Chronic mild stress induces variations in locomotive behavior and metabolic rates in high fat fed rats

Chronic mild stress (CMS) has been often associated to the pathogenesis of many diseases including obesity. Indeed, visceral obesity has been linked to the development of metabolic syndrome features and constitutes a serious risk factor for cardiovascular diseases and diabetes. In order to study possible mechanistic relationships between stress and the onset of obesity, we developed during 11 weeks a model of high-fat dietary intake (cafeteria diet) together with a CMS regimen in male Wistar rats. During the experimental period, basal metabolism by indirect calorimetry, rectal temperature, food intake, and locomotive markers were specifically analyzed. After 77 days, animals were sacrificed and body, adiposity and plasma biochemical profiles were also examined. As expected, cafeteria diet in unstressed animals induced a significative increase in body weight, adiposity, and insulin resistance markers. Locomotive variables, specifically distance, rearing and meander, were significantly increased by CMS on the first weeks of stress. Moreover, this model of CMS in Wistar rats increased significantly energy expenditure, and apparently interplayed with the dietary treatment on the muscle weight/fat weight ratio. In summary, this chronic stress model did not affected weight gain in control and high fat fed animals, but induced an interaction concerning the metabolic muscle/fat repartitioning.     

Influence of single administration of different diets on the energy metabolism at temperatures of 10,20 and 30 degrees C in the golden hamster.

Fed animals have a higher resting metabolic rate in the thermoneutral zone than fasting ones. The metabolic increase is due to the specific dynamic action of food. With a decline of environmental temperature this increase in metabolism either declines or remains unchanged; decisive is whether the heat is used for thermoregulation or not (Mejsnar and Jansky 1971). The objective of our work was to find out to what extent a single intake of a diet with a different ratio of nutrients can influence resting metabolism in the golden hamster and whether this heat can be used for thermoregulation in the cold. Female golden hamsters aged 6-8 weeks kept at a constant temperature of 22 +/-1 degrees C with twelve-hour alternation of light (6 a.m. - 6 p.m.) and darkness ( 6 p.m. - 6 a.m.) were used for the experiments. The oxygen consumption was assessed after a single intake of a standard, high-carbohydrate (76 cal.% starch), high-fat (80 cal.% margarine) and high-protein (82 cal.% casein) diet-for detailed composition see Fábry (1959). The food was given at 6.m. after previous 20 hours of fasting. Animals were then transferred into the respiration chamber and kept there for three hours, including one hour when they were left to settle down; during this period the oxygen consumption was not measured. Oxygen consumption measurement started at 9 a.m. and lasted till 11 a.m. The metabolism of the animals at rest was assessed at temperatures of 10, 20 and 30 degrees C by measuring the oxygen consumption by the interferometric method (Wollschitt et al. 1935). The results are expressed in ml of oxygen per g of body weight per hour. The relationship between the metabolism at rest and environmental temperatures in hamsters given a single dose of standard, high-proetin, high-fat or high-carbohydrate diet is apparent from Table 1. The maximum increase of oxygen consumption after administration of the experimental diets was found at a temperature of 30 degrees C. At an environmental temperature of 20 degrees C the administration of the high-protein and high-fat diet causes roughly the same increase of metabolism. The high-carbohydrate diet increase is only one third of thevalues found, in the remaining two diets at the same temperature and is non-significant. At the environmental temperature of 10 degrees C all the diets used increased the oxygen consumption insignificantly. The changes in metabolism at different environmental temperatures after administration of various diets expressed as percentage of metabolism at 30 degrees C in animals fed the standard diet indicate that the specific dynamic action of the high-protein and high-fats diets is lower at lowered temperatures. We may thus assume that the heat produced as a result of specific dynamic action of the high-protein and high-fat diets is perhaps used for thermoregulation. The role of specific dynamic action of high-carbohydrate diet for thermoregulation is not clear from our experiments. The role of specific dynamic action of food was assessed by several authors...     

Dietary-induced hypertrophic--hyperplastic obesity in mice

Metabolically intact NMRI mice and genetically obese NZO mice were fed ad lib. either a high-carbohydrate diet (standard) or a high-fat diet for a period of about 11 (NMRI mice) or 38 (NZO mice) wk. In both strains of mice, body weight increased more in the groups fed the high-fat diet. However, caloric intake by NMRI mice fed the high-fat diet was less than that of the controls. In NMRI mice fed the high-fat diet, epididymal and subcutaneous fat cell volumes increased; when these mice were fed the standard diet, only epididymal fat cell volume increased. Epididymal and subcutaneous fat cell numbers increased only in the group fed the high-fat diet. In NMRI mice fed either diet, the postprandial blood glucose was lower in older animals, but plasma insulin remained unchanged. The glucose tolerance deteriorated insignificantly. In NZO mice fed either diet, epididymal fat cell volumes and fat cell numbers increased. In this strain of mice the postprandial blood glucose and plasma insulin exhibited the strain-specific pattern, independent of the diet. In older animals fed either diet the glucose tolerance decreased.     

Dietary gamma-linolenic acid in the form of borage oil causes less body fat accumulation accompanying an increase in uncoupling protein 1 mRNA level in brown adipose tissue

Rats were fed a low-fat diet containing 2% safflower oil or 20% fat diets containing either safflower oil rich in linoleic acid, borage oil containing 25% gamma (gamma)-linolenic acid or enzymatically prepared gamma-linolenic acid enriched borage oil containing 47% gamma-linolenic acid for 14 days. Energy intake and growth of animals were the same among groups. A high safflower oil diet compared with a low-fat diet caused significant increases in both epididymal and perirenal white adipose tissue weights. However, high-fat diets rich in gamma-linolenic acid failed to do so. Compared with a low-fat diet, all the high-fat diets increased mRNA levels of uncoupling protein 1 and lipoprotein lipase in brown adipose tissue. The extents of the increase were greater with high-fat diets rich in gamma-linolenic acid. Various high-fat diets, compared with a low-fat diet, decreased glucose transporter 4 mRNA in white adipose tissue to the same levels. The amount and types of dietary fat did not affect the leptin mRNA level in epididymal white adipose tissue. However, a high safflower oil diet, but not high-fat diets rich in gamma-linolenic acid relative to a low-fat diet, increased perirenal white adipose tissue leptin mRNA levels. All high-fat diets, relative to a low-fat diet, increased the hepatic mitochondrial fatty acid oxidation rate and fatty acid oxidation enzyme mRNA abundances to the same levels. High-fat diets also increased these parameters in the peroxisomal pathway, and the increases were greater with high-fat diets rich in gamma-linolenic acid. The physiological activity in increasing brown adipose tissue gene expression and peroxisomal fatty acid oxidation was similar between the two types of borage oil differing in gamma-linolenic acid content. It was suggested that dietary gamma-linolenic acid attenuates body fat accumulation through the increase in gene expressions of uncoupling protein 1 in brown adipose tissue. An increase in hepatic peroxisomal fatty acid oxidation may also contribute to the physiological activity of gamma-linolenic acid in decreasing body fat mass.     

Response of rat exocrine pancreas to high-fat and high-carbohydrate diets

Intake of diets with high fat content is a risk factor for acute pancreatitis and pancreatic cancer. The underlying mechanisms leading to the development of these diseases due to high fat intake are currently unknown. The current study was designed in rats to determine the physiologic and pathological consequences of a highfat diet that contained excess amounts of cottonseed oil or a high-carbohydrate diet that contained high amounts of sucrose on the exocrine pancreas. Rats were maintained on the diets for 4 weeks, and a cannula was inserted into the right jugular vein and one into the pancreatic duct for collection of pancreatic juice. Volume of the pancreatic juice and concentrations of amylase, lipase, and trypsinogen in the pancreatic juice were measured before and after infusions of CCK-8. Results showed that basal and CCK-stimulated pancreatic outputs of volume, amylase and lipase but not trypsinogen, were significantly elevated in intact rats given a high-fat diet when compared with rats given a high-carbohydrate diet. Forty-eight hours later, rats were sacrificed, and parts of the pancreas were removed for isolation of pancreatic acinar cells and for histopathologic studies. Pancreatic acini isolated from rats on a high-fat diet showed significantly lower basal and CCK-stimulated amylase release when compared with those on a high-carbohydrate diet. Histology of the pancreas of rats on a high-carbohydrate diet appeared normal; however, the pancreas of rats on high-fat diet showed significant alterations in exocrine pancreas. These results showed abnormalities in the exocrine pancreas of rats on a high-fat diet, that were not found in rats on a high-carbohydrate diet; further, they support the contention that a high-fat diet has a deleterious effect on the pancreas.     

The effect of dietary fat content on lactation energetics in the European hare (Lepus europaeus)

European hares selectively feed on plants with high fat and hence energy content. We hypothesized that these dietary requirements limit the ability of hares to adjust daily food intake during periods of high energy requirements, namely lactation. Our measurements in captive lactating females show that does kept on a low-fat diet increased food intake compared to does on a high-fat diet but assimilated significantly lower amounts of energy. Further, does fed a low-fat diet showed a prolonged rise of food intake during lactation, reduced milk energy content and lower milk mass production at large litter sizes. We hypothesize that impaired milk production under suboptimal fat supply is due to the inability of females to increase the capacity of nutrient-processing organs rapidly enough to meet the high energy demands of precocial juveniles with high metabolic costs. Thus, in hares, the production of precocial young may be viewed as a constraint, caused by their inability to dig thermally buffered burrows, rather than as an adaptive reproductive strategy. We suggest that the interaction of lactation energetics, dietary requirements, and reduced plant diversity in modern agricultural landscapes has facilitated the decline of hare populations across Europe over the last decades.     

Effect of dietary lipid content on lipid transport and storage during larval development of Manduca sexta

Manduca sexta larvae were raised on diets containing either 1.2% fat (control diet), 5.9% fat (high-fat diet) or on a fat-free diet. Insects raised on the control and high-fat diets did not differ significantly in body weight, whereas animals raised on the fat-free diet were significantly smaller. The fat content of the diet had no effect on the hemolymph concentration of lipophorin. During the larval period, lipophorin isolated from animals on the high-fat diet contained more lipid, and lipophorin isolated from animals on the fat-free diet contained less lipid than lipophorin isolated from control animals. However, lipophorin isolated from animals during the prepupal period had the same composition regardless of diet. Compared to controls, animals on the high-fat diet had a larger mass of fat body which contained more stored triacylglycerol, while animals on the fat-free diet had a smaller mass of fat body which contained less stored triacylglycerol. As the fat content of the diet was increased, the fatty acid composition of fat body triacylglycerols reflected more closely that of the dietary lipid.     

Modeling Energy Dynamics in Mice with Skeletal Muscle Hypertrophy Fed High Calorie Diets

Retrospective and prospective studies show that lean mass or strength is positively associated with metabolic health. Mice deficient in myostatin, a growth factor that negatively regulates skeletal muscle mass, have increased muscle and body weights and are resistant to diet-induced obesity. Their leanness is often attributed to higher energy expenditure in the face of normal food intake. However, even obese animals have an increase in energy expenditure compared to normal weight animals suggesting this is an incomplete explanation. We have previously developed a computational model to estimate energy output, fat oxidation and respiratory quotient from food intake and body composition measurements to more accurately account for changes in body composition in rodents over time. Here we use this approach to understand the dynamic changes in energy output, intake, fat oxidation and respiratory quotient in muscular mice carrying a dominant negative activin receptor IIB expressed specifically in muscle. We found that muscular mice had higher food intake and higher energy output when fed either chow or a high-fat diet for 15 weeks compared to WT mice. Transgenic mice also matched their rate of fat oxidation to the rate of fat consumed better than WT mice. Surprisingly, when given a choice between high-fat diet and Ensure® drink, transgenic mice consumed relatively more calories from Ensure® than from the high-fat diet despite similar caloric intake to WT mice. When switching back and forth between diets, transgenic mice adjusted their intake more rapidly than WT to restore normal caloric intake. Our results show that mice with myostatin inhibition in muscle are better at adjusting energy intake and output on diets of different macronutrient composition than WT mice to maintain energy balance and resist weight gain.     

Comparison of Osborne-Mendel and S5B/PL Strains of Rat: Central Effects of Galanin,NPY, β-Casomorphin and CRH on Intake of High-Fat and Low-Fat Diets

The effects of central administration of galanin, neuropeptide Y (NPY), β-casomorphin_(1–7) and corticotropin releasing hormone (CRH) on intake of either a high-fat or low-fat diet have been compared in two strains of rat, the dietary fat-sensitive Osborne-Mendel (OM) rat and the dietary fat-resistant S5B/Pl rat. Injection of galanin (0.1, 0.3 nmoles) into the 3rd cerebral ventricle stimulated the intake of both a high-fat and a low-fat diet in OM rats in a dose dependent manner but the response was significantly smaller in rats fed the low-fat diet. In S5B/Pl rats, galanin had a small stimulatory effect on food intake but only at a high dose (2 nmole). β-casomor-phin_(1–7) (5 nmoles), an opioid-like peptide, increased the intake of the high-fat but not the low-fat diet in OM rats, whereas S5B/Pl rats fed either a high-fat or a low-fat diet did not respond to β-caso-morphin/j.yy Both strains showed a similar stimulatory response to NPY (0.1, 0.5 nmoles) on the intake of the high-fat or the low-fat diet, but the magnitude of the response was attenuated in S5B/Pl rats. In contrast, the anorectic effects of CRH (0.26 nmoles) on food deprived animals was similar in both strains for both diets. We speculate that the regulatory system controlling the intake of fat activated by galanin and β-casomorphin_(1–7) may be defective in S5B/Pl rats.     

Paraventricular opioids alter intake of high-fat but not high-sucrose diet depending on diet preference in a binge model of feeding

Previous work from our laboratory indicates that when rats are given a choice between a high-fat and a high-sucrose diet, opioid blockade with naltrexone (NTX) in a reward-related site (central amygdala) inhibits intake of the preferred diet only, whereas NTX injected into a homeostasis-related site, such as the hypothalamic paraventricular nucleus (PVN), inhibits intake of both diets. However, other work suggests that opioids increase intake of fat specifically. The present study further investigates the role of PVN opioids in food choices made by calorically-replete animals. We used a binge model with chow-maintained rats given 3-h access to a choice of a high-fat or high-sucrose diet 3 days a week. We hypothesized that intra-PVN injection of the mu-opioid agonist, DAMGO (0, 0.025, 0.25, and 2.5 nmol) would enhance, and NTX (0, 10, 30, and 100 nmol) would inhibit intake of both diets to an equal extent. We found that when animals were divided into groups according to sucrose or fat preference, DAMGO increased fat intake in fat-consuming animals, while having no effect on intake of either diet in sucrose-consuming animals. NTX, however, inhibited fat intake in both groups. Intra-PVN NTX did not inhibit intake of sucrose when presented in the absence of a fat choice, but did so when injected peripherally. Furthermore, intra-PVN and systemic NTX inhibited intake of chow by 24-h-food-deprived animals. These results indicate a complex role for PVN opioids in food intake with preference, nutrient type, and energy state affecting the ability of these compounds to change behavior.     

Low-carbohydrate diets affect energy balance and fuel homeostasis differentially in lean and obese rats

In parallel with increased prevalence of overweight people in affluent societies are individuals trying to lose weight, often using low-carbohydrate diets. Nevertheless, long-term metabolic consequences of those diets, usually high in (saturated) fat, remain unclear. Therefore, we investigated long-term effects of high-fat diets with different carbohydrate/protein ratios on energy balance and fuel homeostasis in obese (fa/fa) Zucker and lean Wistar rats. Animals were fed high-carbohydrate (HC), high-fat (HsF), or low-carbohydrate, high-fat, high-protein (LC-HsF-HP) diets for 60 days. Both lines fed the LC-HsF-HP diet displayed reduced energy intake compared with those fed the HsF diet (Zucker, -3.7%) or the HC diet (Wistar rats, -12.4%). This was not associated with lower weight gain relative to HC fed rats, because of increased food efficiencies in each line fed HsF and particularly LC-HsF-HP food. Zucker rats were less glucose tolerant than Wistar rats. Lowest glucose tolerances were found in HsF and particularly in LC-HsF-HP-fed animals irrespective of line, but this paralleled reduced plasma adiponectin levels, elevated plasma resistin levels, higher retroperitoneal fat masses, and reduced insulin sensitivity (indexed by insulin-induced hypoglycemia) only in Wistar rats. In Zucker rats, however, improved insulin responses during glucose tolerance testing and tendency toward increased insulin sensitivities were observed with HsF or LC-HsF-HP feeding relative to HC feeding. Thus, despite adverse consequences of LC-HsF diets on blood glucose homeostasis, principal differences exist in the underlying hormonal regulatory mechanisms, which could have benefits for B-cell functioning and insulin action in the obese state but not in the lean state.     

The role of dietary fatty acids in the pathology of metabolic syndrome

Dysfunctional lipid metabolism is a key component in the development of metabolic syndrome, a very frequent condition characterized by dyslipidemia, insulin resistance, abdominal obesity and hypertension, which are related to an elevated risk for type 2 diabetes mellitus. The prevalence of metabolic syndrome is strongly associated with the severity of obesity; its physiopathology is related to both genetics and food intake habits, especially the consumption of a high-caloric, high-fat and high-carbohydrate diet. With the progress of scientific knowledge in the field of nutrigenomics, it was possible to elucidate how the majority of dietary fatty acids influence plasma lipid metabolism and also the genes expression involved in lipolysis and lipogenesis within hepatocytes and adipocytes. The aim of this review is to examine the relevant mechanistic aspects of dietary fatty acids related to blood lipids, adipose tissue metabolism, hepatic fat storage and inflammatory process, all of them closely related to the genesis of metabolic syndrome.     

Acute changes in the response to peripheral leptin with alteration in the diet composition

Dietary induced obesity in rodents is associated with a resistance to leptin. We have investigated the hypothesis that dietary fat per se alters the feeding response to peripheral leptin in rats that were fed either their habitual high- or low-fat diet or were naively exposed to the alternative diet. Osborne-Mendel rats were adapted to either high- or low-fat diet. Food-deprived rats were given either leptin (0.5 mg/kg body wt ip) or saline, after which they were provided with either their familiar diet or the alternative diet. Food intake of rats adapted and tested with the low-fat diet was reduced 4 h after leptin injection, whereas rats adapted and tested with a high-fat diet did not respond to leptin. Leptin was injected again 1 and 5 days after the high-fat diet-adapted rats were switched to the low-fat diet. Leptin reduced the food intake on both days. In contrast, when low-fat diet-adapted rats were switched to a high-fat diet, the leptin inhibitory response was present on day 1 but not observed on day 5. Peripheral injection of leptin increased serum corticosterone level and decreased hypothalamic neuropeptide Y mRNA expression in rats fed the low-fat but not the high-fat diet for 20 days. The data suggest that dietary fat itself, rather than obesity, may induce leptin resistance within a short time of exposure to a high-fat diet.     

Loss of regulation of lipogenesis in the Zucker diabetic rat. II. Changes in stearate and oleate synthesis

De novo lipogenesis and dietary fat uptake are two major sources of fatty acid deposits in fat of obese animals. To determine the relative contribution of fatty acids from these two sources in obesity, we have determined the distribution of c16 and c18 fatty acids of triglycerides in plasma, liver, and epididymal fat pad of Zucker diabetic fatty (ZDF) rats and their lean littermates (ZL) under two isocaloric dietary fat conditions. Lipogenesis was also determined using the deuterated water method. Conversion of palmitate to stearate and stearate to oleate was calculated from the deuterium incorporation by use of the tracer dilution principle. In the ZL rat, lipogenesis was suppressed from 70 to 24%, conversion of palmitate to stearate from 86 to 78%, and conversion of stearate to oleate from 56 to 7% in response to an increase in the dietary fat-to-carbohydrate ratio. The results suggest that suppression of fatty acid synthase and stearoyl-CoA desaturase activities is a normal adaptive mechanism to a high-fat diet. In contrast, de novo lipogenesis, chain elongation, and desaturation were not suppressed by dietary fat in the ZDF rat. The lack of ability to adapt to a high-fat diet resulted in a higher plasma triglyceride concentration and excessive fat accumulation from both diet and de novo synthesis in the ZDF rat.     

High-fat diet prevents eating response and attenuates liver ATP decline in rats given 2,5-anhydro-D-mannitol

Administration of the fructose analog 2,5-anhydro-D-mannitol (2,5-AM) stimulates eating in rats fed a low-fat diet but not in those fed a high-fat diet that enhances fatty acid oxidation. The eating response to 2,5-AM treatment is apparently triggered by a decrease in liver ATP content. To assess whether feeding a high-fat diet prevents the eating response to 2,5-AM by attenuating the decrease in liver ATP, we examined the effects of the analog on food intake, liver ATP content, and hepatic phosphate metabolism [using in vivo 31P-NMR spectroscopy (NMRS)]. Injection (intraperitoneal) of 300 mg/kg 2,5-AM increased food intake in rats fed a high-carbohydrate/low-fat diet, but not in those fed high-fat/low-carbohydrate (HF/LC) food. Liver ATP content decreased in all rats given 2,5-AM compared with saline, but it decreased about half as much in rats fed the HF/LC diet. NMRS on livers of anesthetized rats indicated that feeding the HF/LC diet attenuates the effects of 2,5-AM on liver ATP by reducing phosphate trapping. These results suggest that rats consuming a high-fat diet do not increase food intake after injection of 2,5-AM, because the analog is not sufficiently phosphorylated and therefore fails to decrease liver energy status below a level that generates a signal to eat.     

Effects of a Fat Substitute,Sucrose Polyester,on Food Intake,Body Composition,and Serum Factors in Lean and Obese Zucker Rats

Sucrose polyester, a fat substitute, has shown promise in reducing blood cholesterol and body weight of obese individuals. Effects of this compound in the Zucker rat, a genetic model of obesity, are unknown. Thus, we examined food intake, body weight, body composition, and several metabolic parameters in sera of lean and obese female Zucker rats. Eight-week-old lean and obese animals were given a choice between a control diet (15% corn oil) and fat substitute diet (5% corn oil and 10% sucrose polyester) for 2 days. Next, one-half of the lean and obese groups received control diet; the remaining lean and obese rats received fat substitute diet for 18 days. Cumulative food intake was depressed in fat substitute groups relative to control-fed animals; however, this effect was more predominant in obese animals. Obese rats consuming fat substitute diet (O-FS) gained less weight as compared to obese control-fed animals (O-C). Lean rats given fat substitute (L-FS) did not have significantly different body weights as compared to the L-C group. Fat substitute groups, combined, had lower body fat and higher body water as compared to controls. The O-FS group had lower serum glucose and insulin and higher fatty acid levels compared to the O-C group. There were no differences in serum cholesterol, HDL, or triglyceride levels due to fat substitute diet. These data suggest that the obese Zucker rat is unable to defend its body weight when dietary fat is replaced with sucrose polyester.     

Consumption of a high-fat diet rapidly exacerbates the development of fatty liver disease that occurs with chronically elevated glucocorticoids

Chronically elevated glucocorticoids (GCs) and a high-fat diet (HFD) independently induce insulin resistance, abdominal obesity, and nonalcoholic fatty liver disease (NAFLD). GCs have been linked to increased food intake, particularly energy-dense "comfort" foods. Thus we examined the synergistic actions of GCs and HFD on hepatic disease development in a new rodent model of chronically elevated GCs. Six-week-old male Sprague-Dawley rats received exogenous GCs, via subcutaneous implantation of four 100-mg corticosterone (Cort) pellets, to elevate basal GC levels for 16 days (n = 8-10 per group). Another subset of animals received wax pellets (placebo) to serve as controls. Animals from each group were randomly assigned to receive a 60% HFD or a standard high-carbohydrate (13% fat and 60% carbohydrate) diet. Cort + HFD resulted in central obesity, despite a relative weight loss, a 4-fold increase in hepatic lipid content, hepatic fibrosis, and a 2.8-fold increase in plasma alanine aminotransferase levels compared with placebo + chow controls. Hepatic injury developed independent of inflammation, as plasma haptoglobin levels were reduced with Cort treatment. Insulin resistance and hepatic steatosis occurred with Cort alone; these outcomes were further exacerbated by the HFD in the presence of elevated Cort. In addition to fatty liver, the Cort + HFD group also developed severe insulin resistance, hyperinsulinemia, hyperglycemia, and hypertriglyceridemia, which were not evident with HFD or Cort alone. Thus a HFD dramatically exacerbates the development of NAFLD and characteristics of the metabolic syndrome in conditions of chronically elevated Cort.