLN PL compared with lean ctl rats (P<0.05). Concanavalin A-stimulated IL-2 production did not differ from lean rats even though obese ctl rats had a lower proportion of CD4(+)CD25(+) cells (P<0.05). Feeding FO to obese rats increased the incorporation of (n-3) PUFA into MLN PL and normalized production of IL-1beta (HFO only), IL-4 and IL-10 to the levels similar to lean ctl rats (P<0.05). CONCLUSION: We demonstrate for the first time that obese JCR:LA-cp rats have impaired responses of MLN immune cells to mitogen stimulation and altered PL fatty acid composition. Feeding FO lowered the ex vivo inflammatory response (HFO only) and production of Th2 cytokines, without changing IL-2 production from ConA-stimulated splenocytes, which may occur independent of leptin signalling.

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.

Apolipoprotein B48: a novel marker of metabolic risk in overweight children?

Clinical studies in adults indicate there is a positive and significant association between insulin resistance, dyslipidaemia, fasting intestinally derived lipoproteins [via apoB48 (apolipoprotein B48)] and visceral fat. All of these factors contribute to increased risk of CVD (cardiovascular disease). Since little is known about postprandial dyslipidaemia in overweight children, we sought to compare fasting levels of apoB48 with the HOMA-IR (homoeostasis model assessment of insulin resistance) score, classic lipid profile and VAT (visceral adipose tissue). Pre-pubertal, overweight boys and girls were recruited from the wider-Edmonton area (Alberta). Body composition was determined using both dual-energy X-ray absorptiometry and MRI (magnetic resonance imaging). Fasting apoB48 was quantified in plasma using an adapted SDS/PAGE immunoblotting technique, and insulin, glucose, TC (total cholesterol), TAG (triacylglycerol), LDL (low-density lipoprotein) and HDL (high-density lipoprotein) were determined by calorimetric assay. In this overweight sample, we observed elevated fasting apoB48 concentrations, greater than the normal adult range. In addition, apoB48 was significantly related to HOMA-IR and TAG levels. Although apoB48 was positively correlated with TC and LDL and negatively associated with HDL, these relationships did not achieve significance. Our ongoing MRI analysis reveals a positive relationship between apoB48 and VAT volume. To our knowledge, this is the first study to report apoB48 concentrations in overweight pre-pubertal children. Thus this article will provide a brief rationale for our study and its methodology.

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.

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake. KEY RESULTS: Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1 beta. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction. CONCLUSIONS AND IMPLICATIONS: Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG.

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

AIMS: 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. METHODS: Insulin-resistant cp/cp rats of the JCR:LA-cp strain were treated with mixed isomers of CLA (1.5% w/w in the chow) and/or CrP at 80 microg/kg/day (expressed as Cr) from 4 weeks of age to 12 weeks of age. Plasma insulin, lipid and adiponectin levels, aortic vascular function, renal function and glomerular sclerosis were assessed. RESULTS: CLA administration reduced food intake, body weight and fasting insulin in JCR:LA-cp rats. Plasma adiponectin levels were significantly elevated in rats treated with both CLA and CrP. Aortic hypercontractility was reduced and the relaxant response to the nitric oxide-releasing agent acetylcholine (Ach) was increased in CrP-treated rats. Striking reductions were also observed in the level of urinary albumin and the severity of glomerular sclerosis in rats treated specifically with CLA. CONCLUSIONS: CLA and CrP have beneficial effects ameliorating several of the pathophysiologic features of an insulin-resistant rat model. These supplements may be useful adjuncts in the management of patients with the metabolic syndrome and warrant further study.