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.

First detection of Chlamydia psittaci from a wild native passerine bird in New Zealand.

AIMS: To undertake disease surveillance for Chlamydia psittaci in native birds as part of a pilot study to examine pathogen diversity on Hauturu-o-Toi/Little Barrier Island. To retrospectively review the Massey University post-mortem database to determine previous cases of avian chlamydiosis in New Zealand. METHODS: Mistnetting of forest birds was conducted across an elevational gradient on Hauturu-o-Toi/Little Barrier Island. Minitip culture swabs were used to collect cloacal samples from native birds. These swabs were screened for Chlamydia family DNA using two PCR methods. Positive results were sequenced. A retrospective review of the Massey University post-mortem database of all avian cases from 1990 to 2011 was conducted. RESULTS: Ten native birds including four bellbirds (Anthornis melanura), three rifleman (Acanthisitta chloris), two hihi (Notiomyces cincta), and one whitehead (Mohoua albicilla) were sampled and one otherwise healthy female hihi was positive by both PCR screening methods for Chlamydophila. Sequencing confirmed 99-100% genetic similarity to C. psittaci. A retrospective review of the Massey University post-mortem database revealed no previous diagnoses of avian chlamydiosis in wild native New Zealand birds although it has been detected in captive parrots, and wild and captive exotic pigeons. CONCLUSIONS: This is the first report of the detection of C. psittaci from a wild native bird in New Zealand. The bird was a Passeriforme from an endangered species that was captured free-living on Little Barrier Island. The incidence of avian chlamydiosis in native birds in New Zealand appears to be very low, based on the retrospective review of the post-mortem database. CLINICAL RELEVANCE: It is unlikely that avian chlamydiosis is a significant problem for hihi population health. The detection of this organism has greater significance for other more susceptible species on Little Barrier Island and for human health, particularly for conservation workers involved in wildlife translocations. It further suggests that passerine birds may be a reservoir for C. psittaci in New Zealand ecosystems.

Use of the pre-operative shuttle walk test to predict morbidity and mortality after elective major colorectal surgery.

High-risk surgery is performed in every acute hospital. These patients often have increased peri-operative risk related to their poor cardiorespiratory reserve. Formal risk assessment is recommended for such patients; cardiopulmonary exercise testing is a well established triage tool, but is unavailable in many hospitals. We investigated whether a simple exercise test could predict postoperative outcome using a prospective trial of 121 patients undergoing elective major abdominal surgery. Each patient completed a shuttle walk test and was followed up for 30 days after surgery. There was one postoperative death (0.8%), with 53 patients (44%) developing complications. The mean (SD) shuttle walk test distance was significantly different between patients who suffered complications and those who did not (276.6 (134.5) vs 389.6 (138.9) m, respectively; p < 0.001). A cut-off distance of 250 m had a specificity of 0.88 and a sensitivity of 0.58 to predict postoperative complications. Patients unable to complete a shuttle walk test above this cut-off distance were three times more likely to have a postoperative morbidity. We conclude that the shuttle walk test can help identify patients who are at increased peri-operative risk.

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.

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.

Enhanced cell death in MeCP2 null cerebellar granule neurons exposed to excitotoxicity and hypoxia.

Rett syndrome (RTT) is associated with mutations in the transcriptional repressor gene MeCP2. Although the clinical and neuropathological signs of RTT suggest disrupted synaptic function, the specific role of methyl-CpG binding protein 2 (MeCP2) in postmitotic neurons remains relatively unknown. We examined whether MeCP2 deficiency in central neurons contributes to the neuropathogenesis in RTT. Primary cerebellar granule neuronal cultures from wild-type (WT) and MeCP2-/- mice were exposed to N-methyl-d-aspartate (NMDA) and AMPA-induced excitotoxicity and hypoxic-ischemic insult. The magnitude of cell death in MeCP2-/- cells after excitotoxicity and hypoxia was greater than in the WT littermate control cultures and occurred after shorter exposures that usually, in the WT, would not cause cell death. Pretreatment with the growth factor fibroblast growth factor 1 (FGF-1) under conditions at which WT cells showed complete neuroprotection, only partially protected MeCP2-/- cells. To elucidate specifically the effects of MeCP2 knockout (KO) on cell death, we examined two death cascade pathways. MeCP2-/- neurons exposed to 6 h of hypoxia exhibited enhanced activation of the proapoptotic caspase-3 and increased mitochondrial release of apoptosis inducing factor (AIF) compared with WT neurons, which did not show significant changes. However, pretreatment with the caspase inhibitor ZVAD-FMK had little or no effect on AIF release and its subcellular translocation to the nucleus, suggesting caspase-independent AIF release and their independent contribution to hypoxia-induced cell death. Reintroduction of intact MeCP2 gene in MeCP2-/- cells or MeCP2 gene silencing by MeCP2siRNA in WT cells further confirmed the differential sensitivity of the WT and MeCP2-/- cells and suggest a direct role of MeCP2 in cell death. These results clearly demonstrate increased cell death occurred in neurons lacking MeCP2 expression via both caspase- and AIF-dependent apoptotic mechanisms. Our findings suggest a novel, yet unknown, role for MeCP2 in central neurons in the control of neuronal response to cell death.

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.

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.

Impaired postprandial apolipoprotein-B48 metabolism in the obese, insulin-resistant JCR:LA-cp rat: increased atherogenicity for the metabolic syndrome.

AIM: Postprandial lipaemia is a significant contributor to the development of dyslipidaemia and cardiovascular disease, which has more recently been shown as a potential risk factor for obesity and pre-diabetes. Clinically however, the diagnosis of early insulin-resistance remains confounded due to the fact that aberrations in lipid metabolism are not often readily identified using classic indicators of hypercholesterolemia (i.e. LDL). METHODS: In this study, we assessed the metabolism of apolipoprotein-B48 (apoB48)-containing lipoproteins in an animal model of obesity and insulin-resistance, the JCR:LA-cp rat. The contribution of lipoproteins from the intestine was assessed by measuring plasma apoB48 concentration in the postprandial period following an oral fat load. Plasma apoB48 was measured by improved enhanced chemiluminescent detection and other biochemical parameters measured by established analysis. RESULTS: Fasting concentrations of plasma apoB48, postprandial apoB48 area under the curve (AUC), as well as incremental-AUC (iAUC), were all significantly greater in the obese phenotype compared to lean controls. Fasting apoB48 correlated significantly with apoB48-iAUC, triglyceride (TG)-iAUC and insulin-iAUC. In addition, there was a highly significant association with fasting insulin and the postprandial ratio of TG:apoB48, a relationship not often detected in humans during insulin-resistance. CONCLUSIONS/INTERPRETATION: We conclude that the JCR:LA-cp rat can be used as a model of postprandial lipemia to explore chylomicron metabolism during the onset and development of insulin-resistance, including the increased cardiovascular complications of the metabolic syndrome.

Insulin-sensitizing and cardiovascular effects of the sodium-hydrogen exchange inhibitor, cariporide, in the JCR: LA-cp rat and db/db mouse.

The effects of the sodium-hydrogen (Na/H) exchange inhibitor cariporide (HOE642), on insulin sensitivity and vascular function were studied in the JCR:LA-cp rat and the db/db mouse. In the insulin-resistant rat, cariporide reduced fasting insulin levels (42%, P < 0.02) and insulin response in a meal tolerance test (50%, P < 0.01), indicating increased insulin sensitivity. The ACE inhibitor, ramipril, used as a reference agent, reduced the insulin response to the meal, but not fasting levels. The EC50 for acetylcholine-mediated relaxation of phenylephrine-precontracted aortic rings was significantly lower in cariporide-treated rats (P < 0.002), but not in ramipril-treated rats. Flow response of the coronary circulation to bradykinin was significantly greater in both cariporide- and ramipril-treated rats, (3-fold decrease in the EC50, P < 0.05). Cariporide-treated hearts were smaller, slower beating, with greater developed LVP. In the obese db/db mouse, chronic treatment with cariporide obviated vascular hypercontractility and improved endothelial function. Thus, cariporide had beneficial effects on the abnormal insulin metabolism and associated vascular dysfunction in the JCR:LA-cp insulin-resistant rat, which develops advanced cardiovascular disease and ischemic myocardial lesions. It also improved vascular function in a similar mouse model of insulin resistance. These effects were markedly greater than those of ramipril.

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

AIMS/HYPOTHESIS: The 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 METHODS: Insulin-resistant JCR:LA-cp rats were treated with arginine-silicate-inositol complex or arginine-HCl at 1.0 g 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. RESULTS: Arginine-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/INTERPRETATION: Treatment 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.

Leptin and the control of respiratory gene expression in muscle.

Leptin plays a central role in the regulation of fatty acid homeostasis, promoting lipid storage in adipose tissue and fatty acid oxidation in peripheral tissues. Loss of leptin signaling leads to accumulation of lipids in muscle and loss of insulin sensitivity secondary to obesity. In this study, we examined the direct and indirect effects of leptin signaling on mitochondrial enzymes including those essential for peripheral fatty acid oxidation. We assessed the impact of leptin using the JCR:LA-cp rat, which lacks functional leptin receptors. The activities of marker mitochondrial enzymes citrate synthase (CS) and cytochrome oxidase (COX) were similar between wild-type (+/?) and corpulent (cp/cp) rats. In contrast, several tissues showed variations in the fatty acid oxidizing enzymes carnitine palmitoyltransferase II (CPT II), long-chain acyl-CoA dehydrogenase (LCAD) and 3-hydroxyacyl-CoA dehydrogenase (HOAD). It was not clear if these changes were due to loss of leptin signaling or to insulin insensitivity. Consequently, we examined the effects of leptin on cultured C(2)C(12) and Sol8 cells. Leptin (3 days at 0, 0.2, or 2.0 nM) had no direct effect on the activities of CS, COX, or fatty acid oxidizing enzymes. Leptin treatment did not affect luciferase-based reporter genes under the control of transcription factors involved in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), nuclear respiratory factor-2 (NRF-2)) or fatty acid enzyme expression (peroxisome proliferator-activated receptors (PPARs)). These studies suggest that leptin exerts only indirect effects on mitochondrial gene expression in muscle, possibly arising from insulin resistance.

Developmental changes in adipose and muscle lipoprotein lipase activity in the atherosclerosis-prone JCR:LA-corpulent rat.

OBJECTIVE: To characterize the developmental changes in adipose and muscle lipoprotein lipase (LPL) activity in the atherosclerosis-prone JCR:LA-corpulent rat, and to test the hypothesis that tissue-specific abnormalities in LPL activity precede the establishment of obesity. DESIGN: Lean (+/?) and obese cp/cp male JCR:LA rats were studied at 4, 5 and 8 weeks of age, that is at the onset of obesity, and at a time when obesity is well established. Assessment was made of plasma variables related to glucose and lipid metabolism and of LPL activity in several adipose depots, skeletal muscles and the heart. RESULTS: At week 4, body weights were identical in both genotypes and began to diverge at week 5. Eight-week-old cp/cp rats weighed 35% more than their lean counterparts. Perirenal and epididymal adipose depot weights were also identical in both genotypes at week 4 and began to increase in cp/cp rats at week 5, whereas the subcutaneous depot of 4-week-old cp/cp rats was slightly enlarged. At week 4, the cp/cp rats were hyperinsulinemic (5-fold), hyperleptinemic (30-fold) and hypertriglyceridemic (3-fold) compared to their lean counterparts, and their liver contained twice as much triglyceride. The 4-week-old cp/cp rats displayed 2-7-fold higher LPL specific activity in the various adipose depots compared to lean rats, and enzyme activity remained higher in obese than in lean rats at all subsequent ages. In contrast, LPL activity in the vastus lateralis, gastrocnemius and heart muscles of 4-week-old obese rats was approximately half that observed in lean animals. CONCLUSION: Profound, persistent alterations in the tissue-specific modulation of LPL activity are established in the JCR:LA cp/cp rat prior to the development of frank obesity. The increase in adipose tissue LPL activity and its decrease in muscle tissues are likely to be related to the concomitant alterations in insulinemia and triglyceridemia, respectively. The pre-obesity, tissue-specific alterations in LPL activity may be considered as an integrated adaptation to increased lipid flux aimed at driving lipids toward storage sites and limiting their uptake by triglyceride-laden muscles.

The physiology and clinical applications of vasopressin in critical illness.

OBJECTIVE: To present the physiology of vasopressin, and review published data on its use in critically ill patients. DATA SOURCES: A review of articles on the clinical use of vasopressin in critical care medicine up to 2002 and identified through a MEDLINE search. SUMMARY OF REVIEW: Vasopressin (antidiuretic hormone) acts via vasopressinergic receptors to maintain osmotic and baroreceptor homeostasis. It has complex and varying effects depending on serum levels, coexisting disease states and organs studied. Synthetic vasopressin is available for clinical use. In large doses (e.g. 40 U) it has vasoconstrictor effects comparable to epinephrine during cardiopulmonary resuscitation. The use of much lower "replacement" doses (e.g. 0.04 U/min) may have a marked vasopressor effect in clinical states associated with vasopressin deficiency; for example sepsis, the organ donor and after cardiopulmonary bypass. These doses are much lower than those leading to cardiovascular effects in healthy patients and may avoid the adverse vasoconstrictor effects seen at "pharmacological" doses. The use of vasopressin to reduce portal pressure and bleeding in oesophageal varices is well established. CONCLUSIONS: Vasopressin has widespread effects throughout the body and has several important clinical applications in the critically ill patient.

Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat.

The corpulent JCR:LA-cp rat (cp/cp) is a useful model for study of the metabolic consequences of obesity and hyperinsulinemia. To assess the effect of hyperinsulinemia on VLDL secretion in this model, we measured rates of secretion of VLDL in perfused livers derived from cp/cp rats and their lean littermates. Livers of cp/cp rats secreted significantly greater amounts of VLDL triglyceride and apolipoprotein, compared with lean littermates. The content of apoB, apoE, and apoCs in both perfusate and plasma VLDL was greater in the cp/cp rat, as was the apolipoprotein (apo)C, apoA-I, and apoA-IV content of plasma HDL. Triglyceride content was also greater in cp/cp livers, as was hepatic lipogenesis and expression of lipogenic enzymes and sterol regulatory element binding protein-1 (SREBP-1). Hepatic mRNAs for apoE, and apoA-I were higher in livers of cp/cp rats. In contrast, the steady state levels of apoC-II, apoC-III, and apoB mRNAs were unchanged. Thus, livers of obese hyperinsulinemic cp/cp JCR:LA-cp rats secrete a greater number of VLDL particles that are enriched in triglyceride, apoE, and apoC. Greater secretion of VLDL in the cp/cp rat in part results from higher endogenous fatty acid synthesis, which in turn may occur in response to increased expression of the lipogenic enzyme regulator SREBP-1c.

Conditioned taste aversion induced by wheel running is not due to novelty of the wheel.

Under a within-subjects design, food- and water-restricted rats showed a significant reduction in consumption of a flavor associated with the opportunity to run compared to another flavor associated with a novel wheel without the opportunity to run. Furthermore, there was no evidence that consumption of the flavor paired with the novel wheel differed from a home cage control.

High glucose concentrations induce oxidative damage to mitochondrial DNA in explanted vascular smooth muscle cells.

Oxidative stress is considered to be one of the mechanisms leading to atherosclerosis. It occurs in response to injury or to altered metabolic state. Alterations in cell growth (proliferation or apoptosis) can also contribute to the pathogenesis of atherosclerosis and is influenced by oxidative stress. Smooth muscle cells (SMC) from aortic explants of JCR:LA-cp homozygous cp/cp corpulent rats who are genetically predisposed to develop atherosclerosis exhibit increased SMC proliferation, which can be attenuated by exercise and food restriction. This study was conducted to characterize the effects fo oxidative stress and high glucose media on cell growth and its relationship to mitochondrial DNA integrity and gene expression in explanted aortic SMC from corpulent and lean JCR:LA-cp rats. The results show that SMC from the cp/cp rat appear to be resistant to oxidant-induced cell death and that they accumulate mitochondrial DNA mutations, probably as a result of a reduction in apoptosis. These data suggest that susceptibility to age- and glucose-related atherosclerosis may be related to alterations in redox signaling.

Protection of vascular wall function in insulin-resistant rats from copper oxidative stress.

The effects of oxidative stress on vascular function in the insulin-resistant state were assessed in mesenteric resistance arteries of obese, insulin-resistant (cp/cp) and lean, normal (+/?) JCR : LA-cp rats. Nitric oxide-mediated relaxation of noradrenaline-contracted arteries in response to acetylcholine was impaired after 2 h of incubation with Cu(2+) in both genotypes, with or without the continuing presence of Cu(2+). Relaxation was enhanced on initial exposure to Cu(2+), and post-incubation removal of the Cu(2+) resulted in a greater impairment of relaxation. Arteries from cp/cp rats were less impaired in function by Cu(2+) incubation than were those of +/? controls. Sodium nitroprusside-mediated relaxation was impaired by exposure to Cu(2+), with an accompanying increase in EC(50). The impairment in acetylcholine-mediated relaxation in the arteries from both cp/cp and +/? rats was completely inhibited by co-incubation with copper-zinc superoxide dismutase and catalase, confirming that the impairment associated with Cu(2+) incubation was due to oxidative stress. The impairment appears to involve both smooth muscle and the endothelium. The cp/cp rats showed greater resistance to the effects of oxidative stress on arterial function, possibly due to an adaptation to oxidative stress on arterial function associated with the insulin-resistant state.