Serum leptin, lipids, free fatty acids, and fat pads in long-term dehydroepiandrosterone-treated Zucker rats

The obese Zucker rat has a genetically flawed leptin system and is a model of hyperphagia, obesity, hyperlipidemia, and markedly elevated leptin levels. Dehydroepiandrosterone (DHEA) administration reduces hyperphagia, hyperlipidemia, and obesity in Zucker rats. Since serum leptin levels are associated with body fat, we wondered what the effects of fat pad weight reduction from DHEA administration would have on leptin levels. This experiment investigated the effects of DHEA on intra-abdominal fat pads, serum lipids, and peripheral leptin in male lean and obese Zucker rats that were administered DHEA in their food from 4 weeks of age to 20 weeks. Lean and obese rats received plain chow or chow containing DHEA. Additional chow-fed groups of lean and obese weight-matched controls and obese pair-fed rats helped to control for the reduced body weight, food intake, and fat pad weights seen with DHEA administration. DHEA administration to lean Zucker rats reduced body weight and fat pad weights, but leptin levels showed a lower trend. Among obese rats, both DHEA treatment and pair-feeding reduced body weight and fat pad weights, but only DHEA lowered leptin levels. The weight-matched controls had reductions in fat pad weights similar to the DHEA-treated group, but with increased leptin levels. Thus, DHEA may exert a small, independent effect on leptin levels in this animal model, but the reduction is less than what would be expected.     

Topiramate Reduces Energy and Fat Gains in Lean (Fa/?) and Obese (fa/fa) Zucker Rats

Objective: This study examined the effects of topiramate (TPM), a novel neurotherapeutic agent reported to reduce body weight in humans, on the components of energy balance in female Zucker rats. Research Methods and Procedures: A 2 × 3 factorial experiment was performed in which two cohorts of Zucker rats differing in their phenotype (phenotype: lean, Fa/?; obese, fa/fa) were each divided into three groups defined by the dose of TPM administered (dose: TPM 0, vehicle; TPM 15, 15 mg/kg; TPM 60, 60 mg/kg). Results: The reduction in body weight gain induced by TPM in both lean and obese rats reflected a decrease in total body energy gain, which was more evident in obese than in lean rats. Whereas TPM administration did not influence the intake of digestible energy in lean rats, it induced a reduction in food intake in obese animals. In lean, but not in obese rats, apparent energy expenditure (as calculated by the difference between energy intake and energy gain) was higher in rats treated with TPM than in animals administered the vehicle. The low dose of TPM decreased fat gain (with emphasis on subcutaneous fat) without affecting protein gain, whereas the high dose of the drug induced a reduction in both fat and protein gains. The effects of TPM on muscle and fat depot weights were representative of the global effects of TPM on whole body fat and protein gains. The calculated energetic efficiency (energy gain/energy intake) was decreased in both lean and obese rats after TPM treatment. TPM dose independently reduced hyperinsulinemia of obese rats, but it did not alter insulinemia of lean animals. Discussion: The present results provide sound evidence for the ability of TPM to reduce fat and energy gains through reducing energetic efficiency in both lean and obese Zucker rats.     

Subchronic treatment with metformin produces anorectic effect and reduces hyperinsulinemia in genetically obese Zucker rats.

The effect of subchronic metformin treatment on food intake, weight gain and plasma and tissue hormone levels was investigated in genetically obese male Zucker rats and in their lean controls. Metformin hydrochloride (320 mg/kg/day for 14 days in the drinking water) significantly reduced 24 hour food intake both after one and two weeks treatment in obese rats. In contrast, metformin had only a transient effect on food intake in lean animals. The reduced food intake was associated with body weight decrease, particularly in obese rats. Metformin markedly reduced also the hyperinsulinemia of the obese animals without altering their plasma glucose or pancreatic insulin content which may reflect an improved insulin sensitivity after metformin treatment. Metformin did not change plasma corticosterone levels or insulin and somatostatin concentrations in the pancreas. Metformin reduced pyloric region somatostatin content in lean rats. It is concluded that metformin has an anorectic effect and reduces body weight and hyperinsulinemia in genetically obese Zucker rat.     

Time-Dependent Effects of Progressive Gamma -Linolenate Feeding on Hyperphagia,Weight Gain,and Erythrocyte Fatty Acid Composition During Growth of Zucker Obese Rats

Obese Zucker rats (fa/fa) have low levels of arachidonic acid (AA) in liver phospholipids (PL). We have previously shown that a 70% gamma-linolenate concentrate (GLA; an AA intermediate) fed at a fixed dose (0.07 g/day) normalized hepatic PL AA and reduced weight gain selectively in the obese animals. In a follow-up study, 16 obese (fa/fa) and 16 lean (Fa/Fa) 4-week-old male rats were randomized into 4 groups of 8 each and gavaged daily with soybean oil (SOY) containing 55% 18:2ω6 (an AA precursor) or GLA, using a progressive dose (≤ 5% of total calories) based on body weight. A defined diet with 11% of energy as SOY was fed ad libitum for 60 days. GLA obese had lower body weight (p<0.0001) and 60-day cumulative food intake (p<0.05) compared to SOY obese, but neither parameter differed between the lean groups. For the last twenty days cumulative food intake was identical for GLA obese and SOY lean, whereas SOY obese consumed 18% more (p<0.05). Thus the progressive dose of GLA selectively suppressed hyperphagia in obese Zucker rats. Erythrocytes collected at 15-day intervals showed parallel increases in AA in both genotypes over time, suggesting normal AA availability during rapid growth. Thus, the reduced PL AA in the livers from the obese rats probably reflects impaired distribution in selected tissues rather than reduced hepatic production. Due to the potential health risks of enriching tissue lipids with AA, great caution is advised in considering GLA as therapy for human obesity.     

Effects of 2 G on adiposity, leptin, lipoprotein lipase, and uncoupling protein-1 in lean and obese Zucker rats.

Male Zucker rats were exposed to 2 G for 8 wk to test the hypothesis that the leptin regulatory pathway contributes to recovery from effects of 2 G on feeding, growth, and nutrient partitioning. After initial hypophagia, body mass-independent food intake of the lean rats exposed to 2 G surpassed that of the lean rats maintained at 1 G, but food intake of the obese rats exposed to 2 G remained low. After 8 wk at 2 G, body mass and carcass fat were less in both genotypes. Leptin and percent fat were lower in lean rats exposed to 2 G vs. 1 G but did not differ in obese rats exposed to 2 G vs. 1 G. Although exposure to 2 G did not alter uncoupling protein-1 levels, it did elicit white fat pad-specific changes in lipoprotein lipase activity in obese but not lean rats. We conclude that 2 G affects both genotypes but that the lean Zucker rats recover their food intake and growth rate and retain "normal" lipoprotein lipase activity to a greater degree than do the obese rats, emphasizing the importance of a functional leptin regulatory pathway in this acclimation.     

Very low-carbohydrate versus isocaloric high-carbohydrate diet in dietary obese rats

Objective: The effects of a very low‐carbohydrate (VLC), high‐fat (HF) dietary regimen on metabolic syndrome were compared with those of an isocaloric high‐carbohydrate (HC), low‐fat (LF) regimen in dietary obese rats. Research Methods and Procedures: Male Sprague‐Dawley rats, made obese by 8 weeks ad libitum consumption of an HF diet, developed features of the metabolic syndrome vs. lean control (C) rats, including greater visceral, subcutaneous, and hepatic fat masses, elevated plasma cholesterol levels, impaired glucose tolerance, and fasting and post‐load insulin resistance. Half of the obese rats (VLC) were then fed a popular VLC‐HF diet (Weeks 9 and 10 at 5% and Weeks 11 to 14 at 15% carbohydrate), and one‐half (HC) were pair‐fed an HC‐LF diet (Weeks 9 to 14 at 60% carbohydrate). Results: Energy intakes of pair‐fed VLC and HC rats were less than C rats throughout Weeks 9 to 14. Compared with HC rats, VLC rats exhibited impaired insulin and glycemic responses to an intraperitoneal glucose load at Week 10 and lower plasma triacylglycerol levels but retarded loss of hepatic, retroperitoneal, and total body fat at Week 14. VLC, HC, and C rats no longer differed in body weight, plasma cholesterol, glucose tolerance, or fasting insulin resistance at Week 14. Progressive decreases in fasting insulin resistance in obese groups paralleled concomitant reductions in hepatic, retroperitoneal, and total body fat. Discussion: When energy intake was matched, the VLC‐HF diet provided no advantage in weight loss or in improving those components of the metabolic syndrome induced by dietary obesity and may delay loss of hepatic and visceral fat as compared with an HC‐LF diet.     

Effect of photoperiod on body weight and food intake of obese and lean Zucker rats

Although the rat is usually not considered to be sensitive to photoperiod, under some experimental conditions photoperiod responses are unmasked. In addition, we have observed photoperiod-induced changes in body weight gain in lean and obese Zucker rats. In this experiment, body mass, food intake, body composition, brown adipose tissue (BAT) thermogenic state, and blood concentrations of corticosterone, insulin, and glucose were evaluated under one of two lighting conditions: a short (10 h light: 14 h dark) or a long (14 h light: 10 h dark) photoperiod. Plasma corticosterone and glucose concentrations measured under fasting conditions were unaffected by photoperiod in either genotype. The amount of BAT mitochondrial protein isolated was less in long photoperiod rats. BAT mitochondrial GDP binding was unaffected by photoperiod in the lean rats, but tended to be lower in long photoperiod obese rats than in short photoperiod obese rats. Although, photoperiod had no effect on daily food intake of rats exposed to the short versus long photoperiod, body mass was heaviest in obese rats raised in long photoperiod. Plasma insulin was increased in both lean and obese rats in long photoperiod. In addition, fat storage appeared to shift to internal depots in the lean rats exposed to long photoperiod. Our data demonstrate that photoperiod does have an effect on male Zucker rats with respect to body weight and fat distribution, with the obese rats being more sensitive to changes in photoperiod than the lean rats.     

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.     

Subdiaphragmatic vagal deafferentation affects body weight gain and glucose metabolism in obese male Zucker (fa/fa) rats

We investigated the effect of subdiaphragmatic vagal deafferentation (SDA) on food intake, body weight gain, and metabolism in obese (fa/fa) and lean (Fa/?) Zucker rats. Before and after recovery from surgery, food intake and body weight gain were recorded, and plasma glucose and insulin were measured in tail-prick blood samples. After implantation of a jugular vein catheter, an intravenous glucose tolerance test (IVGTT) was performed, followed by minimal modeling to estimate the insulin sensitivity index. Food intake relative to metabolic body weight (g/kg(0.75)) and daily body weight gain after surgery were lower (P < 0.05) in SDA than in sham obese but not lean rats. Before surgery, plasma glucose and insulin concentrations were lower (P < 0.05) in lean than in obese rats but did not differ between surgical groups within both genotypes. Four weeks after surgery, plasma glucose and insulin were still similar in SDA and sham lean rats but lower (P < 0.05) in SDA than in sham obese rats. IVGTT revealed a downward shift of the plasma insulin profile by SDA in obese but not lean rats, whereas the plasma glucose profile was unaffected. SDA decreased (P < 0.05) area under the curve for insulin but not glucose in obese rats. The insulin sensitivity index was higher in lean than in obese rats but was not affected by SDA in both genotypes. These results suggest that elimination of vagal afferent signals from the upper gut reduces food intake and body weight gain without affecting the insulin sensitivity index measured by minimal modeling in obese Zucker rats.     

Effect of adrenalectomy on in vivo glucose metabolism in insulin resistant Zucker obese rats

Lean (Fa/?) and obese (fa/fa) Zucker rats were adrenalectomized (ADX) in order to assess the contribution of adrenal hormones to insulin resistance of the obese Zucker rat. Glucose utilization was measured using an insulin suppression test. Sham-operated obese rats gained almost twice as much weight as sham-operated lean littermates. However, body weight gain of ADX animals was comparable in both genotypes. It was significantly less than that of the respective sham-operated controls. Body weight differences can be accounted for almost entirely by a marked loss of adipose tissue. Although insulin resistance may be attributable to obesity in part, steroid hormones are thought to be directly antagonistic to insulin for glucose metabolism. Adrenalectomy resulted in a decrease in serum glucose concentrations for both lean and obese Zucker rats compared with their respective sham-operated groups. Serum insulin concentration of lean ADX rats was 23% of sham-operated controls; in obese ADX rats, it was 9% of controls. Elevated levels of steady state serum glucose (SSSG) levels in sham-operated obese rats demonstrate a marked resistance to insulin induced glucose uptake compared with sham-operated lean animals. Adrenalectomy caused a marked improvement in insulin sensitivity of obese rats. The hyperglycemic SSSG levels of the obese rats were reduced 2.5 times by ADX. These results indicate that insulin resistance of Zucker obese rats can be ameliorated by ADX, suggesting adrenal hormones contribute to insulin resistance in these animals.     

Central Exendin‐4 Infusion Reduces Body Weight without Altering Plasma Leptin in (fa/fa) Zucker Rats

Objective: To investigate whether chronic administration of the long‐acting glucagon‐like peptide‐1 receptor agonist exendin‐4 can elicit sustained reductions in food intake and body weight and whether its actions require an intact leptin system. Research Methods and Procedures: Male lean and obese Zucker (fa/fa) rats were infused intracerebroventricularly with exendin‐4 using osmotic minipumps for 8 days. Results: Exendin‐4 reduced body weight in both lean and obese Zucker rats, maximum suppression being reached on Day 5 in obese (8%) and Day 7 in lean (16%) rats. However, epididymal white adipose tissue weight was not reduced, and only in lean rats was there a reduction in plasma leptin concentration. Food intake was maximally suppressed (by 81%) on Day 3 in obese rats but was reduced by only 18% on Day 8. Similarly, in lean rats food intake was maximally reduced (by 93%) on Day 4 of treatment and by 45% on Day 8. Brown adipose tissue temperature was reduced from Days 2 to 4. Plasma corticosterone was elevated by 76% in lean but by only 28% in obese rats. Discussion: Chronic exendin‐4 treatment reduced body weight in both obese and lean Zucker rats by reducing food intake: metabolic rate was apparently suppressed. These effects did not require an intact leptin system. Neither does the absence of an intact leptin system sensitize animals to exendin‐4. Partial tolerance to the anorectic effect of exendin‐4 in lean rats may have been due to elevated plasma corticosterone and depressed plasma leptin levels, but other counter‐regulatory mechanisms seem to play a role in obese Zucker rats.     

The Presence of the “fa” Gene in Heterozygous (FA/fa) Lean Female Rats: Effects on Body Weight,Body Fat and Serum Leptin

CLEARY, MARGOT P., AND FREDERICK C. PHILLIPS. The presence of the “fa” gene in heterozygous (FA/fa) lean female rats: effects on body weight, body fat and serum leptin. Obes Res. Objective: In previous studies, suckling lean heterozygous (FA/fa) pups had higher body fat levels in comparison to lean homozygous (FA/FA) pups. However, in older male rats fed either low- or high-fat diets, we found no effects of the “fa” gene in heterozygous lean rats compared to homozygous lean rats. Other studies have reported effects of the “fa” gene on aspects of insulin metabolism for lean heterozygous female rats compared to their homozygous counterparts. In the present study, the effect of the “fa” gene on body weight and body fat in lean female rats was investigated. Research Methods and Procedures: Homozygous lean female rats were obtained by mating homozygous lean male and female rats. Heterozygous lean female rats were obtained by mating homozygous obese male rats with heterozygous lean female rats. Following weaning, rats were maintained on a standard laboratory diet until 10 weeks of age when they were killed after an overnight fast. Results: Body weight (p<0. 03) and inguinal (p = 0. 01) and combined retroperitoneal+parametrial (p = 0. 06) fat pad weights were heavier in heterozygous lean compared to homozygous lean female rats. Combined fat pad-to-body weight ratio (p = 0. 05) and fat cell sizes (p = 0. 06) were also higher in the heterozygous lean compared to homozygous lean rats. No differences in serum triacylglycerol, cholesterol, glucose, or insulin concentrations were found between the two groups, but serum leptin levels were significantly higher (p<0. 004) in heterozygous lean rats. Discussion: These results indicate that effects of the “fa” gene are present during the postweaning period in lean female rats. Implications for increased body fat and leptin with respect to sexual maturation and fertility are discussed.     

Dietary induction of hepatic glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme in lean and obese female Zucker rats

Responses of the hepatic lipogenic enzymes, glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), and malic enzyme (ME) to starvation refeeding and diet shifting were determined in lean and obese female Zucker rats. Rats were either fed nonpurified diet, starved 48 hr, and then refed nonpurified diet or one of the refined carbohydrate diets containing either glucose, fructose, cornstarch, or sucrose for 72 hr, or shifted from nonpurified diet directly to one of the refined carbohydrate diets for 72 hr. Initial activities were greater in obese than lean rats for all three enzymes studied. Similar to other strains of female rats, lean Zucker rats failed to demonstrate a starve-refeed response when refed nonpurified diet. Obese female littermates showed a statistically significant increase in enzymes when refed a nonpurified diet. Both lean and obese female Zucker rats demonstrated increases in enzyme activities above controls when starved and refed any of the refined carbohydrate diets. The greatest responses were observed when female rats were starved and refed sucrose; activities increased 2.6- to 3.5-fold in lean and 3.0- to 4.3-fold in obese Zuckers. In lean females 50-70% of the starve-refeed response observed with G6PDH and ME can be accounted for by simply shifting from a nonpurified diet to the respective refined carbohydrate diet, whereas in obese females only 33-55% of the increase could be attributed to diet shifting. Plasma testosterone/estrogen ratios were consistently 1.5 times higher in obese than in lean female rats. This phenotypic difference may potentiate the heightened starve-refeed overshoot response observed in obese rats.     

Dehydroepiandrosterone alters Zucker rat soleus and cardiac muscle lipid profiles

High levels of serum free fatty acids (FFA) and lower proportions of polyunsaturated (PU) FAs, specifically arachidonic acid (AA), are common in obesity, insulin resistance (IR), and type 2 diabetes mellitus. Dehydrepiandrosterone (DHEA) decreases body fat content, dietary fat consumption, and insulin levels in obese Zucker rats (ZR), a genetic model of human youth onset obesity and type 2 diabetes. This study was conducted to investigate DHEA's effects on lean and obese ZR serum FFA levels and total lipid (TL) FA profiles in heart and soleus muscle. We postulated that DHEA alters serum FFA levels and tissue TL FA profiles of obese ZR so that they resemble the levels and profiles of lean ZR. If so, DHEA may directly or indirectly alter tissue lipids, FFA flux, and perhaps lower IR in obese ZR. Lean and obese male ZR were divided into six groups with 10 animals in each: obese ad libitum control, obese pair-fed, obese DHEA, lean ad libitum control, lean pair-fed, and lean DHEA. All animals had ad libitum access to a diet whose calories were 50% fat, 30% carbohydrate, and 20% protein. Only the diets of the DHEA treatment groups were supplemented with 0.6% DHEA. Pair-fed groups were given the average number of calories per day consumed by their corresponding DHEA group, and ad libitum groups had 24-h access to the DHEA-free diet. Serum FFA levels and heart and soleus TL FA profiles were measured. Serum FFA levels were higher in obese (approximately 1 mmol/L) compared to lean (approximately 0.6 mmol/L) ZR, regardless of group. In hearts, monounsaturated (MU) FA were greater and PU FA were proportionally lower in obese compared to the lean rats. In soleus, saturated and MU FA were greater and PU FA were proportionally lower in the obese compared to the lean rats. DHEA groups displayed significantly increased proportions of TL AA and decreased oleic acid in both muscle types. Mechanisms by which DHEA alters TL FA profiles are a reflection of changes occurring within specific lipid fractions such as FFA, phospholipid, and triglyceride. This study provides initial insights into DHEA's lipid altering effects.     

Difructose anhydride III decreases body fat as a low-energy substitute or by decreasing energy intake in non-ovariectomized and ovariectomized female rats

We evaluated the effects of difructose anhydride III (DFAIII) on body weights of ovariectomized rats, which are a good model for obesity by estrogen deficiency-induced overeating. Female rats (10 weeks old) were subjected to ovariectomy or sham operation and then fed with or without a diet containing 3% or 6% DFAIII for 33 days or pair-fed control diet during the same period. Rats fed DFAIII showed significantly decreased food intake, energy intake, body weight gain, body energy accumulation, and fat tissue weight than control group, regardless of ovariectomy. DFAIII may decrease body fat dependent of reduced food/energy intake. Compared with the respective pair feeding groups, rats fed DFAIII showed significantly decreased body energy and fat tissue weight, regardless of ovariectomy, suggesting its potential as a low-energy substitute for high-energy sweeteners. The low energy of DFAIII may contribute to decreased body fat, which may not be dependent on obesity.     

In vivo lipogenesis and enzyme levels in adipose and liver tissues from pair-fed genetically obese and lean rats

Genetically obese Zucker rats pair-fed to lean controls were similar in body weight and food intake, however, epididymal fat pads were considerably larger than lean controls. $\text{In}$$\text{vivo}$ incorporation of acetate-¹⁴C into adipose tissue lipid was not significantly different, however, $\text{in}$$\text{vivo}$ liver lipogenesis was elevated in the obese rat. Characterization of enzyme profiles in both liver and adipose tissues revealed that enzymes normally associated with lipogenesis were elevated in liver tissue from obese rats. Malic enzyme and citrate cleavage enzyme were both depressed in adipose tissue of obese animals. From these data, it appears that the liver may be prominently involved in the development of excessive blood lipid and enlarged fat cells in the Zucker obese rat.     

Serum and gene expression levels of leptin and adiponectin in rats susceptible or resistant to diet-induced obesity

The aim of the present study was to identify the role of leptin and adiponectin in the development of resistance or susceptibility to diet-induced obesity in rats. For this purpose, male Wistar rats were fed with standard laboratory diet (control group) or cafeteria diet. After 15 days, two groups of rats with different response respect to the cafeteria diet were identified, and were assigned as diet-induced obesity (DIO) and diet resistant (DR) rats. The high-fat diet induced a very significant increase in both body and fat mass weight in DIO group. However, DR rats, gained even less weight than control-fed animals. Food intake was increased in cafeteria-fed rats (both DIO and DR) in comparison to control group; but hyperphagia was higher in DIO rats. In addition, feed efficiency (the ratio of weight gained to calories consumed) was significantly decreased in DR as compared to DIO rats. Regarding leptin, a significant increase in both adipose tissue gene expression and serum levels was observed in DIO rats in comparison with other groups (control and DR). A significant increase in both adiponectin circulating levels and adipose tissue mRNA expression was also observed in DIO animals as compared with the other groups. These data suggest that the susceptibility to obesity of DIO rats might be secondary, at least in part, to an earlier development of leptin resistance, which could lead to alterations in food intake (hyperphagia) and energetic metabolism. However, neither changes in leptin or adiponectin seem to be involved in the adaptive mechanisms that confer resistance to high fat intake.     

Restoration of coronary endothelial function in obese Zucker rats by a low-carbohydrate diet

A popular diet used for weight reduction is the low-carbohydrate diet, which has most calories derived from fat and protein, but effects of this dietary regimen on coronary vascular function have not been identified. We tested the hypothesis that obesity-induced impairment in coronary endothelial function is reversed by a low-carbohydrate diet. We used four groups of male Zucker rats: lean and obese on normal and low-carbohydrate diets. Rats were fed ad libitum for 3 wk; total caloric intake and weight gain were similar in both diets. To assess endothelial and vascular function, coronary arterioles were cannulated and pressurized for diameter measurements during administration of acetylcholine or sodium nitroprusside or during flow. When compared with lean rats, endothelium-dependent acetylcholine-induced vasodilation was impaired by approximately 50% in obese rats (normal diet), but it was restored to normal by the low-carbohydrate diet. When the normal diet was fed, flow-induced dilation (FID) was impaired by >50% in obese compared with lean rats. Similar to acetylcholine, responses to FID were restored to normal by a low-carbohydrate diet. N(omega)-nitro-L-arginine methyl ester (10 microM), an inhibitor of nitric oxide (NO) synthase, inhibited acetylcholine- and flow-induced dilation in lean rats, but it had no effect on acetylcholine- or flow-induced vasodilation in obese rats on a low-carbohydrate diet. Tetraethylammonium, a nonspecific K(+) channel antagonist, blocked flow-dependent dilation in the obese rats, suggesting that the improvement in function was mediated by a hyperpolarizing factor independent of NO. In conclusion, obesity-induced impairment in endothelium-dependent vasodilation of coronary arterioles can be dramatically improved with a low-carbohydrate diet most likely through the production of a hyperpolarizing factor independent of NO.     

Effects of phenotype, sex, and diet on plasma lipids in LA/N-cp rats

The LA/N-corpulent (cp) rat is a recently developed congenic strain which exhibits obesity. The effects of phenotype and sex on serum and lipoprotein lipid content were examined in LA/N-cp rats fed either a control or an atherogenic diet high in saturated fat and protein. Obese rats were pair-fed to equivalent lean animals. Results from this study indicate that sex, phenotype, and diet exert significant effects on plasma and lipoprotein cholesterol content. Plasma cholesterol levels were higher in obese compared with lean rats, females than in males, and rats consuming the atherogenic diet compared with the control diet. Plasma and lipoprotein triglyceride levels were significantly increased only in obese compared with lean animals. The increased plasma cholesterol and triglyceride was observed primarily in the chylomicron and very low density lipoprotein fractions. Increased levels of plasma cholesterol were not a result of increased dietary cholesterol absorption or increased liver cholesterol biosynthesis. These data suggest that LA/N-cp rats can serve as a unique rodent model for the study of the interrelationships between hyperlipidemia, obesity, and coronary heart disease.     

Single intracerebroventricular bolus injection of a recombinant adenovirus expressing leptin results in reduction of food intake and body weight in both lean and obese Zucker fa/fa rats

Leptin acts as a satiety factor within the central nervous system by binding to its receptor located in the hypothalamus. A missense mutation of the leptin receptor induces hyperphagia and obesity in the obese Zucker fa/fa rat. Since the CNS is an important target of leptin action, we hypothesized that leptin gene transfer into the lateral cerebral ventricle could efficiently lead to inhibition of food intake and reduction of body weight in obese fa/fa rats as well as in lean animals. A single intracerebroventricular injection of an adenoviral vector containing a cDNA encoding leptin resulted in the expression of leptin in the ependymal cells lining the ventricle and the secretion of leptin into the cerebrospinal fluid (CSF). During the first week after injection, when high concentrations of leptin were produced in the CSF, the reducing effects of leptin on food intake and body weight were comparable in lean and in obese fa/fa rats. The subsequent decline in CSF leptin levels, that was similar in lean and obese fa/fa rats, resulted in the faster resumption of food intake and body weight gain in obese than in lean animals, confirming a reduced sensitivity to leptin in the obese group. The results of this study show that leptin gene delivery into the cerebral ventricles allows for the production of elevated leptin concentrations in CSF, and they support the hypothesis that the impaired sensitivity to leptin may be overcome in obese fa/fa rats.