A moderately high fat diet promotes salt-sensitive hypertension in obese zucker rats by impairing nitric oxide production

The objective of this research was to examine the contribution of a moderately high fat (MHF) diet to the development of salt-sensitive hypertension in obese Zucker rats. Lean and obese Zucker rats were fed either a MHF diet or a diet of standard rat chow (control diet) for 10 weeks. From week 4 through week 10, the drinking water was supplemented with 1% NaCl. Blood pressure was measured weekly, and urinary excretion of nitric oxide metabolites (NO(x)) was determined at weeks 4 and 10. At week 10, renal nitric oxide synthase (NOS) activity was assessed in kidney homogenates. Blood pressures of obese, but not lean, rats on the MHF fat diet were significantly increased by salt-supplementation, whereas blood pressures of rats on the control diet were not appreciably affected. NO(x) excretion was increased in response to salt-supplementation in rats on the control diet, with the effect being particularly dramatic in obese rats. After salt-supplementation, NO(x) excretion by rats on the MHF diet was lower than rats on the control diet. In obese rats on the MHF diet, this decrease in NO production was accompanied by a reduction in renal NOS activity. These results indicate that obese rats are more inclined than lean rats to develop diet-induced hypertension in response to a moderately high fat, salt-supplemented diet. Furthermore, they suggest that MHF diet-induced defects in NO production may promote the salt-sensitivity of blood pressure in obese Zucker rats, which appear to require more NO to maintain blood pressure during a salt challenge.     

Renal disease in rats with Type 2 diabetes is associated with decreased renal nitric oxide production

Aims/hypothesis In several other models of chronic renal disease, decreases in renal nitric oxide activity and nitric oxide synthase (NOS) protein abundance have been demonstrated. Here, we studied diabetic obese Zucker (ZDF Gmi fa/fa) rats that develop severe hyperglycaemia and renal disease, together with their lean control animals, to determine if renal nitric oxide deficiency also occurs in this model.Methods Obese Zucker rats aged 10 to 12 weeks were maintained on Purina 5008 diet until 4, 8, or 11 months of age and compared with similarly maintained, 4- and 11-month-old lean Zucker rats. NOS activity and abundance of endothelial NOS (eNOS) and neuronal NOS (nNOS) were measured on homogenates of kidney cortex. Blood was analysed for glucose, lipids, creatinine, and blood urea nitrogen and kidney tissue was obtained for histology.Results Obese rats exhibited severe hyperglycaemia from 4 months of age and developed increasing hyperlipidaemia, proteinuria, and decreasing renal function with age compared to lean counterparts. At 4 months cortical NOS activity and nNOS abundance were lower in obese rats than in lean ones. At 11 months NOS activity remained depressed and nNOS abundance had declined further in obese rats. Glomerulosclerosis in the obese rats was mild at 4 months, becoming severe by 11 months. Lean rats had only mild age-dependent increases in glomerular injury.Conclusions/interpretation The chronic renal disease that occurs in hyperglycaemic, obese Zucker rats is associated with decreased renal cortical nitric oxide production and increasing renal injury, although the changes do not resemble those of diabetic nephropathy in man.     

Effects of palatable diets on body weight and adipose tissue cellularity in the adult obese female Zucker rat (fa/fa)

Obese 7–8 mo-old female Zucker rats (fa/fa) and their lean littermates (Fa/?) exhibited the same percentage increase in body weight during a 50-day period when both groups of animals were fed a highly palatable snack food diet (SF). A subsequent 50-day period of refeeding with standard laboratory chow caused rats of both genotypes to shed the excess weight gained on SF. These findings suggest that lean and obese Zucker female rats are comparably responsive to a highly palatable diet. When a second group of female fa/fa rats were fed either SF or another palatable, semipurified high fat diet for 135 days, beginning at 2–3 mo of age, they were found to have substantially more fat cells in all depots studied that did female (fa/fa) rats that had been fed only chow. Thus, the obese Zucker rat is also comparable to normal rats with respect to the phenomenon of diet-induced adipocyte hyperplasia.     

Nitrogen balances of lean and obese Zucker rats subjected to a cafeteria diet.

The effects of a cafeteria diet on nitrogen balance in lean (Fa/?) and obese Zucker rats (fa/fa) was studied for two consecutive 15 day periods after weaning. Obese rats were able to absorb a lower proportion of dietary nitrogen than the lean controls. Cafeteria diet increased the retention of dietary nitrogen, and lowered urinary nitrogen losses in both obese and lean rats. Urea constituted practically the only product of urinary nitrogen excretion in obese rats, whereas it accounted for only about 75% of that eliminated by Fa/? rats. Nitrogen accretion in the body was highest for the younger animals, and again increased with cafeteria feeding. Obese fa/fa rats showed a lower percentage of body nitrogen retention than their lean counterparts; obese rats were able, however, to accumulate large amounts of nitrogen and fat, in part because of their higher intake. A significant part of the absorbed nitrogen was not found in either the body or the urine; the cafeteria diet markedly increased the weight of this fraction of nitrogen unaccounted for. In conclusion, the effects of cafeteria feeding on weight and nitrogen handling were comparable in lean and obese rats, i.e. the effects of genetic and dietary obesity seem to be additive with regard to nitrogen extraction and excretion for Zucker rats.     

Urinary organic acid profiles in obese (ob/ob) mice: indications for the impaired omega-oxidation of fatty acids.

As a means of generating an hypothesis to explain genetic obesity of the C57BL/6J ob/ob mouse, we used gas chromatography-mass spectrometry to compare the urinary organic acid profiles of obese (ob/ob) and lean (+/?) mice on both a chow and a chemically simplified diet. More than 60 peaks were found and quantified; 45 peaks were identified. No acid was excreted in greater amounts by lean mice and none was excreted exclusively by either lean or obese mice. When normalized to body weight (obese mice being 40% heavier) and to creatinine excretion (30% greater in obese mice), however, only the daily excretion of malate, 2-hydroxyglutarate, aconitate, 3-hydroxy-3-methylglutarate, oxalate, ethylmalonate, and 4-hydroxyphenylacetate were significantly greater in obese mice. When allowed to eat only an all-fat (Crisco) diet for 4 days, the excretion of adipate rose 10-fold in lean mice, but only threefold in obese mice. Adipate excretion by Zucker rats also increased on the Crisco diet, but was indistinguishable between lean and fatty rats, suggesting that omega-oxidation might be impaired in obese mice but not in fatty rats. This suggestion complements an earlier proposal that a comparative increase in ethylmalonate excretion, which was also characteristic of fatty Zucker rats, might be explained by an increased concentration of butyryl-CoA due to inadequate beta-oxidation. An impairment of omega-oxidation in the obese mouse may also explain why urinary 3-hydroxy-3-methylglutarate, which is derived from short chain products of beta-oxidation, is increased in obese mice but not in fatty rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of nitric oxide in thermoregulation and hypoxic ventilatory response in obese Zucker rats

To examine the role of nitric oxide (NO) on thermoregulation and control of breathing in obesity, awake obese and age-matched lean Zucker (Z) rats underwent a sustained hypoxic challenge. Body temperature (Tb), oxygen consumption (V O(2)) and ventilation (V E) were measured during room air and during 30-min of hypoxia (10% O(2)) after intraperitoneal administration of either 100 mg/kg of N(G)-nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS inhibitor, 25 mg/kg of 7-nitroindazole (7-NI), a selective neuronal NOS inhibitor, or equal volume of vehicle (dimethyl sulfoxide: DMSO) as control. Tb in obese rats during room air was significantly lower than that of lean rats. Hypoxia induced a more pronounced drop in Tb and V O(2) in lean rats than in obese rats. Tb in lean Z rats dropped significantly by approximately 0.2 degrees C after L-NAME and, more markedly, by approximately 1.1 degrees C after 7-NI compared with control during room air, whereas Tb in obese Z rats was unaffected. L-NAME and 7-NI attenuated hypoxia-induced hypothermia or hypometabolism in lean rats, but not in obese rats. Lean rats exhibited an abrupt increase in V E in response to hypoxia followed by a gradual decline in V E. In contrast, obese rats displayed an initial increase in V E that plateaued during sustained hypoxia. Both L-NAME and 7-NI induced marked decreases in V E during room air and hypoxia compared with control lean rats, whereas V E was virtually unaffected by either agent in obese rats. The present results suggest that the blunted thermoregulatory and ventilatory responses to hypoxia in obese Z rats may be attributed to reduced activity of NOS in the central nervous system.     

Hypercorticosteronuria and diminished pituitary responsiveness to corticotropin-releasing factor in obese Zucker rats

Metabolic defects in obese (fa/fa) Zucker rats have previously been shown to be reversed by adrenalectomy; however, hypercorticosteronemia has not been demonstrated. We now report that the total daily excretion of corticosterone and urea nitrogen are significantly greater (P less than 0.01) in obese Zucker rats than in age-matched lean Zucker rats. This excessive excretion of corticosterone is not of autonomous adrenal origin, since dexamethasone treatment (20 micrograms/kg X day) for 2 days induced a proportionate reduction in corticosterone excretion (approximately 50%) in both obese and lean Zucker rats. Corticosterone excretion was further suppressed to levels not different from those in lean rats after 2 days of dexamethasone (40 micrograms/kg X day). Both the peak and total pituitary beta-endorphin secretion in response to an iv bolus of corticotropin-releasing factor (CRF) were diminished in obese Zuckers. The response to CRF in obese Zucker rats was dampened and superimposable on that of dexamethasone-treated lean Zucker rats, suggesting the existence of chronic hypercorticosteronemia as a component of this genetic obesity. These observations provide evidence for a compensatory alteration of the pituitary-adrenal axis. We suggest that corticosterone turnover may be increased in obese Zucker rats.     

DOPAMINE FAILS TO INHIBIT Na,H-EXCHANGER IN PROXIMAL TUBULES OF OBESE ZUCKER RATS

Dopamine via the activation of D₁-like receptors inhibits Na,K-ATPase and Na,H-exchanger and subsequently increases sodium excretion. We have previously reported that dopamine failed to inhibit Na,K-ATPase in the proximal tubules (PTs) of obese Zucker rats. The present study was designed to determine the effect of dopamine on Na,H-exchanger in PTs of lean and obese Zucker rats, and examine D₁-like receptor-coupled signal transduction pathway mediating the inhibition of Na,H-exchanger. We found that dopamine inhibited Na,H-exchanger in the PTs of lean rats but this response was absent in obese rats. In brush border membranes, [³H]SCH 23390 binding revealed a, ～45% reduction in D₁-like receptor binding sites in obese compared to lean rats. Dopamine stimulated cAMP accumulation in PTs of lean but not in obese rats. Forskolin-mediated stimulation of cAMP was similar in lean and obese rats. Dopamine as well as forskolin and dibutyryl cAMP-mediated stimulation of protein kinase A (PKA) was reduced in PTs of obese compared to lean rats. The data suggest that reduction in D₁-like receptor binding sites, defective coupling with signaling pathway and inability of PKA activation may be responsible for the failure of dopamine to inhibit Na,H-exchanger in PTs of obese rats. This phenomenon may contribute to an increase in sodium reabsorption and development of hypertension in obese Zucker rats.     

Increased sensitivity of the obese Zucker rat to deoxycorticosterone-salt-induced hypertension

OBJECTIVE: The objective of this study was to test the hypothesis that obesity increases the sensitivity of rats to experimentally induced hypertension. DESIGN AND METHODS: To induce hypertension, unilaterally nephrectomized lean and obese Zucker rats were injected with 25 mg/kg of deoxycorticosterone acetate (DOCA) twice weekly for 5 weeks and given water containing 1% NaCl to drink. Unilaterally nephrectomized control rats were injected with vehicle and drank tap water. Systolic blood pressure (SBP) was measured by the tail cuff method. Renal histology and urinary albumin excretion were used to assess the effects of the experimental treatment on the kidney. RESULTS: Obese rats exhibited a significant rise in SBP at 4 days after the start of DOCA-salt treatment. In contrast, SBP of DOCA-treated lean rats was not significantly elevated from pretreatment measurements until day 22. Moreover, SBP was significantly higher during the plateau phase of blood pressure development in obese DOCA-salt treated rats (196 mmHg) than in correspondingly treated lean rats (150 mmHg). Both obesity and DOCA-salt treatment promoted glomerulosclerosis and mild tubulointerstitial damage in the kidney with DOCA-salt treatment exacerbating the effect of obesity. Urinary albumin excretion was significantly greater in obese control rats compared with lean controls and in DOCA-treated obese rats relative to vehicle-treated obese rats. CONCLUSION: Results of this study indicate that obese Zucker rats are more sensitive to mineralocorticoid-induced hypertension than lean rats. This study provides experimental evidence supporting the epidemiological findings that obesity is a risk factor for the development of hypertension.     

Bromocriptine reduces steatosis in obese rodent models

BACKGROUND/AIMS: Obesity is a risk factor for glucose intolerance, steatosis, and oxidative stress, characteristics of nonalcoholic fatty liver disease. Bromocriptine may have anti-obesity, insulin-sensitizing, lipolytic, and antioxidant properties. We, therefore, hypothesized that bromocriptine would improve markers of nonalcoholic fatty liver disease in obese rodent models. METHODS: We performed a randomized, controlled experiment in genetically obese fatty Zucker rats and diet-induced obese rats to assess for behavioral and peripheral anti-obesity actions of bromocriptine (10mg/kg) that would improve nonalcoholic fatty liver disease. RESULTS: Behaviorally, food intake decreased and locomotor activity increased in bromocriptine-treated fatty Zucker and dietary-induced obese rats. Peripherally, liver triglycerides were significantly reduced and hepatic manganese superoxide dismutase significantly increased in bromocriptine-treated fatty Zucker and diet-induced obese rats compared to controls. Blood glucose was significantly lower in bromocriptine-treated Zucker rats compared to fatty controls and was no different than that of lean controls. CONCLUSIONS: Improvements in obesigenic behaviors, glucose tolerance, hepatic lipid accumulation, and mitochondrial oxidative stress observed in genetically obese and diet-induced obese rodents indicate that bromocriptine may be promising as a broad-based therapy for nonalcoholic fatty liver disease.     

The effect of vigorous treadmill exercise on adipose tissue development in the Zucker rat

Four-week-old male lean and obese Zucker rats were subjected to intense daily exercise for a 10-week period. The exercise regimen used (running 6 days/week for 90 min/day on a treadmill at 1.3 Km/h at an 8 per cent grade) was designed to maximize the amount of exercise performed. Lean and obese runners (LR and OR) gained significantly less weight than sedentary controls (LS and OS). Food intake was lower in LR and unchanged in OR compared with control animals. Exercise increased adrenal weight in runners of both phenotypes. Gastrocnemius muscle weight was significantly higher in OR compared to OS. Despite the intense exercise regimen, carcass fat of OR was reduced only 12 per cent versus OS. In contrast, exercise decreased carcass fat by 32 per cent in LR versus LS. This decrease in body fat of LR was due to smaller adipocytes. Exercise did not affect adipocyte size in obese rats. However, OR had fewer carcass adipocytes. These results indicate that exercise had substantially different effects on adipose tissue cellularity of lean and obese rats. The results of the present study indicate that a program of intense treadmill exercise initiated immediately post weaning only modestly reduced adipose tissue growth in obese Zucker rats. Furthermore, it did not normalize body composition.     

Effects of Salt Rich Diet in the Obese Zucker Rats: Studies on Renal Function During Isotonic Volume Expansion

Obese Zucker rats (OZR) are hyperinsulenemic, hyperglycemic and dyslipidemic and develop salt dependent hypertension. Since salt sensitivity is considered to be due to impaired handling of renal sodium excretion, these studies were conducted in the obese and lean Zucker rats (LZR) anesthetized with Inactin to evaluate renal function under basal conditions and during acute isotonic fluid volume expansion (VE). Mean Arterial blood pressure (MBP), heart rate (HR), renal blood flow(RBF) and glomerular filtration rate (GFR) were not significantly different between the lean Zucker rats fed normal diet or that fed salt rich diet(8% NaCl). However, basal UV and UNaV were significantly greater in the LZR fed high salt. During VE essentially identical increases occurred in GFR, UV and UNaV in both the lean groups. In the OZR fed salt rich diet also, there were no significant changes in the heart rate, RBF and GFR. However, arterial blood pressure of the OZR fed salt rich diet was significantly greater than that of the OZR on the normal diet as well as that of both the lean groups. Also, as in the LZR, basal UV and UNaV were significantly greater in the salt fed obese rats. During volume expansion there were no impairments in the ability of the obese groups fed normal or salt rich diet to eliminate sodium and water during volume load. In fact, the net sodium and water excretions during and 60 min after VE in both the obese groups were significantly greater than that of corresponding lean groups. Furthermore, these values in the OZR fed salt rich diet were significantly greater than that of the obese rats on normal salt diet perhaps due to the contribution of ‘pressure natriuretic mechanisms’. These data demonstrate that although OZR are salt sensitive, the renal mechanisms that would collectively respond to acute isotonic VE were fully functional. An unexpected and a novel finding in these studies is that the salt rich diet, in addition to increasing arterial blood pressure also significantly lowered plasma of insulin levels and enhanced glucose and cholesterol levels in the obese Zucker rats.     

Oleate metabolism in isolated hepatocytes from lean and obese Zucker rats. Influence of a high fat diet and in vitro response to glucagon

The uptake and metabolism of [1-¹⁴C]oleate (0.3 mmol/L) were studied in isolated hepatocytes from lean and obese Zucker rats fed either a control (low-fat) diet or a high-fat diet. With the control diet, [1-¹⁴C]oleate uptake was increased by 70% in the obese rats, and fat-feeding decreased this uptake to values comparable to that of their lean littermates. Interestingly, the hepatocyte mean surface area was increased in the obese mutants by 21% with the control diet and by 30% with the high-fat diet. The possible reasons for the differences in oleate uptake are discussed. With the control diet, cells from the obese rats showed a four-fold rise in [1-¹⁴C]oleate esterification, while ketogenesis (β-hydroxybutyrate + acetoacetate production) as well as the radioactive acid-soluble products were greatly depressed. Production of CO₂ was very low and similar in both groups of animals. Adaptation to the high-fat diet in the obese rats resulted in a reversal between esterification and oxidation of oleate: the latter became the major metabolic pathway as in the lean rats. The ketogenic capacity was greatly if not completely restored. In the lean animals, glucagon stimulated ketogenesis both in the presence or absence of oleate and decreased [1-¹⁴C]oleate esterification. In the obese rats, the hormone exerted a significant ketogenic effect only if oleate was present and did not influence its esterification. The data demonstrate the following abnormalities in the hepatocytes of obese Zucker rats: (1) an enlargement of cell size, (2) an increased oleate uptake, (3) a virtual absence of a ketogenic response to exogenous oleate, and (4) a markedly increased esterification of the latter. The metabolic defects, but not the cell size, appear to be largely corrected by an adaptation to a high-fat diet. The hepatic response to glucagon was decreased in the obese rats at the level of endogenous ketogenesis.     

Relationship between lipogenesis,ketogenesis, and malonyl-CoA content in isolated hepatocytes from the obese Zucker rat adapted to a high-fat diet

The relationship between lipogenesis and ketogenesis and the concentration of malonyl coenzyme A (CoA) was investigated in hepatocytes from adult obese Zucker rats and their lean littermates fed either a control low-fat diet or a high-fat diet (30% lard in weight). With the control diet, lipogenesis—although strongly inhibited in the presence of either 1 mmol/L oleate, 10^?6 mol/L glucagon or 0.1 mmol/L TOFA (a hypolipidemic drug)—remained about fifteen-fold higher in the obese rats than in the lean rats. In contrast, ketogenesis under some conditions (oleate + TOFA) was not significantly lower (30%) as compared with the lean rats. After adaptation to the high-fat diet, lipogenesis was depressed fourfold in the lean rats and ninefold in the obese ones; however its magnitude remained significantly higher in the latter, namely at a value close to that measured in control-fed lean rats. Ketogenesis was comparable in lean and obese rats and much higher in the presence of 1 mmol/L oleate than of 0.3 mmol/L oleate, whereas lipogenesis did not vary with increasing oleate concentration in the medium. Acetyl-CoA carboxylase activity measured in liver homogenates was higher in the obese group, but was stepwise inhibited by increasing concentrations of oleyl-CoA regardless of the diet for both lean and obese rats, thus showing no abnormality of in vitro responsiveness to this inhibitor. With the control diet, hepatocyte malonyl-CoA levels were significantly higher in the obese rats, both in the basal state and after inhibition of lipogenesis by oleate and TOFA. However, after the high-fat diet, there was no longer a significant difference between the genotypes. These results show that in the obese Zucker rats, ketogenesis is dependent on hepatocyte malonyl-CoA content in the sense that their ketogenic capacity becomes “normalized” when malonyl-CoA is decreased to the levels found in the lean littermates, as it is the case after fat-feeding. This normalization of malonyl-CoA levels in spite of higher lipogenesis in the obese rats may result from the activities of enzymes of its formation and utilization.     

Deposition of dietary fatty acids in young Zucker rats fed a cafeteria diet.

The content and accretion of fatty acids in 30, 45 and 60-day-old Zucker lean Fa/? and obese fa/fa rats fed either reference chow or a cafeteria diet has been studied, together with their actual fatty acid intake during each period. Diet had little overall effect on the pattern of deposition of fatty acids, but quantitatively the deposition of fat was much higher in cafeteria-fed rats. The fat-rich cafeteria diet allowed the direct incorporation of most fatty acids into the rat lipids, whilst chow feeding activated lipogenesis and the deposition of a shorter chain and more saturated pattern of fatty acids. Genetic, obesity induced a significant expansion of net lipogenesis when compared with lean controls. Cafeteria-fed obese rats accrued a high proportion of fatty acids, which was close to that ingested, but nevertheless showed a net de novo synthesis of fatty acids. It is postulated that the combined effects of genetic obesity and a fat-rich diet result in high rates of fat accretion with limited net lipogenesis. Lean Zucker rats show a progressive impairment of their delta 5-desaturase system, a situation also observed in obese rats fed a reference diet. In Zucker obese rats, cafeteria feeding resulted in an alteration of the conversion of C18:2 into C20:3. The cafeteria diet fully compensated for these drawbacks by supplying very high amounts of polyunsaturated fatty acids.     

Spontaneous activity and adipose cellularity in the genetically obese Zucker rat (fafa)

The development of spontaneous activity was studied in obese and lean Zucker rats. Rats were given access to activity wheels for 3 hr/day before weaning and for 24 hr/day after weaning. Zucker obese rats are less active than lean rats. This decreased activity occurs at weaning and follows the onset of hyperphagia and obesity. At 8 wk of age exercised lean and obese rats have less total fat and fewer adipocytes than their appropriate controls. Adipose cell size is decreased only in exercised lean rats. When rats are exercised until 8 wk of age and then confined until 6 mo of age, body weight and fat is elevated in these formerly active rats compared to control rats. Adipose cell number is permanently decreased only in formerly active lean rats. Exercise has no long-term effect in decreasing cell number in obese rats.     

Anti-obesity effect of two different levels of dehydroepiandrosterone in lean and obese middle-aged female Zucker rats

Dehydroepiandrosterone has previously been shown to prevent weight gain in growing lean and obese mice and rats. In the present study, lean and obese female Zucker rats were treated with either 0.6 or 1.0 percent DHEA in the diet from 8 until 14 months of age. In lean rats, 0.6 percent DHEA prevented weight gain and 1.0 percent DHEA resulted in significant weight loss compared to initial body weight. Control lean rats had a significant weight gain. Both 0.6 and 1.0 percent DHEA obese rats lost weight over the experimental period while control obese rats gained weight. Food intake of DHEA-treated obese rats was lowered compared to control obese rats but was similar to that of all lean groups. DHEA lowered serum insulin levels in both lean and obese rats relative to control groups. Both 0.6 and 1.0 percent DHEA lean rats had elevated hepatic G6PD activity compared to control lean rats. DHEA obese rats had lowered G6PD activity compared to the control obese rats. Hepatic malic enzyme was elevated by DHEA treatment in both lean and obese Zucker rats. Adipose tissue weights were lowered substantially in DHEA treated lean and obese rats versus their control groups. These data indicate that DHEA treatment in adult rats has an anti-obesity effect.     

Effects of salt rich diet in the obese Zucker rats: studies on renal function during isotonic volume expansion

Obese Zucker rats (OZR) are hyperinsulenemic, hyperglycemic and dyslipidemic and develop salt dependent hypertension. Since salt sensitivity is considered to be due to impaired handling of renal sodium excretion, these studies were conducted in the obese and lean Zucker rats (LZR) anesthetized with Inactin to evaluate renal function under basal conditions and during acute isotonic fluid volume expansion (VE). Mean Arterial blood pressure (MBP), heart rate (HR), renal blood flow(RBF) and glomerular filtration rate (GFR) were not significantly different between the lean Zucker rats fed normal diet or that fed salt rich diet(8% NaCI). However, basal UV and UNaV were significantly greater in the LZR fed high salt. During VE essentially identical increases occurred in GFR, UV and UNaV in both the lean groups. In the OZR fed salt rich diet also, there were no significant changes in the heart rate, RBF and GFR. However, arterial blood pressure of the OZR fed salt rich diet was significantly greater than that of the OZR on the normal diet as well as that of both the lean groups. Also, as in the LZR, basal UV and UNaV were significantly greater in the salt fed obese rats. During volume expansion there were no impairments in the ability of the obese groups fed normal or salt rich diet to eliminate sodium and water during volume load. In fact, the net sodium and water excretions during and 60 min after VE in both the obese groups were significantly greater than that of corresponding lean groups. Furthermore, these values in the OZR fed salt rich diet were significantly greater than that of the obese rats on normal salt diet perhaps due to the contribution of pressure natriuretic mechanisms'. These data demonstrate that although OZR are salt sensitive, the renal mechanisms that would collectively respond to acute isotonic VE were fully functional. An unexpected and a novel finding in these studies is that the salt rich diet, in addition to increasing arterial blood pressure also significantly lowered plasma of insulin levels and enhanced glucose and cholesterol levels in the obese Zucker rats.     

Cholesterol homeostasis in lean and obese male Zucker rats

Studies were performed in male Zucker rats to determine the metabolic effect of genetic obesity on whole body cholesterol homeostasis. Lean and obese mature Zucker rats were studied during intake of either a chow diet or a semisynthetic diet containing 10% corn oil; in addition growing animals were studied during constant body weight gain on a chow diet. Under all conditions the obese Zucker rats had significantly higher levels of total plasma cholesterol and triglyceride; however, measurements of the specific activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and of the rate of whole body cholesterol synthesis by sterol balance techniques demonstrated that the lean and obese animals did not differ in their endogenous rates of cholesterol synthesis. When sterol balance data were calculated per kilogram body weight, lean male Zucker rats synthesized a greater amount of cholesterol per day than obese animals. These studies demonstrate that the obese male Zucker rat, in many ways a model of human obesity, does not overproduce cholesterol and thus fails to exhibit one of major characteristics of the obese human.     

Influence of clenbuterol on energy balance, thermogenesis and body composition in lean and genetically obese Zucker rats

Daily injection of lean Zucker rats with a beta 2-adrenergic agonist (clenbuterol, 1 mg/kg) for 22 day increased weight gained by 38 per cent; there were significant increases in carcass protein and water, but fat content was unaltered. Clenbuterol did not affect energy intake or expenditure, the acute thermogenic response to food, or brown adipose tissue (BAT) activity (assessed from mitochondrial purine nucleotide (GDP) binding). In obese Zucker rats, clenbuterol significantly depressed energetic efficiency and increased the thermogenic response to food and BAT activity in these mutants. Body weight gain was not significantly affected by clenbuterol in obese Zucker rats but this was because of a 19 per cent reduction in fat content accompanied by a simultaneous 13 per cent increase in protein content. The ratio of protein/fat gained during the study was increased by 50 and 173 per cent by clenbuterol in lean and obese rats, respectively. Thus, clenbuterol exhibits potent anabolic effects on lean body mass in genetically obese as well as lean rats, but also increases thermogenesis and reduces body fat content in the obese mutants.