Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced obesity and hypertension

In obesity-related hypertension, activation of the renin-angiotensin system (RAS) has been reported despite marked fluid volume expansion. Adipose tissue expresses components of the RAS and is markedly expanded in obesity. This study evaluated changes in components of the adipose and systemic RAS in diet-induced obese hypertensive rats. RAS was quantified in adipose tissue and compared with primary sources for the circulating RAS. Male Sprague-Dawley rats were fed either a low-fat (LF; 11% kcal as fat) or moderately high-fat (32% kcal as fat) diet for 11 wk. After 8 wk, rats fed the moderately high-fat diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups based on their body weight gain (body weight: OR, 566 +/- 10; OP, 702 +/- 20 g; P < 0.05). Mean arterial blood pressure was increased in OP rats (LF: 97 +/- 2; OR: 97 +/- 2; OP: 105 +/- 1 mmHg; P < 0.05). Quantification of mRNA expression by real-time PCR demonstrated a selective increase (2-fold) in angiotensinogen gene expression in retroperitoneal adipose tissue from OP vs. OR and LF rats. Similarly, plasma angiotensinogen concentration was increased in OP rats (LF: 390 +/- 48; OR: 355 +/- 24; OP: 530 +/- 22 ng/ml; P < 0.05). In contrast, other components of the RAS were not altered in OP rats. Marked increases in the plasma concentrations of angiotensin peptides were observed in OP rats (angiotensin II: LF: 95 +/- 31; OR: 59 +/- 20; OP: 295 +/- 118 pg/ml; P < 0.05). These results demonstrate increased activity of the adipose and systemic RAS in obesity-related hypertension.     

Differences in response to corticotropin-releasing factor after short- and long-term consumption of a high-fat diet

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF(2) receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF(1) receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.     

The effect of high-fat diet on plasma ghrelin and leptin levels in rats

Ghrelin and leptin regulate appetite and energy homeostasis in humans and rodents. The effects of different nutritional factors on ghrelin and leptin secretion are not well documented in rats. Therefore, the aim of our study was to investigate the effect of a high-fat diet on plasma ghrelin and leptin levels and on adiposity. Twenty male Wistar rats, body weight220–260 g, were used in the study. Rats were randomized either on a standard chow diet (n=10) or on a high-fat diet (a mixture of nuts) forad libitum 11-week period. Body weight was measured once per week. At the end of the nutritional period, rats were sacrificed. Blood was collected for determination of lipids and glucose, as well as plasma ghrelin and leptin levels by ELISA method. The weight of different organs was determined. Rats fed on a high-fat diet showed significant increase in total body weight compared to control group. The long-term intake of high-fat diet caused hyperleptinemia and hypoghrelinemia. There was a significant positive correlation between plasma leptin levels and epididymal fat mass, liver and heart. In contrast, ghrelin levels showed inverse correlation with epididymal fat mass and liver weight. In conclusion, long-term intake of high-fat diet induced changes in plasma ghrelin and leptin in male rats, as well as in epididymal fat mass, liver and heart weights.     

Neuropeptide Y Expression and Endogenous Leptin Concentrations in a Dietary Model of Obesity

LAUTERIO, THOMAS J., MICHAEL J. DAVIES, MARK DEANGELO, MICHAEL PEYSER, AND JAMES LEE. Neuropeptide Y expression and endogenous leptin concentrations in a dietary model of obesity. Obes Res. Objective: To determine how leptin concentrations and neuropeptide (NPY) are regulated in a model of dietary obesity in relation to relative growth (RG) and relative food consumption (RFC). Research Methods and Procedures: Sprague—Dawley rats were fed a moderately high-fat diet for 14 weeks over which time animals diverged into obesity-prone (OP) and obesity-resistant (OR) populations. RG rates and RFC were calculated weekly. Following the study, an adiposity index was calculated and arcuate nucleus (ARC) NPY expression was determined by in situ hybridization (ISH) or ribonuclease protection (RPA) assays. Results: Body weights were greater in OP rats after 2 weeks on the diet compared to OR rats and remained different throughout the study. RG and RFC were greater in OP rats compared to OR rats only during the first 2 weeks of the study. Leptin concentrations rose in both groups during the experiment, but the increase was greater in OP rats than in OR rats. Insulin changes paralleled those for leptin. ARC NPY mRNA expression was not different between OP and OR rats as measured by ISH and RPA. Discussion: Although NPY expression has been reported to be different initially in OP and OR rats, this difference dissipates following divergence of body weight. RFC and RG data suggest the initial NPY elevation may contribute to increased weight gain of OP rats during the first 2 weeks of the diet. Higher relative leptin concentrations in OP rats may be necessary to normalize differences in adiposity and apparent leptin and insulin resistance of OP rats.     

Inherent capacity for lipogenesis or dietary fat retention is not increased in obesity-prone rats

Obesity results from positive energy balance and, perhaps, abnormalities in lipid and glycogen metabolism. The purpose of this study was to determine whether differences in lipogenesis, retention of dietary fat, and/or glycogenesis influenced susceptibility to dietary obesity. After 1 wk of free access to a high-fat diet (HFD; 45% fat by energy) rats were separated on the basis of 1 wk body weight gain into obesity-prone (OP; > or =48 g) or obesity-resistant groups (OR; < or =40 g). Rats were either studied at this time (OR1, OP1) or continued on the HFD for an additional 4 wk (OR5, OP5). Weight gain and energy intake were greater (P < or = 0.05) in OP vs. OR at both 1 (53 +/- 2 vs. 34 +/- 1 g; 892 +/- 27 vs. 755 +/- 14 kcal) and 5 (208 +/- 7 vs. 170 +/- 7 g; 4,484 +/- 82 vs. 4,008 +/- 72 kcal) wk, respectively. Rats were injected with (3)H(2)O and were either provided free access to an HFD meal containing labeled fatty acids (fed; n = 10 or 11/group) or were fasted (n = 10/group) overnight. The amount of food or (14)C tracer eaten overnight was equivalent between OP and OR rats. In liver, the fraction of (3)H retained in glycogen or lipid was not significantly different between OR and OP groups. Retention of dietary fat in the liver was not increased in OP rats. In adipose tissue, retention of (3)H was approximately 49% greater (P < or = 0.05) in OP1 vs. OR1 and approximately 30% greater in OP5 vs. OR5, but retention of dietary fat was not elevated in OP vs. OR. At the same time, fat pad weight (sum of epididymal, retroperitoneal, mesenteric) was 49% greater in OP1 rats vs. OR1 rats and 65% greater in OP5 vs. OR5 rats (P < or = 0.05). Thus a greater capacity for lipogenesis or retention of dietary fat does not appear to be included in the OP phenotype. The characteristic increase in energy intake associated with OP rats appears to be necessary and critical to accelerated weight and fat gain.     

The skeletal muscle Wnt pathway may modulate insulin resistance and muscle development in a diet-induced obese rat model

The Wnt signaling pathway is involved in lipid metabolism and obesity development. Skeletal muscle, a pivotal tissue for metabolism, is regulated by the Wnt signaling. However, little is known of this pathway's involvement in insulin sensitivity and myogenesis in animals. The current study focused on the potential role of Wnt signaling in insulin sensitivity and myogenic events and its further impact on intramuscular fat accumulation. Obesity resistant (OR) and obesity prone (OP) rats were fed a high-fat (HF, 45% kcal fat) diet for 13 weeks. Body weight and circulating triglyceride (TG) were measured and gastrocnemius muscle was collected for analysis of gene expression and protein amount. OP rats had higher body weight and blood TG than OR, and our study demonstrated that the skeletal muscle of OR and OP rats had different levels of β-catenin, which also corresponded to the expression of Wnt downstream genes. The expression of insulin receptor substrate (IRS) was significantly lower in OP than OR skeletal muscle, as was the protein amount of phosphorylated Akt, myocyte enhancer factor-2 (MEF2), and GLUT4. Expression of Myogenic regulatory factor (Myf) 5 and Myf3 (MyoD) were decreased significantly in OP skeletal muscle when compared to OR. Additionally, intramuscular fat was higher in OP than in OR rats. Thus, we propose that the differential Wnt signaling in the skeletal muscle of OR and OP rats is highly likely associated with the differences in insulin sensitivity and myogenic capability in these two strains.     

High‐fat Diet‐induced Ultradian Leptin and Insulin Hypersecretion are Absent in Obesity‐resistant Rats*

Objective: Sprague‐Dawley rats fed a high‐fat diet (HFD) are either obesity prone (OP) or obesity resistant (OR). We tested the hypothesis that differences in the ultradian rhythmic patterns of insulin and ghrelin in OP vs. OR rats promote obesity in OP rats. Research Methods and Procedures: Rats were fed regular chow or an HFD, and ultradian fluctuations in leptin, insulin, and ghrelin were analyzed in blood samples collected at 5‐minute intervals from intrajugular cannulae of freely moving rats. Results: Regular chow feeding resulted in a slow weight gain accompanied by small increases in insulin and leptin and a decrease in ghrelin discharge, with only the pulse amplitude significantly altered. Similar changes were observed in OR rats, despite HFD consumption. In contrast, OP rats exhibited a high rate of weight gain and marked hyperinsulinemia, hyperleptinemia, and hypoghrelinemia; amplitude was altered, but frequency was stable. In a short‐term experiment, HFD elicited similar secretory patterns of smaller magnitude even in the absence of weight gain. Discussion: We showed that three hormonal signals of disparate origin involved in energy homeostasis were secreted in discrete episodes, and only the pulse amplitude component was vulnerable to age and HFD consumption. Increases in insulin and leptin and decreases in ghrelin pulse amplitude caused by HFD were exaggerated in OP rats relative to OR rats and preceded the weight increase. These findings show that a distinct genetic predisposition in the endocrine organs of OR rats confers protection against high‐fat intake‐induced ultradian hypersecretion of obesity‐promoting hormonal signals.     

Leptin prevents obesity induced by a high-fat diet after diet-induced weight loss in the marsupial S. crassicaudata

The aims of this study were to determine in the marsupial Sminthopsis crassicaudata, the effects of leptin on food intake, body weight, tail width (a reflection of fat stores), and leptin mRNA, after caloric restriction followed by refeeding ad libitum with either a standard or high-fat preferred diet. S. crassicaudata (n = 32), were fed standard laboratory diet (LabD; 1.01 kcal/g, 20% fat) ad libitum fo 3 days. On days 4-10, animals received LabD at 75% of basal intake and then (days 11-25) were fed either LabD or a choice of LabD and mealworms (MW; 2.99 kcal/g, 30% fat); during this time, half the animals (n = 8) in each group received either leptin (2.5 mg/kg) or PBS intraperitoneally two times daily. On day 26, animals were killed and fat was removed for assay of leptin mRNA. At baseline, body weight, tail width, and food intake were similar in each group. After caloric restriction, body weight (P < 0.001) and tail width (P < 0.001) decreased. On return to ad libitum feeding in the PBS-treated animals, body weight and tail width returned to baseline in the LabD-fed animals (P < 0.001) and increased above baseline in the MW-fed animals (P < 0.001). In the LabD groups, tail width (P < 0.001) and body weight (P < 0.001) decreased after leptin compared with PBS. In the MW groups, the increase in tail width (P < 0.001) and body weight (P = 0.001) were attenuated after leptin compared with PBS. The expression of leptin mRNA in groups fed MW were greater in PBS than in leptin-treated animals (P < 0.05). Therefore, after diet-induced weight loss, leptin prevents a gain in fat mass in S. crassicaudata; this has potential implications for the therapeutic use of leptin.     

Behavioral components of high-fat diet hyperphagia: meal size and postprandial satiety

Previously, rats fed a high-fat liquid diet (HF) ad libitum consumed more kilocalories and had greater weight gain than rats fed a liquid high-carbohydrate diet (HC) of equivalent energy density (Warwick, Z. S., and H. P. Weingarten. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 269: R30-R37, 1995). The present series of experiments sought to clarify the behavioral expression of HF hyperphagia by comparing HF and HC with regard to meal size and magnitude of postingestive satiety effect. Meal size of HF was greater than HC at 2.3 kcal/ml and also when diets were formulated at 1.15 kcal/ml. In a preload-test meal paradigm, an orally consumed HF preload was less satiating than a calorically equivalent HC preload across a range of preload volumes and intermeal intervals. Sensory-specific satiety was ruled out as an explanation of the relatively greater intake of test meal after an HF preload meal; an intragastrically delivered HF preload was less satiating than intragastric HC. Furthermore, a fat (corn oil emulsion) preload was less satiating than a carbohydrate (sucrose) preload when an evaporated milk test meal was used. These findings indicate that hyperphagia on an HF diet is expressed in increased meal size and decreased intermeal interval.     

Effects of PPARgamma and PPARalpha agonists on serum leptin levels in diet-induced obese rats.

Leptin and peroxisome proliferator-activated receptors are two important adipose tissue factors involved in energy metabolism regulation. It has been shown that PPARgamma agonists decrease leptin levels. However, the effects of PPARalpha agonists on leptin have not been investigated much. The aim of this study was to compare the effects of a PPARgamma agonist rosiglitazone (RSG) and PPARalpha agonist gemfibrozil (G) on body weight and serum insulin and leptin levels in diet-induced obese rats. Male Wistar rats were divided into six groups according to diet and drug therapy. After four weeks, serum glucose, triglyceride, insulin and leptin levels were significantly decreased in the high-fat-fed and RSG-treated groups compared to the group fed a high-fat diet only (162 +/- 19 vs. 207 +/- 34 mg/dl, 58 +/- 20 vs. 112 +/- 23 mg/dl, 3.1 +/- 1.0 vs. 15.2 +/- 4.0 ng/ml, 1.6 +/- 0.5 vs. 3.6 +/- 1.6 ng/ml, respectively). However, these parameters were not statistically different in RSG animals treated with a standard diet compared to the standard diet group. The high fat+RSG group gained much more weight compared to high-fat and high-fat+G groups (p > 0.05). Additionally, serum glucose, insulin and leptin levels were significantly decreased in the high-fat-fed and G-treated group compared to high-fat group (149 +/- 19 vs. 207 +/- 34 mg/dl, 57 +/- 16 vs. 112 +/- 23 mg/dl, 4.3 +/- 2.1 vs. 15.2 +/- 4.0 ng/ml, 1.6 +/- 0.4 vs. 3.6 +/- 1.6 ng/ml, respectively). These results suggest that PPARalpha agonists may decrease serum glucose, insulin and leptin levels as PPARgamma agonists do in diet-induced obese rats.     

Changes in expression of skeletal muscle proteins between obesity-prone and obesity-resistant rats induced by a high-fat diet

A primary goal in obesity research is to determine why some people become obese (obesity-prone, OP) and others do not (obesity-resistant, OR) when exposed to high-calorie diets. The metabolic changes that cause reduced adiposity and resistance to obesity development have yet to be determined. We thus performed proteomic analysis on muscular proteins from OP and OR rats in order to determine whether other novel molecules are involved in this response. To this end, rats were fed a low- or high-fat diet for 8 weeks and were then classified into OP and OR rats by body weight gain. OP rats gained about 25% more body weight than OR rats, even though food intake did not differ significantly between the two groups. Proteomic analysis using 2-DE demonstrated differential expression of 26 spots from a total of 658 matched spots, of which 23 spots were identified as skeletal muscle proteins altered between OP and OR rats by peptide mass fingerprinting. Muscle proteome data enabled us to draw the conclusion that enhanced regulation of proteins involved in lipid metabolism and muscle contraction, as well as increased expression of marker proteins for oxidative muscle type (type I), contributed to obesity-resistance; however, antioxidative proteins did not.     

Trafficking of dietary fat in obesity-prone and obesity-resistant rats

The trafficking of dietary fat was assessed in obesity-prone (OP) and obesity-resistant (OR) male and female rats. Test meals containing [1-(14)C]palmitate were delivered through gastric feeding tubes while rats consumed a high-carbohydrate diet (HCD) or after 5 days of a high-fat diet (HFD). Over the subsequent 24 h, the appearance of (14)C was followed in the GI tract, skeletal muscles (SM), liver, adipose tissues (AT), and expired CO(2). There was no difference in the production of (14)CO(2) between OP and OR rats consuming a HCD. However, after 5 days on HFD, OR rats produced significantly more (14)CO(2) after the test meal than OP rats (P < 0.001 females, P = 0.03 males). The differential oxidation of dietary fat between OP and OR rats on HFD was not due to differences in absorption but rather was associated with preferential disposition of tracer to AT in OP rats. Measurements of lipoprotein lipase in part explained increased tracer uptake by AT in OP rats but were not consistent with increased SM tracer uptake in OR rats. Surprisingly, female rats oxidized more tracer than male rats irrespective of phenotype or diet. These results are consistent with the notion that differences in the partitioning of dietary fat between storage in AT and oxidation in SM and liver that develop shortly after the introduction of a HFD may in part underlie the differential tendency for OR and OP rats to gain weight on this diet.     

High molecular weight poly-gamma-glutamic acid regulates lipid metabolism in rats fed a high-fat diet and humans

We investigated the effect of high molecular weight polygamma- glutamic acid (hm gamma-PGA) on adiposity and lipid metabolism of rats in the presence of an obesity-inducing diet. Thirty-two Sprague-Dawley rats were fed either a normal-fat (11.4% kcal fat, NFC) or high-fat (51% kcal fat, HFC) diet. After 5 weeks, half of each diet-fed group was treated with hm gamma-PGA (NFP or HFP) for 4 weeks. The HFC group had significantly higher body weight, visceral fat mass, fasting serum levels of total cholesterol, LDL cholesterol, and leptin, and lower serum HDL cholesterol level compared with those of the NFC group (p < 0.05). Treatment with hm gamma-PGA decreased body weight gain and perirenal fat mass (p<0.05), fasting serum total cholesterol, and mRNA expression of glucose-6- phosphate dehydrogenase (G6PD), regardless of dietary fat contents (p < 0.01). However, hm gamma-PGA increased serum HDL cholesterol in the HFC group (p < 0.05). In vitro, 3-hydroxy-3-methylglutaryl coenzyme-A (HMGCoA) reductase activity was suppressed by the addition of hm gamma-PGA. In agreement with observations in animal study, the supplementation of hm gamma-PGA (150 mg/day) to 20 female subjects in an 8-week double-blind, placebocontrolled study resulted in a tendency to decrease total cholesterol and LDL cholesterol concentrations. We thus conclude that dietary supplementation of hm gamma-PGA may act as a hypocholestrolemic agent, secondary to its inhibitor effect on HMG-CoA reductase, and decrease abdominal adiposity by decreasing hepatic lipogenesis. The present study is an important first step in establishing the effect of hm gamma-PGA on cholesterol levels in rats and humans.     

"Liking" and "wanting" of sweet and oily food stimuli as affected by high-fat diet-induced obesity, weight loss, leptin, and genetic predisposition

Cross-sectional studies in both humans and animals have demonstrated associations between obesity and altered reward functions at the behavioral and neural level, but it is unclear whether these alterations are cause or consequence of the obese state. Reward behaviors were quantified in male, outbred Sprague-Dawley (SD) and selected line obesity-prone (OP) and obesity-resistant (OR) rats after induction of obesity by high-fat diet feeding and after subsequent loss of excess body weight by chronic calorie restriction. As measured by the brief access lick and taste-reactivity paradigms, both obese SD and OP rats "liked" low concentrations of sucrose and corn oil less, but "liked" the highest concentrations more, compared with lean rats, and this effect was fully reversed by weight loss in SD rats. Acute food deprivation was unable to change decreased responsiveness to low concentrations but eliminated increased responsiveness to high concentrations in obese SD rats, and leptin administration in weight-reduced SD rats shifted concentration-response curves toward that seen in the obese state in the brief access lick test. "Wanting" and reinforcement learning as assessed in the incentive runway and progressive ratio lever-pressing paradigms was paradoxically decreased in both obese (compared with lean SD rats) and OP (compared with OR rats). Thus, reversible, obesity-associated, reduced "liking" and "wanting" of low-calorie foods in SD rats suggest a role for secondary effects of the obese state on reward functions, while similar differences between select lines of OP and OR rats before induction of obesity indicate a genetic component.     

AT1-receptor antagonism reverses the blood pressure elevation associated with diet-induced obesity

Previous studies in our laboratory demonstrated that rats exhibiting obesity in response to a moderately high-fat (MHF) diet developed hypertension associated with activation of the local and systemic renin-angiotensin system. In this study, we examined the effect of the angiotensin type 1 (AT(1))-receptor antagonist, losartan, on blood pressure in obesity-prone (OP) and obesity-resistant (OR) rats fed a MHF diet. Using telemetry monitoring, we characterized the evolution of blood pressure elevations during the development of obesity. Male Sprague-Dawley rats were implanted with telemetry transducers for chronic monitoring of blood pressure, and baseline measurements were obtained. Rats were then switched to the MHF diet (32% kcal as fat) and were segregated into OP and OR groups at week 5. At week 9 on the MHF diet, OP rats exhibited significantly greater 24-h mean arterial blood pressure compared with OR rats (OP: 105 +/- 4 mmHg, OR: 96 +/- 2 mmHg; P < 0.05). Elevations in blood pressure in OP rats were manifest as an increase in systolic pressure. Administration of losartan to all rats at week 9 resulted in a reduction in blood pressure; however, losartan had the greatest effect in OP rats (percent decrease in mean arterial pressure by losartan; OP: 19 +/- 4, OR: 10 +/- 2%; P < 0.05). These results demonstrate that elevations in blood pressure occur subsequent to established obesity in rats fed a high-fat diet. Moreover, these results demonstrate the ability of losartan to reverse the blood pressure increase from diet-induced obesity, supporting a primary role for the renin-angiotensin system in obesity-associated hypertension.     

Postweaning low-calcium diet promotes later-life obesity induced by a high-fat diet

The aim of this study was to investigate the effects of a postweaning low-calcium diet on later obesity and explore the underlying mechanisms. Ninety-six male rats were weaned at 3 weeks of age, fed standard (STD: 0.50% calcium, n=48) and low-calcium (LC: 0.15% calcium, n=48) diets for 3 weeks, and then fed the standard diet for a 3-week washout period successively. Finally, the STD rats were divided into STD control and high-fat diet (HFD) groups, and the LC ones into LC control and LC+HFD (LCHF) groups. The STD and LC rats were fed the standard diet, while the HFD control and LCFD ones were fed a high-fat diet for 6 weeks to induce obesity. During the three feeding periods, adenosine-monophosphate-activated protein kinase (AMPK) and its responsive proteins phospho-acetyl-coA carboxylase, carnitine palmitoyltransferase 1 and uncoupling protein 3 were persistently down-regulated in the LC group (decreased by 18%, 24%, 18% and 20%, respectively) versus the STD group, and these effects were significantly more pronounced in the LCHFD group (decreased by 21%, 30%, 23% and 25%, respectively) than the HFD group by a later high-fat stimuli, causing more fat and body weight in adulthood. However, lipolysis enzymes, serum leptin, insulin and lipids were not significantly affected until the body weight and fat content changed at 15 weeks of age. The results suggest that the low-calcium diet after weaning promotes rat adult-onset obesity induced by high-fat diet, which might be achieved by programming expressions of genes involved in AMPK pathway.     

Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring

Epidemiological and animal studies suggest that the alteration of hormonal and metabolic environment during fetal and neonatal development can contribute to development of metabolic syndrome in adulthood. In this paper, we investigated the impact of maternal high-fat (HF) diet on hypothalamic leptin sensitivity and body weight gain of offspring. Adult Wistar female rats received a HF or a control normal-fat (C) diet for 6 wk before gestation until the end of the suckling period. After weaning, pups received either C or HF diet during 6 wk. Body weight gain and metabolic and endocrine parameters were measured in the eight groups of rats formed according to a postweaning diet, maternal diet, and gender. To evaluate hypothalamic leptin sensitivity in each group, STAT-3 phosphorylation was measured in response to leptin or saline intraperitoneal bolus. Pups exhibited similar body weights at birth, but at weaning, those born to HF dams weighed significantly less (-12%) than those born to C dams. When given the HF diet, males and females born to HF dams exhibited smaller body weight and feed efficiency than those born to C dams, suggesting increased energy expenditure programmed by the maternal HF diet. Thus, maternal HF feeding could be protective against adverse effects of the HF diet as observed in male offspring of control dams: overweight (+17%) with hyperleptinemia and hyperinsulinemia. Furthermore, offspring of HF dams fed either C or HF diet exhibited an alteration in hypothalamic leptin-dependent STAT-3 phosphorylation. We conclude that maternal high-fat diet programs a hypothalamic leptin resistance in offspring, which, however, fails to increase the body weight gain until adulthood.     

Effect of high-fat diet during gestation, lactation, or postweaning on physiological and behavioral indexes in borderline hypertensive rats

Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or "junk food" diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance.