Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats

Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in obese humans and animals may be associated with obesity and the metabolic syndrome. We investigated the effect of inhibition of 11beta-HSD with glycyrrhetinic acid (GE), an effective 11beta-HSD inhibitor, on body weight regulation in obese Zucker rats, which have a defect in the leptin receptor gene. GE (280 mg/kg/d) was administered in drinking water to 8-week-old male Zucker rats for 14 weeks. GE had no effect on food intake or weight gain, and did not affect hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels in obese rats. In contrast, average daily food intake and body weight on week 14 were significantly reduced by GE in lean rats (both P <.0001). Hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels were also significantly decreased by GE in lean rats (both P <.05). GE had no significant effect on plasma corticosterone levels in obese rats but lowered them in lean rats (P <.05). Plasma leptin levels declined in both GE-treated obese and lean rats (both P <.01). In conclusion, long-term GE treatment decreased weight gain in lean Zucker rats but not in obese Zucker rats. These findings suggest that the differing responses of 11beta-HSD1 to GE in obese and lean Zucker rats are closely associated with the different weight-gain responses. Furthermore, the weight-lowering effect of GE may require intact leptin receptors.     

Exercise training improves insulin sensitivity in the obese Zucker rat

The effect of exercise on in vivo insulin sensitivity was examined in lean and obese Zucker rats. Rats (6 to 7 weeks of age) were swum two hours per day or kept sedentary for 8 weeks. Exercise decreased body weight gain as well as percent of fat in both genotypes. Sedentary obese rats had 62% higher gastrocnemius citrate synthase activity per gram of muscle than did lean rats. Exercise increased activity of this oxidative enzyme similarly in both genotypes. Compared to lean rats, obese rats had higher plasma-insulin levels and were less sensitive to insulin during an insulin tolerance test. Although training had no effect on plasma-insulin levels, exercise trained obese rats showed a greater drop in plasma glucose relative to sedentary controls following intravenous injection of three concentrations of insulin. It was concluded that moderate exercise training improved the insulin sensitivity of the obese Zucker rat.     

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.     

Mechanisms of dysregulation of 11 beta-hydroxysteroid dehydrogenase type 1 in obese Zucker rats

Obesity has been associated with alterations in glucocorticoid metabolism in both man and rodents, but the underlying mechanisms remain undefined. We have previously reported tissue-specific alterations in 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) in obese Zucker rats predicting that reactivation of corticosterone is decreased in liver but increased in omental fat. The mechanisms of dysregulation of 11 beta-HSD1 in obesity are not known, and in this study we have investigated the potential role of glucocorticoids and insulin. In one experiment lean and obese Zucker rats were adrenalectomised, and in a second experiment they were sensitised to insulin by treatment with either metformin or rosiglitazone. Adrenalectomy (ADX) of obese animals attenuated weight gain, normalised hepatic 11 beta-HSD1 kinetics by an effect on V(max) (V(max)in sham-operated animals, 6.6+/-1.1 nmol/min per mg in lean vs 3.4+/-0.6 in obese, P<0.01; in ADX animals 5.9+/-1.1 in lean vs 6.9+/-1.8 in obese, NS), and reversed the difference in omental fat 11 beta-HSD1 activity (18.9+/-4.2% in lean ADX vs 8.2+/-2.3 in obese ADX, P=0.03). Both metformin and rosiglitazone improved insulin sensitivity in obese, but not lean animals, and had no effect on 11 beta-HSD1 activity in either liver or fat. However, both treatments normalised adrenal hypertrophy in obese animals (48+/-29 mg in obese vehicle vs 37+/-1.2 in metformin and 38+/-1.8 in rosiglitazone treated, both P<0.01), and rosiglitazone tended to attenuate hypercorticosteronaemia in obese rats. Neither treatment attenuated weight gain; in fact, weight gain was enhanced by rosiglitazone in obese rats. In summary, altered 11 beta-HSD1 activity in obese Zucker rats is reversible following adrenalectomy, but the mechanism is unclear since adrenalectomy also normalises many other metabolic abnormalities. The current study suggests that hyperinsulinaemia is not responsible for tissue-specific dysregulation of 11 beta-HSD1. However, insulin sensitisation did reverse adrenal hypertrophy, suggesting that hyperinsulinaemia may be a key factor contributing to activation of the hypothalamic- pituitary-adrenal (HPA) axis in obesity independently of tissue-specific changes in 11 beta-HSD1.     

The effect of jejunoileal bypass (JIB) in the obese Zucker rat on a sub-group of enteroendocrine cells

The effect of jejunoileal bypass in lean and obese Zucker rats on a number of enteroendocrine cell types was investigated 5 weeks following surgery to remove 80 percent of the small bowel from continuity. The endocrine cells containing somatostatin, cholecystokinin, gastric inhibitory polypeptide, enteroglucagon and neurotensin were investigated. In control rats enteroglucagon cell number was decreased in obese compared to lean animals (5 +/- 1 vs 11 +/- 1 cells/mm). Following jejunoileal bypass the enteroglucagon cell population increased two-fold in both the functional and bypassed bowel in obese rats but was not elevated in lean animals. A significant increase in the number of cholecystokinin cells in the bypassed loop of the jejunum in both lean and obese bypassed rats was observed. The cholecystokinin cell population was also markedly elevated in the functional jejunum of obese but not lean bypassed rats. Only small changes were noted in cell numbers of gastric inhibitory polypeptide, somatostatin and neurotensin containing cells, suggesting that individual cell types have specific stimuli for proliferation. Epithelial height, a measure of intestinal adaptation, was similar in lean and obese rats in both the control and bypassed states, but weight loss in obese bypassed animals was significantly greater than that of lean bypassed rats. The hyperinsulinemia of obese rats was only partially normalized by jejunoileal bypass. These data indicate that jejunoileal bypass has effects on specific enteroendocrine cells which differ between lean and obese Zucker rats, and between individual cell types.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of diazoxide on brain capillary insulin receptor binding and food intake in hyperphagic obese Zucker rats.

Insulin is believed to act as a central adiposity signal by binding to hypothalamic and other brain insulin receptors. Entry of circulating insulin into the brain is accomplished by a saturable receptor-mediated transendothelial transport system and is believed to be impaired in hyperinsulinemic, insulin-resistant, and hyperphagic obese Zucker rats. Theoretically, if hyperinsulinemia is decreased simultaneously while brain capillary insulin binding is increased, uptake of insulin into the brain can be enhanced leading to reduced food intake. To test this hypothesis, we administered diazoxide (DZ, 150 mg/kg/day), an inhibitor of glucose-mediated insulin secretion, or vehicle (control) to 7-week-old female obese and lean Zucker rats for 4 weeks (n = 24-28/subgroup-strain). Animals were assigned to either fasted (FD) or free-fed (FF) protocol for determination of plasma and cerebrospinal fluid (CSF) insulin and brain capillary insulin binding at the end of 4 weeks. DZ obese consumed fewer calories (P<0.01) and gained less weight than control obese (P<0.01), whereas DZ lean had similar amounts of caloric intake and weight gain compared with lean controls. DZ obese had lower fasting and random plasma glucose than control obese (P<0.05). FD and FF DZ-treated obese and lean rats had lower plasma insulin than their respective obese (P<0.01) and lean (P<0.01) controls. FD and FF DZ-treated obese rats demonstrated higher CSF insulin (P<0.05) and CSF/ plasma insulin ratio (P<0.01) than their controls, while only FF DZ lean animals showed higher CSF/plasma insulin ratio (P<0.01) than their controls (P<0.05). This was associated with enhanced brain capillary insulin binding in FD and FF DZ-treated obese (P<0.01) and lean (P<0.05) animals compared with their respective controls. It was concluded that DZ treatment in obese Zucker rats caused a decrease in insulin secretion and partially reversed impaired insulin binding to brain capillaries, leading to enhanced brain insulin uptake, and resulted in reduced food intake and weight gain observed in these animals.     

The metabolic clearance rate of corticosterone in lean and obese male Zucker rats

The obese Zucker rat is an animal model of human juvenile-onset obesity. These rats exhibit numerous endocrine and metabolic abnormalities. Adrenalectomy of obese rats has been shown to reduce or reverse several of these abnormalities, thereby implying that corticosterone may contribute to the expression of obesity in this animal. Furthermore, it has been shown that the circadian rhythm of plasma corticosterone is disturbed in obese Zucker rats resulting in elevated morning plasma corticosterone concentrations in obese rats as compared to lean rats. In a effort to better elucidate the mechanism of the elevated morning levels of plasma corticosterone, the metabolic clearance rate of corticosterone was determined in the morning for lean and obese male Zucker rats (12 to 20 weeks). Additionally, the biliary and urinary excretion of labeled corticosterone and/or its metabolites were determined. The metabolic clearance rate of corticosterone was significantly greater in obese rats than in their lean counterparts. Both the metabolic clearance rate and the volume of compartments significantly correlated with body weight. No correlation was found between body weight and the elimination rate constant. The increased metabolic clearance rate of obese rats appeared to be due to an increase in the physiologic distribution of corticosterone and not to an alteration in the enzymes responsible for corticosterone metabolism. It appears that the metabolic clearance rate of corticosterone in obese Zucker rats does not contribute to elevated morning concentrations of plasma corticosterone previously observed in these animals. It suggests that the adrenal corticosterone secretion rate must actually be greater than one would expect from the plasma corticosterone concentrations alone.     

Effects of coadministered growth hormone (GH)-releasing hormone and GH-releasing hexapeptide on maladaptive aspects of obesity in Zucker rats.

The purpose of this study was to determine the effect of chronic pharmacological stimulation of the pituitary gland on GH hyposecretion and other maladaptive aspects of obesity. Obese Zucker rats were coadministered GH-releasing hormone (GHRH; 3 micrograms/kg) and GH-releasing hexapeptide (GHRP-6; 300 micrograms/kg), a potent combination of synergistic GH secretagogues, once daily for 60 consecutive days. Although pituitary weights and GH concentrations were higher in obese rats administered the peptides than in obese rats administered saline, stimulated GH secretion was lower in obese rats than in lean rats. However, compared to those in lean rats, plasma insulin-like growth factor-I and insulin concentrations were higher in the obese rats regardless of treatment. The GH secretagogues did not alter food intake or body weight gain in sexually mature obese rats, whereas body weight gain was significantly increased when they were administered to prepubertal obese rats. Although glucose tolerance was impaired in both groups of obese rats, it improved in obese rats administered GHRH and GHRP-6 compared to that in obese rats administered saline. On the other hand, plasma cholesterol concentrations were elevated in obese rats administered the GH secretagogues but not saline. In conclusion, the results of this study suggest that hyposensitivity to GHRH and GHRP-6 in obese Zucker rats results from high concentrations of plasma insulin-like growth factor-I that negatively feedback on stimulated GH secretion. Nonetheless, daily episodes of endogenous GH secretion resulting from chronic coadministration of GH secretagogues significantly influenced the pituitary gland as well as lipid and carbohydrate metabolism.     

Short Term Natriuretic Responses in the Conscious Zucker Obese Rat

Renal clearance studies were conducted in conscious, chronically catheterized obese and lean Zucker rats to investigate the natriuretic responses to i) acute IV infusion of isotonic NaCl= 5% of total body weight and ii) IV infusion of α rat atrial natriuretic peptide (ANP) in a dose of 300 ng/kg/min. In the baseline state, arterial blood pressure (BP) was significantly higher in obese vs lean rats. Absolute values of GFR and sodium excretion were similar but lower in obese vs lean rats when factored for body weight. In the 2 h period during and after NaCl infusion, obese rats showed a greater natriuresis vs lean while BP rose significantly and similarly. ANP infusion was natriuretic in obese rats but had no effect on lean rats. ANP lowered BP in both groups but BP remained higher in obese vs lean rats at all times. These studies show that in the chronic, unstressed preparation the 6–8 month old, female Zucker obese rat has a higher BP vs the 6–8 month old lean Zucker. The short term natriuretic response to either a NaCl load or ANP infusion is greater in obese vs lean Zuckers and the depressor response to ANP is intact in obese Zuckers. Thus the higher BP in this model of obesity is unlikely to be due to either a defective response to ANP or to a defect in the renal response to acute sodium challenge.     

Atherogenesis in two strains of obese rats. The fatty Zucker and LA/N-corpulent

Two strains of obese rats, the fatty Zucker and the LA/N-corpulent have been compared at 6 months age for the presence of vascular and myocardial disease. Both strains, when obese, exhibit a VLDL hyperlipidemia with elevated triglycerides and moderate elevations of plasma cholesterol concentrations compared to the lean rats of the same strain. The hyperlipidemia is more modest in the fatty Zucker than the corpulent LA/N, and the serum lipid concentrations of the lean Zucker are lower than those of the lean LA/N. Apolipoprotein concentrations were similar and elevated in the two obese genotypes compared to the lean genotypes which were also similar to each other. Male and female obese animals of both strains exhibited hyperinsulinemia under fasting conditions and after oral glucose, with obese male LA/N rats exhibiting the most severe hyperinsulinemia. Glucose tolerance was impaired in obese LA/N animals but was normal in lean rats of both strains and fatty Zucker rats of both sexes. The glucose intolerance observed in obese LA/N animals was more severe in the male than in the female rats. Unlike the corpulent rat, which develops atherosclerotic lesions, the fatty Zucker shows no evidence of advanced vascular lesions on scanning electron microscopy. The fatty Zucker also does not develop the myocardial lesions that are frequent in the male corpulent LA/N rat. It is suggested that the initiation of the atherogenic process is dependent upon elevated insulin levels or transient hyperglycemia. Development of the advanced lesions appears to require the presence of hyperlipidemia.     

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.     

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.     

Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

OBJECTIVES: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. METHODS: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. RESULTS: DZ-treated animals showed lower fasting plasma insulin levels (P<0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P<0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P<0.001) and glucose-6-phosphatase (P<0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P<0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P<0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P<0.01), glycogen synthase activity (P<0.0001) and glycogen content (P<0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P<0.02). CONCLUSIONS: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.     

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.     

Obese Zucker (fa/fa) rats exhibit normal target sensitivity to corticosterone and increased drive to adrenocorticotropin during the diurnal trough.

Genetically obese Zucker (fa/fa) rats exhibit numerous metabolic and endocrine disorders associated with modest hypercorticosteronemia and reported changes in peripheral target tissue sensitivity to glucocorticoids. In this study we investigated phenotypic differences in basal and stress-induced ACTH and corticosterone (B) secretion in intact and adrenalectomized lean and obese male Zucker rats. In addition, we determined whether differences in the sensitivity to B of plasma ACTH and insulin secretion as well as other peripheral B targets could be observed between the two phenotypes. There were no significant differences in basal ACTH or B in either the morning (AM) or evening (PM) in intact obese and lean rats; however, mean B was increased in the obese rats in the AM, and signs of chronically increased adrenocortical activity were observed, including increased adrenal weight and intraadrenal phenylethanolamine-N-methyl transferase activity and decreased thymus weight. In a second experiment, B was significantly elevated 3 min after either administration in obese compared to lean rats; however, there was no significant difference in B between the groups at 10 min, nor were ACTH levels at these times different. Five days after adrenalectomy with sc B replacement, ACTH was decreased as a function of B in both phenotypes under AM basal and stress conditions. The IC50 values for inhibition of basal ACTH by B were 3.16 and 4.17 micrograms/dl in lean and obese rats, respectively. Under stress conditions, the IC50 values were not different (4.39 micrograms/dl for lean and 4.24 micrograms/dl for obese rats). B dose-dependent increases in body and epididymal fat depot weights were greater in obese than in lean rats, an expected result because of elevated insulin levels in this group. Insulin exhibited only small B-dependent increases, and thymus weight decreased in a B-dependent fashion; there were no differences in the sensitivity to B of these measures between lean and obese rats. We conclude that 1) there is no evidence for altered sensitivity to B in obese rats for any of the B-sensitive end points measured; and 2) basal adrenocortical activity is slightly elevated, and the sensitivity of ACTH to B feedback is decreased in obese rats under AM conditions in the absence of external stress.(ABSTRACT TRUNCATED AT 400 WORDS)     

Defective dopamine receptor function in proximal tubules of obese zucker rats

Some of the pathophysiological consequences of obesity include insulin resistance, increased renal sodium reabsorption, and the development of hypertension. Dopamine promotes renal sodium excretion via activation of D(1)-like receptors present on the proximal tubules. Reduced dopamine-induced natriuresis and a defect in D(1)-like receptor function have been reported in the proximal tubules of hypertensive animals. The present study investigated D(1)-like dopamine receptors and associated G proteins as the initial signaling components in the proximal tubular basolateral membranes of obese Zucker and control lean Zucker rats. We found that the obese rats were hyperinsulinemic, hyperglycemic, and hypertensive compared with the lean rats. Dopamine produced concentration-dependent inhibition of Na,K-ATPase activity in the proximal tubules of lean rats, whereas the inhibitory effect of dopamine was reduced in obese rats. The D(1)-like receptors measured by [(3)H]SCH 23390 binding revealed an approximately 45% decrease in B(max) without a change in K(d) in the basolateral membranes of obese rats compared with lean rats. Although we found an increase in G(q)/11alpha and no change in G(s)alpha in the basolateral membranes of obese rats, dopamine and SKF 38393 failed to stimulate G proteins as measured by [(35)S]GTPgammaS binding in obese rats, suggesting a receptor-G protein coupling defect. We conclude that decrease in D(1)-like dopamine receptor binding sites and diminished activation of G proteins, resulting perhaps from defective coupling, led to the reduced inhibition by dopamine of Na,K-ATPase activity in the proximal tubules of obese Zucker rats. Such a defect in renal dopamine receptor function may contribute to sodium retention and development of hypertension in obese rats.     

Glucose metabolism in isolated adipocytes from lean and obese Zucker rats following treatment with dehydroepiandrosterone

Previous work has demonstrated that chronic administration of dehydroepiandrosterone (DHEA) to obese Zucker rats reduces the severity of hyperinsulinemia that is usually present. There were also significant decreases in body weight, fat depot weight, and adipose tissue cellularity. It was hypothesized that the decreased serum insulin was a reflection of improved tissue responsiveness to insulin. The purpose of the present study was to evaluate this hypothesis by examining the insulin response in isolated adipocytes of DHEA-treated rats. Glucose incorporation into CO2, fatty acids, and glyceride-glycerol was measured in isolated parametrial and retroperitoneal adipocytes. Cells from control and DHEA-treated lean rats and control and DHEA-treated obese rats were used, as well as cells from a group of obese rats pair-fed to the DHEA-obese rats. Increased basal and insulin-stimulated rates of incorporation of glucose into CO2 and fatty acids were found in adipocytes from DHEA-lean rats compared to control, lean rats. In contrast, cells from DHEA-treated obese rats tended to incorporate less glucose into CO2 and fatty acids than either the control or pair-fed obese rats. These data indicate that the decrease in serum insulin levels seen in DHEA-treated obese rats is not due to an improvement of adipose tissue responsiveness.     

Carbohydrate metabolism in lean and obese Zucker rats

Carbohydrate metabolism was evaluated in lean and obese Zucker rats. Plasma glucose concentration, renal and hepatic gluconeogenesis, and hepatic glycogen content and rates of synthesis were investigated in 2-mo and 8-mo-old animals. Mild hyperglycemia was observed in obese Zucker rats compared to lean rats and was more pronounced in males than in females. Rates of glucose disappearance were normal in both female and male rats, although there was a trend toward decreased clearance in the male. Total organ hepatic and kidney PEPCK activity and kidney glucose production were elevated in obese compared to lean rats. Total organ hepatic glycogen levels and rates of glycogen synthesis were increased significantly in obese compared to lean, the increase being greater in males than females. The mild hyperglycemia present in obese Zucker rats is not associated with delayed disappearance of intravenously administered glucose, but may be due to the increased production of glucose by whole kidney and liver.     

Angiotensin II type 2 receptor agonist directly inhibits proximal tubule sodium pump activity in obese but not in lean Zucker rats

We have reported recently that the renal angiotensin II type 2 (AT2) receptors are upregulated and involved in promoting natriuresis/diuresis in obese but not in lean Zucker rats. In the present study, we tested the hypothesis that there is an enhanced AT2 receptor signaling via NO/cGMP pathway leading to greater inhibition of the Na(+), K(+)-ATPase (NKA) activity in the proximal tubules (PT) of obese rather than lean Zucker rats. The AT2 agonist CGP42112 (0.1 to 100 nmol/L) inhibited (33% at 100 nmol/L) the NKA activity in the PTs of obese but not in lean Zucker rats. The AT2 antagonist PD123319 (1 micromol/L), not the angiotensin II type 1 antagonist losartan (1 micromol/L), significantly diminished the CGP42112-induced inhibition of the NKA activity in obese rats. The AT2 agonist (10 nmol/L)-induced NKA inhibition was abolished by the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 micromol/L), the NO synthase inhibitor NG-nitro-L-arginine methyl ester (100 micromol/L), and the protein kinase G inhibitor K1388 (2 micromole/L). CGP42112 (10 nmol/L) caused an increase in serine phosphorylation of NKA alpha1-subunit in PT of obese rats. Measurement of cGMP and NO revealed that CGP42112 (0.1 to 100 nmol/L) increased cGMP and NO accumulation in the PTs of obese but not lean rats. The CGP42112-induced stimulation of NO and cGMP was blocked by PD123319 (1 micromol/L), NG-nitro-L-arginine methyl ester (100 micromol/L), and 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 micromol/L) but not by losartan (1 micromol/L). The data suggest that the AT2 receptor activation via stimulation of the NO/cGMP/protein kinase G pathway directly inhibits the tubular NKA activity that provides as a mechanism responsible for the AT2 receptor-mediated natriuresis in obese but not in lean Zucker rats.     

Lipoprotein and apolipoprotein distribution in Zucker rats following an endurance running program

We examined the response to 12 weeks of endurance running of the obese Zucker rat and its lean littermate with regard to changes in serum lipids, lipoproteins and apoproteins. The obese Zucker rat is hyperlipoproteinemic, characterized by elevated serum triglyceride and cholesterol levels primarily associated with the very low density lipoprotein (VLDL) fraction. In lean Zucker rats, training did not affect the concentrations of serum lipids or apolipoproteins. In marked contrast, obese Zucker rats that were trained had significant decreases in serum concentrations of triglycerides, free and esterified cholesterol, and apolipoprotein B compared to their sedentary counterparts. Training obese rats caused an increase in the serum concentration of apolipoprotein E (HDL fraction). In contrast, training did not affect the concentration of Apo E in lean rats. The VLDL fraction was most affected by training obese rats showing marked 50-65% decreases in VLDL triglyceride and VLDL cholesterol. HDL cholesterol was unchanged in lean rats whereas training prompted a 29% increase in obese rats. These data show that exercise training altered the metabolic abnormalities of obese Zucker rats which are responsible for the accumulation in serum of VLDL, lipids and apolipoproteins.