Overfeeding In Rats Research Articles

Postnatal overfeeding in rats causes childhood and adulthood obesity associated with vascular dysfunction in a mechanistic and sex-dependent manner

In recent years incidence of childhood obesity has increased globally, regardless of economic status. This phenomenon is a known risk factor for cardiovascular diseases. Here we hypothesized that postnatal overfeeding, a recognized model of childhood obesity, will induce vascular dysfunction in prepubertal and adult rats in a sex-dependent manner. For this, we used the animal model of postnatal overfeeding by litter size reduction. At postnatal day (PND) 1, Wistar rat were divided into a normal litter (NL, mothers were kept with 5 female and 5 male pups) or small litter (SL, mothers were kept with 2 male and 1 female pup). The ratss were evaluated at two time points prepubertal (PND 30 for females and 40 for males due to known sexual maturation differences), and in adulthood (120 for both sex). Body weight (g) and retroperitoneal adipose tissue (fat pad weight/100g of the body n=9-13) were evaluated. Aorta was removed for wall thickness measurements via histology (n=5, μm), and vascular function was performed via pin myograph. Concentration-response curves to phenylephrine [Phenyl, 1nM-10μM, n=6, gram force (gf)] or acetylcholine (ACh 0.1nM100μM, n=7 % relaxation) were performed. To understand the role of the NADPH-derived reactive oxygen species, angiotensin-II and aldosterone, apocynin (APO 10 μM), losartan (LOS 1 μM) or spironolactone (SPR 1 μM) were used respectively. Prepubertal SL rats had higher body weight (female: NL 76±2 vs SL 91±1, g, p<0.05; male: NL 148±2 vs. SL 185±4, g, p<0.05), and adipose tissue deposition (female: NL 0.09±0.01 vs. SL 0.17±0.01, p<0.05; male: NL 0.17±0.09 vs. SL 0.32±0.03, p<0.05] regardless of sex. Interestingly, there were no differences in these parameters at PND 120 for female NL and SL. In contrast, male SL at PND 120 had higher body weight (NL 419±9 vs SL 462±5, g, p<0.05) and retroperitoneal adipose tissue (NL 1.2±0.9 vs SL 1.6±0.1, p<0.05]). No differences were observed in phenyl-induced contraction in aortas from females at PND 30 and 120. On the other hand, endothelial dysfunction was observed at PND 120 in arteries from SL females rats [Maximum response (Rmax): NL 94±1 vs SL 84±2, % p<0.05]. LOS (Rmax: SL 77±1 vs LOS 90±1, % p<0.05) and APO (SL 77±1 vs APO 87±1, % p<0.05] restored endothelial function in these animals. No changes in endothelium-dependent relaxation were observed in arteries from male rats at PND 40 or 120. However, there was an increase in vascular contractility from SL males at PND 40 (Rmax: NL 1.17±0.40 vs SL 1.47±0.06, g, p<0.05), and SPR (SL 1.50 ±0.14 vs SPR 0.93±0.09, g, p<0.05) improved this response, but no differences were observed at PND 120. Further, the aortic thickness was similar between groups at PND 120 regardless of sex. In conclusion, postnatal overfeeding in rats causes childhood obesity associated with vascular dysfunction. These differences were observed in prepubescent and adult rats, and the respective mechanisms are sex-dependent. Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) (Finance code 001). Araucária Foundation for the Support of Scientific and Technological Development of the State of Paraná - Brazil (grant: 215/2022-PBA). National Institutes of Health - R00GM118885, R01HL149762, R00HL151889, and RO1DK132948. Fulbright Program - DDRA foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Maternal programming by high-energy diets primes ghrelin sensitivity in the offspring of rats exposed to chronic immobilization stress

Maternal overnutrition during pregnancy leads to metabolic and immune alterations, including obesity, hyperphagia, and central and peripheral inflammation in offspring. Exposure to high-energy diets during pregnancy primes ghrelin sensitivity to overfeeding in the offspring at early stages of life. Overfeeding has also been partially related to the early stages of chronic stress. We hypothesized that maternal programming sensitizes ghrelin-induced overfeeding following a chronic stress schedule in the offspring. We used a nutritional programming model exposing female Wistar rats to a cafeteria (CAF) or control diet from prepregnancy to weaning. Male offspring were injected with ghrelin and then subjected to a chronic immobilization stress (CIS) schedule, after which food intake was determined. Hypothalamic and plasma accumulation of cytokines and cortisol were evaluated using BioPlex analysis and enzyme-linked immunosorbent assay, respectively. We found that rats exposed to the CAF diet exhibited overfeeding after fasting and peripheral ghrelin administration, which was exacerbated in rats exposed to chronic stress. Offspring exposed to the CAF diet accumulated pro-inflammatory interleukin-6 (IL-6), interferon-γ, and monocyte chemoattractant protein-1 cytokines in plasma, and IL-6 cytokine in the hypothalamus. Ghrelin-sensitive overfeeding in rats exposed to CAF diet + CIS display increased cortisol levels and decreased IL-6 accumulation in plasma. Together, our results suggest that maternal nutritional programming primes susceptibility to ghrelin response for overfeeding after a CIS schedule that mirrors plasma cortisol accumulation in male offspring.

Influence of gestational exercise practice and litter size reduction on maternal care

Mother-pup interactions are extremely important to offspring survival and growth. The goal of this study was to evaluate the influence of prenatal and neonatal interventions on maternal care, analyzing the effect of maternal exercise, as a healthy intervention, and also the litter size reduction, a model that has been widely used to study early overfeeding in rats. Female Wistar rats were divided into 1) sedentary, and 2) swimming exercise for four weeks, starting one week before mating (5 days/week, 30 min/session). One day after birth, the litter was culled to 8 pups (normal) or 3 pups (small) per dam, yielding control and overfed subgroups for each maternal group, respectively. From postnatal days 2–9 the litter was observed 5 periods a day, to evaluate maternal behavior. Litter reduction caused important alterations in maternal behavior, reducing the total time out of the nest and increasing the frequency of maternal care and lactation in several observation periods, justifying the increased pup’s weight gain already demonstrated by this animal model. The practice of maternal exercise did not prevent, but cause the less intensive frequency of non-maternal behavior and lactation in arched-back position, induced by the reduction of litter size. These data demonstrated that small litter size altered maternal behavior, and gestational exercise does not influence significantly these changes.

Effect of perivascular adipose tissue on arterial adrenergic contractions in normotensive and hypertensive rats with high fructose intake.

The aim of this study was to investigate the effect of high fructose intake associated with moderate increase in adiposity on rat arterial adrenergic responses and their modulation by perivascular adipose tissue (PVAT). After eight-week-lasting substitution of drinking water with 10 % fructose solution in adult normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), their systolic blood pressure, plasma triglycerides, and relative liver weight were elevated when compared to their respective control groups. Moreover, in SHR, body weight and relative heart weight were increased after treatment with fructose. In superior mesenteric arteries, PVAT exerted inhibitory influence on adrenergic contractile responses and this effect was markedly stronger in control WKY than in SHR. In fructose-administered WKY, arterial adrenergic contractions were substantially reduced in comparison with the control group; this was caused mainly by enhancement of anticontractile action of PVAT. The diminution of the mesenteric arterial contractions was not observed after fructose treatment in SHR. We conclude that the increase in body adiposity due to fructose overfeeding in rats might have prehypertensive effect. However, in WKY it might cause PVAT-dependent and independent reduction in arterial contractile responses to adrenergic stimuli, which could attenuate the pathological elevation in vascular tone.

A laboratory environment previously associated with a palatablediet can result in overfeeding in rats

Enriched and non-enriched laboratory environments produce various biological and behavioral effects on laboratory animals. One of the most impacted aspects in this regard is eating behavior. We examined associations between enriched vs. non-enriched environments and palatable vs. non-palatable diets on food intake in rats. Experiment 1 demonstrated that there are no significant differences in palatable food consumption irrespective of whether rats were exposed to enriched or non-enriched environments (P>0.05). In contrast, experiment 2 demonstrated that a combination of exposure to either of these environments and palatable food is enough to produce overfeeding in rats (P less than 0.05). These outcomes in rats may offer significant inferences in regards to the regulation of eating behavior in humans.

Pioglitazone in adult rats reverses immediate postnatal overfeeding-induced metabolic, hormonal, and inflammatory alterations.

Immediate postnatal overfeeding in rats, obtained by reducing the litter size, results in early-onset obesity. Such experimental paradigm programs overweight, insulin resistance, dyslipidemia, increased adipose glucocorticoid metabolism [up-regulation of glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)], and overexpression of proinflammatory cytokines in mesenteric adipose tissue (MAT) in adulthood. We studied the effects of pioglitazone, a PPARγ agonist, treatment on the above-mentioned overfeeding-induced alterations. Nine-month-old rats normofed or overfed during the immediate postnatal period were given pioglitazone (3 mg/kg/day) for 6 weeks. Pioglitazone stimulated weight gain and induced a redistribution of adipose tissue toward epididymal location with enhanced plasma adiponectin. Treatment normalized postnatal overfeeding-induced metabolic alterations (increased fasting insulinemia and free fatty acids) and mesenteric overexpression of GR, 11β-HSD11, CD 68, and proinflammatory cytokines mRNAs, including plasminogen-activator inhibitor type 1. Mesenteric GR mRNA levels correlated positively with mesenteric proinflammatory cytokines mRNA concentrations. In vitro incubation of MAT obtained from overfed rats demonstrated that pioglitazone induced a down-regulation of GR gene expression and normalized glucocorticoid-induced stimulation of 11β-HSD1 and plasminogen-activator inhibitor type 1 mRNAs. Our data show for the first time that the metabolic, endocrine, and inflammatory alterations induced by early-onset postnatal obesity can be reversed by pioglitazone at the adulthood. They demonstrate that pioglitazone, in addition to its well-established effect on adipose tissue redistribution and adiponectin secretion, reverses programing-induced adipose GR, 11β-HSD1, and proinflammatory cytokines overexpression, possibly through a GR-dependent mechanism.

Low-intensity and moderate exercise training improves autonomic nervous system activity imbalanced by postnatal early overfeeding in rats.

BackgroundPostnatal early overfeeding and physical inactivity are serious risk factors for obesity. Physical activity enhances energy expenditure and consumes fat stocks, thereby decreasing body weight (bw). This study aimed to examine whether low-intensity and moderate exercise training in different post-weaning stages of life is capable of modulating the autonomic nervous system (ANS) activity and inhibiting perinatal overfeeding-induced obesity in rats.MethodsThe obesity-promoting regimen was begun two days after birth when the litter size was adjusted to 3 pups (small litter, SL) or to 9 pups (normal litter, NL). The rats were organized into exercised groups as follows: from weaning until 90-day-old, from weaning until 50-day-old, or from 60- until 90-days-old. All experimental procedures were performed just one day after the exercise training protocol.ResultsThe SL-no-exercised (SL-N-EXE) group exhibited excess weight and increased fat accumulation. We also observed fasting hyperglycemia and glucose intolerance in these rats. In addition, the SL-N-EXE group exhibited an increase in the vagus nerve firing rate, whereas the firing of the greater splanchnic nerve was not altered. Independent of the timing of exercise and the age of the rats, exercise training was able to significantly blocks obesity onset in the SL rats; even SL animals whose exercise training was stopped at the end of puberty, exhibited resistance to obesity progression. Fasting glycemia was maintained normal in all SL rats that underwent the exercise training, independent of the period. These results demonstrate that moderate exercise, regardless of the time of onset, is capable on improve the vagus nerves imbalanced tonus and blocks the onset of early overfeeding-induced obesity.ConclusionsLow-intensity and moderate exercise training can promote the maintenance of glucose homeostasis, reduces the large fat pad stores associated to improvement of the ANS activity in adult rats that were obesity-programmed by early overfeeding.

Postnatal overfeeding in rats leads to moderate overweight and to cardiometabolic and oxidative alterations in adulthood

In contrast to the masses of data on obesity, few data are available concerning the cardiometabolic and oxidative consequences of moderate overweight. The model of postnatal overfeeding (OF) induces an increase in body weight at weaning that remains during adult life.Litters of Wistar rats were either maintained at 12 pups (normal-fed group, NF), or reduced to 3 pups at birth in order to induce OF. At 6 months of age, metabolic parameters, circulating oxidative stress and aortic and coronary vasoreactivity were assessed. Cardiac susceptibility to ischemia-reperfusion injury was also evaluated ex vivo as were markers of cardiac remodeling. OF led to an increase in body weight at weaning (+50%); the increase in body weight persisted throughout adult life, but was less marked (+10%). Significant increases in plasma levels of fasting glucose, insulin and leptin were found in OF rats. An increase in both plasma hydroperoxides and cardiac superoxide dismutase activity and a decrease in plasma ascorbate were found in OF rats. Vasoreactivity was not modified, but ex vivo, after 30 min of ischemia, isolated hearts from OF rats showed lower recovery of coronary flow along with a greater release of LDH. Studies on heart tissues showed an increase in collagen content and increased expression and activity of MMP-2.Our findings show that moderate overweight in adult rats, induced by postnatal overfeeding, leads to both metabolic and oxidative disturbances as well as a higher susceptibility to cardiac injury after ischemia ex vivo, which may be explained, at least in part, by ventricular remodeling.

Mechanisms of Sympathetic Activation in Obesity-Related Hypertension

Obesity prevalence is soaring in industrialized countries and progressively increasing in the developing world. Altered patterns of nutrition and reduction in work-related energy expenditure have led to obesity becoming a truly global health issue. The central thermodynamic formulation for the origins of obesity, a mismatched energy balance equation, with an excess of dietary calorie intake over body energy expenditure, is a first step in the understanding of this phenomenon but leaves the diverse causal issues unexplored. Dietary calorie intake is modified by multiple social, economic, and cultural issues. Similarly, the reduction in energy expenditure in recent decades has complex origins, deriving from demographic and social change, which includes third-world transition from a labor-intensive agricultural economy to an industrial base, the introduction of household labor-saving devices, the popularity of transportation modes not reliant on physical effort, and from changed recreational habits, particularly in childhood (computer games instead of physical games). The prevalence of childhood obesity is escalating, having whimsically but not entirely unrealistically been attributed to “potato chips and computer chips.” Obesity and hypertension are intimately associated, and both very commonly coexist in individual patients with insulin resistance, hyperinsulinemia, and hyperlipidemia, this clustering of adverse health factors1 being designated the metabolic syndrome. The pathophysiological mechanisms by which obesity leads to hypertension remain uncertain. Understanding these processes might, perhaps, provide a more rational basis for drug treatment of obesity-related hypertension. Attempts at reduction in body weight, although pivotal in the treatment of obesity-related hypertension, more often than not fail, so that antihypertensive drug therapy is often needed. This review analyses the proposition that obesity is characterized by activation of the sympathetic nervous system and that obesity-related hypertension is, in fact, neurogenic, being initiated and sustained by neural mechanisms. At one time, this idea would have been held to fly in the …

Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood

To study the effect of perinatal programming and overfeeding on the hypothalamic control mechanisms of food intake in adult rats. Neonatal programming effects on body weight, food intake, central and peripheral leptin levels, hypothalamic neuropeptides, leptin receptors and central leptin responsiveness in adult rats. Plasma and cerebrospinal fluid (CSF) leptin levels were analyzed using radioimmunoassay. Neuropeptide mRNA levels were analyzed using in situ hybridization. Leptin receptor mRNA levels were analyzed using reverse transcriptase-polymerase chain reaction. Perinatally overfed rats growing up in small litters (SL) maintain their obese and hyperleptinemic phenotype in adulthood. However, leptin levels in CSF are abnormally low considering the plasmatic hyperleptinemia. In contrast to the already reported changes in perinatally overfed juvenile rats, perinatally overfed adult rats did not show any alteration in the expression of leptin receptor isoforms and evaluated neuropeptides. Moreover, SL adult rats showed a normal sensitivity regarding the inhibitory effect of intracerebroventricular leptin administration on food intake. Perinatal overfeeding does not induce alterations in either the anorectic response to central leptin administration or expression of leptin receptors and neuropeptides in adulthood. The leptin resistance to peripheral leptin in SL adult rats may be related to impaired leptin transport across the blood-brain barrier.

Central and peripheral contributions to obesity‐associated hypertension: impact of early overnourishment

Obesity induced by a high-fat diet was associated with increased tail-cuff blood pressure in adult rats. The mechanisms underlying obesity-related hypertension are unclear, but increased sympathetic activation most probably plays a role. Neuroendocrine alterations observed in obesity may influence both feeding patterns and blood pressure. Work from our laboratory has shown that chronic overfeeding in rats leads to changes in neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (alphaMSH) in the hypothalamus. These peptides have central effects on blood pressure, indicating that obesity-related changes in the CNS may impact on cardiovascular function. Population studies suggest that nutrition in early life can influence the subsequent risk of obesity and high blood pressure. To examine the impact of early postnatal overnutrition on blood pressure and adipose-derived mediators, we adjusted rat litters to 3 or 12 pups (overnutrition and control, respectively). Pups raised in small litters were 15% heavier at weaning, and this intervention was associated with a modest elevation of blood pressure and body weight as adults (16 weeks). Animals raised in small litters had increased 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA in white adipose tissue as adults, which may impact on cardiovascular function. Adjustment of diet after weaning, to 30% fat diet or standard chow, allowed comparison of the impact of different periods of overnourishment. Implementation of a high-fat diet at weaning overcame the effect of litter size on body weight from 10 weeks of age. Blood pressure rose progressively with high-fat feeding and was positively correlated with leptin and body weight. Chronic consumption of a high-fat diet led to marked increases in leptin and insulin and modest increases in blood pressure, and impacts on brain transmitters implicated in the regulation of both appetite and blood pressure. Overnourishment during early postnatal development led to profound changes in body weight at weaning, which tended to abate with maturation. It also led to long-term changes in some adipose-derived mediators, possibly increasing cardiovascular risk.

Brown adipose tissue thermogenesis and the energetics of pregnancy and lactation in rodents.

There has been considerable recent interest in the concept that thermogenesis in brown adipose tissue (BAT) may play an important role in the regulation of energy balance, in addition t o its traditional role in the generation of heat for thermoregulatory purposes. This interest has stemmed primarily from studies on the metabolic responses t o voluntary overfeeding in rats given a ‘cafeteria’ diet, and from investigations on the efficiency of energy utilization of various types of obese animal, particularly genetically obese rodents (for reviews see Rothwell & Stock, 1983; Trayhurn, 1984). The main focus has been on providing an explanation for tlie causes of obesity, but consideration of the importance of BAT in whole-body energy metabolism has now extended to other situations. In particular, the activity of BAT during pregnancy and lactation in rodents is currently being investigated in relation t o the overall energetics of reproduction.

Enhanced Nonshivering Thermogenesis Induced by Sucrose Overfeeding in Rats

Enhanced Nonshivering Thermogenesis Induced by Sucrose Overfeeding in Rats