Pair feeding-mediated changes in metabolism: stress response and pathophysiology in insulin-resistant, atherosclerosis-prone JCR:LA-cp rats

Abstract

Russell JC, Proctor SD, Kelly SE, Brindley DN. Pair feedingmediated changes in metabolism: stress response and pathophysiology in insulin-resistant, atherosclerosis-prone JCR:LA-cp rats. Am J Physiol Endocrinol Metab 294: E1078-E1087, 2008. First published April 15, 2008 doi:10.1152/ajpendo.90257.2008.-Rats of the JCR: LA-cp strain, which are homozygous for the cp gene (cp/cp), are obese, insulin-resistant, and hyperinsulinemic. They exhibit associated micro-and macrovascular disease and end-stage ischemic myocardial lesions and are highly stress sensitive. We subjected male cp/cp rats to pair feeding (providing the rats each day with the amount of food eaten by matched freely fed animals), a procedure that alters the diurnal feeding pattern, leading to a state of intermittent caloric restriction. Effects on insulin, glucose, and lipid metabolism, response to restraint stress, aortic contractile/relaxant response, and myocardial lesion frequency were investigated. Pair-fed young (12-wk-old) cp/cp rats had lower insulin and glucose levels (basal and following restraint), consistent with increased insulin sensitivity, but a greater increase in plasma nonesterified fatty acids in response to restraint. These effects were unrelated to lipolytic rates in adipose tissue but may be related to reduced fatty acid oxidation in skeletal muscle. Older (24-wk-old) pair-fed cp/cp rats had significantly reduced plasma triglyceride levels, improved micro-and macrovascular function, and reduced severity of ischemic myocardial lesions. These changes indicate a significant amelioration of end-stage disease processes in this animal model and the complexity of metabolic/physiological responses in studies involving alterations in food intake. The effects illustrate the sensitivity of the JCR:LA-cp rat, an animal model for the metabolic syndrome and associated cardiovascular disease, to the environmental and experimental milieu. Similar stress-related mechanisms may play a role in metabolically induced cardiovascular disease in susceptible human beings. metabolic syndrome; stress; fatty acids; vascular function; myocardial lesions THE METABOLIC SYNDROME, strongly associated with obesity, is a major and increasing cause of cardiovascular morbidity and mortality worldwide. A crucial feature of this disorder is the development of insulin resistance and consequent hyperinsulinemia, which appears to be a major determinant of the associated vasculopathy, atherosclerosis, and ischemic cardiovascular disease (16,27). The underlying origins of the metabolic syndrome remain the subject of debate, and relatively little attention has been paid to the contribution of stress in its various forms. These vary from potentially highly deleterious oxidative stress at a cellular level to neurendocrine and behavioral-environmental stress, all potentially leading to increased cardiovascular disease (6). In contrast, there is evidence that the progression to cardiovascular disease can be alleviated by beneficial effects of exercise and reduced or intermitt...

Cardiometabolic and reproductive benefits of early dietary energy restriction and voluntary exercise in an obese PCOS-prone rodent model

“…The exercise-dietary energy restriction intervention commenced when animals were 3 weeks old (at weaning) and ended when animals were 11 weeks of age (before adulthood), suggesting that early intervention when compared to late intervention (Diane et al 2013b) is more effective in terms of reproductive improvements in this obese PCOS-prone model. Also, compared to previous studies from our group and others, the findings from this current study showed that the combination of energy restriction and voluntary exercise mediates beneficial effects on metabolic and reproductive outcomes in this obese PCOS-prone rodent model compared to dietary energy restriction alone (Bronson 1987, Russell et al 2008, Diane et al 2013a. Our findings that plasma total testosterone, FAI and ovarian follicular morphology were not statistically different between experimental groups are a reflection of the use of younger animals in this PCOSprone model, as these animals do not display the full PCOS phenotype until adulthood (O12 weeks) (Shi et al 2009).…”

“…The FF-Sedentary or Lean-Control groups were also placed in the wheel running apparatus for 4 h/day but the wheels were locked. Previous data from our group has shown that dietary early energy caloric restriction plus sedentary behaviour without exercise significantly improves cardiometabolic parameters in young animals in this rodent model (Russell et al 2008, Diane et al 2013a. Therefore, in this study a dietary ER-Sedentary group was not included, as the aim was to compare the effect of exercise under free feeding and dietary energy restriction conditions.…”

MR Molecular Imaging of Aortic Angiogenesis

“…Body weight and circulating levels of insulin and leptin were reduced relative to the untreated obese animals, but were still elevated compared with the lean controls, in agreement with previous reports (18,19). In earlier studies, the pairing of obese rat food intake to control animals and the feeding of benfluorex or d -fenfluramine have been found to diminish cardiovascular disease and myocardial lesions in this corpulent rat model (14,18,19,34,35). Ad libitum feed consumption in benfluorex-treated obese rats was comparable to the intake of their lean control counterparts, which was mirrored by a low aortic neovascular MR signal in both groups of animals.…”

Alcohol-induced ketonemia is associated with lowering of blood glucose, downregulation of gluconeogenic genes, and depletion of hepatic glycogen in type 2 diabetic db/db mice

“…In this regard, previous studies with pair-fed obese type 2 diabetic rodents have shown that a reduction in food intake contributes to ~53% of the antihyperglycemic effect of liraglutide (a long-acting glucagon-like peptide-1 derivative) [68]. It is noteworthy that on an unrestricted diet, the obese, insulin-resistant rodents (that are also hyperphagic) consume food throughout the 24-h cycle [69,70]. In contrast, on a restricted diet (pair-fed condition), the obese rodents consume all food within 3 to 10 h that would result in fasting or caloric deprivation for the remaining period in the 24-h cycle [69,70].…”

“…It is noteworthy that on an unrestricted diet, the obese, insulin-resistant rodents (that are also hyperphagic) consume food throughout the 24-h cycle [69,70]. In contrast, on a restricted diet (pair-fed condition), the obese rodents consume all food within 3 to 10 h that would result in fasting or caloric deprivation for the remaining period in the 24-h cycle [69,70]. In the present study with type 2 diabetic db/db mice (obese/hyperphagic), we thus avoided pair-feeding and also for the reason that db/db mice were subjected to 4h fasting periods for blood sample collections to measure glucose and βOHB levels (on days 1, 3, 5, 7 and 9) and to perform GGT test (on day 5) during the 9-day treatment protocol.…”