Differential Responsiveness of Obese (fa/fa) and Lean (Fa/Fa) Zucker Rats to Cytokine-Induced Anorexia

Pathophysiological and pharmacological concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the cerebrospinal fluid (CSF) induce anorexia in normal rats. Obesity in humans and rodents is associated with increased TNF-α messenger RNA and protein levels in various cell types. This suggests that obese individuals may have differential regulation of cytokine production and dissimilar responsiveness to cytokines. In the present study, we investigated the effects of the intracerebroventricular (ICV) microinfusion of TNF-α (50, 100, and 500 ng/rat), IL-1β (1.0, 4.0, and 8.0 ng), and TNF-α (100 ng) plus IL-1β (1.0 ng) on obese (fa/fa) and lean (Fa/Fa) Zucker rats. The results show that: TNF-α and IL-1β, and the concomitant administration of TNF-a and IL-ip decreased the short-term (4 hours), nighttime (12 hours), and total daily food intakes in obese and lean rats; IL-1β was more potent relative to TNF-α; obese rats showed greater responsiveness to IL-1β: 8.0 ng IL-1β, for example, decreased the 12-hour food intake by 52% in obese and 22% in lean rats. On the other hand, obese and lean rats did not exhibit a significantly different responsiveness to the anorexia induced by 50,100, or 500 ng TNF-α at the 4-hour period; and the concomitant ICV administration of TNF-α and IL-1β induced anorexia with additive (4-hour period) or synergistic (12-hour and 24-hour periods) effects in obese rats. The effect of TNF-α plus IL-1β in lean rats was greater than additive for the 12-hour and 24-hour periods. The difference in suppression of total daily food intake by TNF-α plus IL-1β in obese (-43%) versus lean (-23%) rats was significantly different (p<0.01). The results show that obese (fa/fa) and lean (Fa/Fa) Zucker rats have differential responsiveness to the ICV microinfusion of two different classes of cytokines.     

Physiological Effects of Dietary PIPS Soybean-Derived Phospholipid in Obese Zucker (fa/fa) Rats

The effects of soybean-derived phospholipid, PIPS NAGASE^TM (PIPS), on obesity-induced diseases were studied in obese rats. Dietary PIPS alleviated hepatomegaly and fatty liver in the rats. These effects were attributable to reduced lipogenesis and enhanced lipolysis in the liver. The results suggest that PIPS can be useful as a dietary component that would reduce the risk of lifestyle-related diseases.     

Influence of Opioids in Hypothalamic Nuclei on Cold Thermogenesis of Lean and Obese LA/N-cp Rats

An overactive endogenous opioid peptide system (EOP) in the hypothalamus of the obese rats could contribute to a subnormal metabolic response to cold stress. Specific mu, delta, kappa opioid receptor antagonists and naloxone were infused into cannulaes aimed at the paraventricular nucleus (PVN) of awake freely moving obese (LA/N-cp corpulent) and lean littermate rats. Metabolic responses were measured by indirect calorimetry during thermoneutrality (30°C) and at 10°C for 60 minutes each. When expressed relative to metabolic body size (kg^?.75) obese rats had lower values (obese = 21.1 ± 1.9 vs. lean = 27.9 ± 2.7 ml·kg^?.75.min, mean ± s.d., p<0.05) at 10°C during saline infusion. EOP antagonist infusions at 30°C had no effect on metabolic rate for either lean or obese animals. Mu (23.5 ± 3.4 ml·kg^.-75· min) and delta (23.0 ± 2.0) antagonism and naloxone (25.0 ± 2.3) significantly increased the metabolic response to cold in obese but not lean rats. These data suggest that certain subtypes of EOP receptors in or near PVN are overactive in obese rats. This overactive state may inappropriately inhibit the thermogenic response to cold stress in obesity.     

Differential Short-Term Distribution of Estrone and Oleoyl-Estrone Administered in Liposomes to Lean and Obese Zucker Rats

Thirteen-week-old female Zucker lean (Fa/Fa) and obese (fa/fa) rats were injected through a cannula inserted in the left jugular vein with 1 mL/kg of ³H-labeled oleoyl-estrone in liposomes (Merlin-2) (i.e., 670 fmol, 84 kBq). The rats were killed 10 minutes later and dissected. The presence of intact or hydrolyzed oleoyl-estrone was later determined in all samples. The pattern of distribution of estrone was quite different from that of oleoyl-estrone both in rats that were lean and in those that were obese. Estrone was better retained by white adipose tissue than oleoyl-estrone. Liver, spleen, and lungs accumulated more oleoyl-estrone and split part of it, from 4.7% (lung, obese) to 27% (liver, lean). The overall high retention of estrone by the rat tissues results in its very low circulating levels. The fast splitting of liposome-carried oleoyl-estrone by most tissues (up to more than 67% by intestine and skin of lean rats) may help explain the rise in blood free estrone. The differences between lean and obese Zucker rats are mainly quantitative in the case of estrone, the main differences being found in blood and adipose tissues. However, when we compare the data for oleoyl-estrone, the differences cannot be dismissed simply as due to differences in body size or the extent of fat deposits. A large portion of the label remained in the blood of the rats that were obese but not in those that were lean, the tissues of which took up more label. Brown adipose tissue shows a fair affinity for oleoyl-estrone in the rats that were lean but practically does not retain label in the rats that were obese, suggesting that oleoyl-estrone may have a direct effect on brown adipose tissue. The decreased uptake of oleoyl-estrone in rats that were obese shows that the mechanism regulating the turnover or disposal of this signal is altered in this type of genetic obesity.     

Decrease in protein tyrosine phosphatase activities in vanadate-treated obese Zucker (fa/fa) rat liver

The inhibitory action of vanadate towards protein tyrosine phosphatase (PTPase) has been considered as a probable mechanism by which it exerts insulin-like effects. In this study, we have examined thein vivo effects of vanadate on PTPases in the liver of obese Zucker rats, a genetic animal model for obesity and type II diabetes. These animals were characterized by hyperinsulinemia and mild hyperglycemia. The number of insulin receptors were significantly (p<0.01) decreased in liver. After chronic administration of vanadate in obese rats, 80% decrease in the plasma levels of insulin was observed. The insulin receptor numbers were significantly (p<0.01) higher in vanadate-treated obese rats as compared to the untreated ones. The hepatic PTPase activities in cytosolic and particulate fractions, with phosphorylated poly glu:tyr (41) and the insulin receptor peptide (residues 1142–1153) as substrates, increased in obese rats. In vanadate-treated obese rat livers, the PTPase activities in both subcellular fractions with these substrates decreased significantly (p<0.001). The decreases in PTPase activities from these groups of rats were further supported by chromatography on a Mono Q column. These data support the view that inhibition of PTPases plays a role in the insulin-mimetic action of vanadate.     

Changes in the phosphorylation state of the inhibitory guanine-nucleotide-binding protein Gi-2 in hepatocytes from lean (Fa/Fa) and obese (fa/fa) Zucker rats

Treatment of intact, 32Pi-labelled hepatocytes from lean Zucker rats with a range of agents including 12-O-tetradecanoyl-phorbol 13-acetate (TPA), vasopressin, and angiotensin II elicited substantial increases in the phosphorylation of the alpha-subunit of the inhibitory G protein of adenylate cyclase (alpha Gi-2). These agonist-induced phosphorylations of alpha Gi-2 were associated with loss of Gi function as assessed by the ability of low concentrations of guanylyl 5'-[beta,gamma imido]triphosphate (p[NH]ppG) to inhibit forskolin-stimulated adenylate cyclase activity. Hepatocytes from obese Zucker rats displayed a resistance to both agonist-induced phosphorylation of alpha Gi-2 and to p[NH]ppG-mediated inhibition of adenylate cyclase. The basal level of alpha Gi-2 phosphorylation in hepatocytes from obese Zucker rats was considerably greater at 1.06 +/- 0.09 mol phosphate/mol alpha Gi-2 than in hepatocytes from lean animals which gave 0.54 +/- 0.09 mol phosphate/mol alpha Gi-2. Incubation with TPA (10 ng/ml, 15 min) approximately doubled the level of phosphorylation of alpha Gi-2 in the hepatocytes from lean animals but had little effect on the phosphorylation of alpha Gi-2 in hepatocytes from obese animals. Incubation of hepatocytes from lean animals with ligands which lead to the phosphorylation of alpha Gi-2 abolished the ability of low concentrations of p[NH]ppG to inhibit adenylate cyclase expressed in isolated membranes. Treatment of hepatocyte plasma membranes from lean but not obese Zucker rats with pure protein kinase C led to the phosphorylation of alpha Gi-2. The resistance to protein-kinase-C-mediated phosphorylation in hepatocyte membranes from obese animals could be overcome by treatment of the membranes with alkaline phosphatase. These results indicate that the defect in guanine-nucleotide-mediated 'Gi function' seen in obese Zucker rats may be due to an inactivating phosphorylation of alpha Gi-2.     

Increased Expression of Complement Component C3 in the Plasma of Obese Zucker fa and LA/N fef Rats Compared with Their Lean Counterparts

Objectives : The objectives of this study were to determine whether there are differences in the electrophoretic profiles of plasma proteins from lean and obese rats and to identify a protein that was found to be more abundant in the plasma of obese rats. Research Methods and Procedures : Plasma proteins from lean and obese Zucker fa and LA/N/fa^frats were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The identity of a band that was differentially expressed was determined by amino acid sequencing and Western blot analysis. Results : A band migrating approximately the same distance as the 116 kDa molecular weight marker was more prominent in plasma from obese rats than in plasma of lean rats. Partial sequencing of the peptide revealed that 17 of the first 18 amino acids at the amino terminus were identical with the corresponding residues in the α-chain of complement component C3. Western blot analysis confirmed the identity of the peptide as complement component C3. Complement C3 activity was measured using a hemolytic assay to determine whether there was a corresponding increase in the biological activity of this component in the serum of obese rats. Serum from obese rats was found to have 1.8 times as much complement component C3 activity as serum from lean rats. Discussion : Elevated levels of complement C3 in genetically obese rats may be relevant because increased amounts of C3 could serve as a reservoir from which increased amounts of acylation stimulating protein, a cleavage product of complement C3, could be produced.     

Hepatic Oxidative Stress,Genotoxicity and Vascular Dysfunction in Lean or Obese Zucker Rats

Metabolic syndrome is associated with increased risk of cardiovascular disease, which could be related to oxidative stress. Here, we investigated the associations between hepatic oxidative stress and vascular function in pressurized mesenteric arteries from lean and obese Zucker rats at 14, 24 and 37 weeks of age. Obese Zucker rats had more hepatic fat accumulation than their lean counterparts. Nevertheless, the obese rats had unaltered age-related level of hepatic oxidatively damaged DNA in terms of formamidopyrimidine DNA glycosylase (FPG) or human oxoguanine DNA glycosylase (hOGG1) sensitive sites as measured by the comet assay. There were decreasing levels of oxidatively damaged DNA with age in the liver of lean rats, which occurred concurrently with increased expression of Ogg1. The 37 week old lean rats also had higher expression level of Hmox1 and elevated levels of DNA strand breaks in the liver. Still, both strain of rats had increased protein level of HMOX-1 in the liver at 37 weeks. The external and lumen diameters of mesenteric arteries increased with age in obese Zucker rats with no change in media cross-sectional area, indicating outward re-modelling without hypertrophy of the vascular wall. There was increased maximal response to acetylcholine-mediated endothelium-dependent vasodilatation in both strains of rats. Collectively, the results indicate that obese Zucker rats only displayed a modest mesenteric vascular dysfunction, with no increase in hepatic oxidative stress-generated DNA damage despite substantial hepatic steatosis.     

Calcitonin mRNA activity in young obese (fa/fa) Zucker rats

Alterations in both calcitonin (CT) secretion and plasma calcium were recently described in adult obese Zucker rats. We have investigated the CT biosynthetic activity of thyroid glands in 30-day-old obese Zucker rats (fa/fa), and their controls (Lean). Plasma calcium level was significantly increased (+0.6 mg/dl) in obese animals, but plasma phosphate was unchanged. Plasma CT levels measured by radioimmunoassay (RIA) were significantly decreased in fatty (0.50 +/- 0.03 vs 0.68 +/- 0.03 ng/ml in Leans; P less than 0.001), but thyroidal hormone content was not different between Lean and fatty rats (68.7 +/- 5.1 in Leans vs 60.5 +/- 3.6 ng/gland in fatty rats). mRNA was extracted from 10 thyroids, and translated in a rabbit reticulocyte lysate (NEN) in the presence of [35S]methionine. After polyacrylamide gel electrophoresis, specific immunoprecipitates were autoradiographed and quantified by integration. A 50% decrease in translatable CT mRNA was observed in fatty rats. In basal conditions, the biosynthetic activity of C cells in obese rats correlates with the secretion rate of the hormone in the face of unchanged thyroidal CT contents.     

In vitro, release of cholecystokinin from hypothalamus and frontal cortex of Sprague-Dawley, Zucker lean (Fa/-) and obese (fa/fa) rats

Cholecystokinin (CCK) has been suggested as a putative satiety factor, whose site of action is in the hypothalamus. The genetically obese (fa/fa) Zucker rat has been proposed as a model of human obesity. Though hypothalamic tissue levels of CCK did not vary between the fa/fa rat and age-matched lean littermates (25.5 +/- 5.7 vs. 27.6 +/- 5.2 pmoles/g tissue) we sought to determine if the releasability of hypothalamic and cortical CCK was the same in lean and obese rats. The in vitro superfusion paradigm was used to study the release of CCK and substance P (sP) from hypothalamus, and CCK and vasoactive intestinal polypeptide (VIP) from frontal cortex. The potassium stimulated release of CCK from obese rat hypothalamic tissue was significantly higher than from lean rat hypothalamus (3.62 +/- 0.3 vs. 1.91 +/- 0.3 fmole equivalents CCK-8/mg tissue/10 min). Similarly, sP release was exaggerated in obese rats in a parallel fashion (5.56 +/- 0.44 vs. 2.761 +/- 0.46 fmoles/mg tissue/10 min). However, the potassium stimulated release of CCK and VIP from cortical tissue was the same in all three groups of rats. The obese Zucker rat thus, may have an anomalous release of CCK and sP from the hypothalamus, but not from the frontal cortex, an area not presumably associated with satiety.     

Multiple defects occur in the guanine nucleotide regulatory protein system in liver plasma membranes of obese (fa/fa) but not lean (Fa/Fa) Zucker rats: loss of functional Gi and abnormal Gs function

Hepatocyte membranes from both lean and obese Zucker rats exhibited adenylate cyclase activity that could be stimulated by glucagon, forskolin, NaF and elevated concentrations of p[NH]ppG. In membranes from lean animals, functional Gi was detected by the ability of low concentrations of p[NH]ppG to inhibit forskolin-activated adenylate cyclase. This activity was abolished by treatment of hepatocytes with either pertussis toxin or the phorbol ester TPA, prior to making membranes for assay of adenylate cyclase activity. In hepatocyte membranes from obese animals no functional Gi activity was detected. Quantitative immunoblotting, using an antibody able to detect the alpha subunit of Gi, showed that hepatocyte plasma membranes from both lean and obese Zucker rats had similar amounts of Gi-alpha subunit. This was 6.2 pmol/mg plasma membrane for lean and 6.5 pmol/mg plasma membrane for obese animals. Using thiol pre-activated pertussis toxin and [32P]-NAD+, similar degrees of labelling of the 40 kDa alpha subunit of Gi were found using plasma membranes of both lean and obese Zucker rats. We suggest that liver plasma membranes from obese Zucker rats express an inactive Gi alpha subunit. Thus lesions in liver Gi functioning are seen in insulin-resistant obese rats and in alloxan- and streptozotocin-induced diabetic rats which also show resistance as regards the acute actions of insulin. Liver plasma membranes of obese animals also showed an impairment in the coupling of glucagon receptors to Gs-controlled adenylate cyclase, with the Kd values for activation by glucagon being 17.3 and 126 nM for lean and obese animals respectively. Membranes from obese animals also showed a reduced ability for high concentration of p[NH]ppG to activate adenylate cyclase. The use of [32P]-NAD+ and thiol-preactivated cholera toxin to label the 43 kDa and 52 kDa forms of the alpha-subunit of Gs showed that a reduced labelling occurred using liver plasma membranes from obese animals. It is suggested that abnormalities in the levels of expression of primarily the 52 kDa form of alpha-Gs may give rise to the abnormal coupling between glucagon receptors and adenylate cyclase in liver membranes from obese (fa/fa) Zucker rats.     

Normal levels of serum corticosterone and hepatic glucocorticoid receptors in obese (fa/fa) rats

In an attempt to understand the hyper-responsiveness to glucocorticoids that is characteristic of genetically obese fa/fa rats, we have measured the levels of free corticosterone in serum from lean and obese rats as well as the number of cytosolic and "nuclear" binding sites in livers of these rats. Both the lean and obese rats had similar amounts of free corticosterone available for biological activity at 4 weeks and 10 weeks of age. Measurement of glucocorticoid binding to hepatic glucocorticoid receptors failed to show any differences between genotypes leading to the suggestion that the abnormal glucocorticoid response in obese rats may be due either to post-receptor defects or to a permissive action of the steroid in the expression of the fa/fa genotype.     

Molecules Implicated in Glucose Homeostasis are Differentially Expressed in the Trachea of Lean and Obese Zucker Rats

Recent studies indicate that the processes mediated by the (T1R2/T1R3) glucose/sugar receptor of gustatory cells in the tongue, and hormones like leptin and ghrelin contribute to the regulation of glucose homeostasis. Altered plasma levels of leptin and ghrelin are associated with obesity both in humans and rodents. In the present study, we evaluated the ultrastructure of the mucosa, and the expression of molecules implicated in the regulation of glucose homeostasis (GLUT2, SGLT1, T1R3, ghrelin and its receptor) in the trachea of an animal model of obesity (Zucker rats). We found that the tracheal epithelium of obese animals was characterized by the presence of poorly differentiated cells. Ciliated and secretory cells were the cell lineages with greatest loss of differentiation. Severe epithelial alterations were associated with marked deposit of extracellular matrix in the lamina propria. The expression pattern of GLUT2 and SGLT1 glucose transporters was similar in the trachea of both the Zucker rat genotypes, whereas that of T1R3 was reduced in ciliated cells of obese rats. A different immunolocalization for ghrelin was also found in the trachea of obese rats. In conclusion, the tracheal morphological alterations in obese animals seem to compromise the expression of molecules involved in the homeostasis of glucose.Key words: Obesity, ultrastructure, ghrelin, ghrelin receptor, sweet receptor, immunohistochemistry     

The fate of 14C derived from radioactively labelled dietary precursors in young rats of the Zucker strain (Fa/- and fa/fa).

The metabolic fate of 14C derived from radioactively labelled dietary precursors was determined in immature (18- and 25-day-old) lean and obese Zucker rats. This included measurement of 14C incorporated into body lipid, non-essential amino acids and expired CO2. Before weaning (18 days) there was no phenotypic difference between the fates of [14C]palmitate and [14C]-glucose. However, after weaning (25 days) all the precursors studied exhibited an increase in the fraction incorporated into lipid in the obese rat as compared with the lean animal. This was reflected in the fate of acetyl-CoA in the tricarboxylic acid cycle. There was little phenotypic difference in the fraction of leucine or valine catabolized. The results presented here suggest that the high rate of lipogenesis found in the obese rat is supported by carbon from all the dietary precursors studied. It is also argued that the decreased protein deposition found in the obese rat is not caused by the high rate of lipogenesis removing precursors for protein synthesis, as has been suggested elsewhere [Cleary, Vasselli & Greenwood (1980) Am. J. Physiol. 238, E284-E292].     

Identification of Biochemical Defects in Pancreatic Islets of fa/fa Rats: A Developmental Study

KIBENGE, MOLLY T AND CATHERINE B CHAN. Identification of biochemical defects in pancreatic islets of fa/fa rats: a developmental study. Obes Res. 1995;3:171–178. Adult obese (fa/fa) Zucker rats hypersecrete insulin in response to glucose and other secretagogues. Functional changes in islet ot2-adrenoceptors (8) and glycolytic regulation (9) have been reported. In this study, the development of these biochemical lesions in islets isolated from suckling (3 week old) and weanling (5 week old) lean and fa/fa rats was investigated and compared to results in adult animals. Glucose (15 mM)-induced insulin secretion was inhibited by mannoheptulose (MH) in lean (n=8) but not fa/fa (n=10) adult rats, indicating loss of sensitivity of glucokinase to competitive inhibition. Sensitivity to MH was somewhat reduced in the islets of 3- and 5-week-old fa/fa (n=7 and 12) compared to lean (n=15 and 9) rats, requiring 30–100 fold higher concentrations to achieve significant inhibition. At 3 weeks of age fa/fa rats did not differ from lean controls in either islet insulin content or body weight, but both parameters were increased in fa/fa rats by 5 weeks. The presence of altered α₂-adrenoceptor function in fa/fa rats could not be confirmed in this study. Unlike the previous report, prazosin did not antagonize α₂-agonist mediated inhibition of insulin secretion. The presence of defective regulation of the glycolytic pathway by mannoheptulose in suckling and weanling rats may contribute to development of hyperinsulinemia in fa/fa rats.     

Nonreceptor-mediated responses of adenylate cyclase in membranes from liver, muscle, and white and brown adipose tissue of obese (fa/fa) and lean (Fa/) Zucker rats

Adenylate cyclase activity was determined in membranes of liver, muscle, white adipose tissue, and brown adipose tissue (BAT) of lean (Fa/) and obese (fa/fa) Zucker rats. Responses were monitored following beta-adrenergic receptor stimulation and addition of GTP, GTP gamma S, or forskolin. beta-Adrenergic responses in liver, white adipose tissue, and BAT were lower in obese than in lean animals. No such difference was observed in muscle membranes. Production of cAMP after addition of guanine nucleotides was lower in liver and white adipose tissue membranes from obese rats compared with their lean littermates. Synthesis of cAMP in muscle membranes of obese animals after addition of GTP was either not different, or slightly higher, than that observed in muscle membranes from lean animals. Furthermore, production of cAMP after forskolin addition to muscle membranes of obese rats was significantly higher than that observed from lean rats under the same conditions. Interestingly, BAT membranes of obese rats were significantly more sensitive to guanine nucleotide activation than those of lean animals. The results confirm recent findings indicating inferior function of G proteins in liver plasma membranes of obese Zucker rats, and extend this observation to adipose tissue. The present results further suggest that the "nonreceptor" components (e.g., G proteins) responsible for the activation of adenylate cyclase in BAT membranes of obese rats are more responsive to stimulation than those of lean animals. Such sensitivity may be related to and perhaps compensate for the reduced thermogenic activity in the obese Zucker rat during the development of obesity.     

Adipose-tissue lipoprotein lipase activity and cellularity in the genetically obese Zucker rat (fa/fa) (Short Communication)

The lipoprotein lipase activity per adipocyte was increased in the genetically obese rat (fa/fa). However, there was no difference between obese and lean animals when the enzyme activities were related to adipocyte surface area. The possible implications of the findings are discussed.     

Remarkable features of ovarian morphology and reproductive hormones in insulin-resistant Zucker fatty (fa/fa) rats

Background

Zucker fatty (fa/fa) rats are a well-understood model of obesity and hyperinsulinemia. It is now thought that obesity/hyperinsulinemia is an important cause of endocrinological abnormality, but to date there have been no reports on the changes in ovarian morphology or the ovarian androgen profile in rat models of obesity and insulin resistance.

Methods

In this study we investigated the effects of obesity and hyperinsulinemia on ovarian morphology and the hormone profile in insulin-resistant Zucker fatty rats (5, 8, 12 and 16 weeks of age, n = 6-7).

Results

Ovaries from 5-week-old fatty rats had significantly greater total and atretic follicle numbers, and higher atretic-to-total follicle ratios than those from lean rats. Ovaries from 12- and 16-week-old fatty rats showed interstitial cell hyperplasia and numerous cysts with features of advanced follicular atresia. In addition, serum testosterone and androstenedione levels significantly declined in fatty rats from age 8 to 16 weeks, so that fatty rats showed significantly lower levels of serum testosterone (12 and 16 weeks) and androstenedione (all weeks) than lean rats. This may reflect a reduction of androgen synthesis during follicular atresia. Serum adiponectin levels were high in immature fatty rats, and although the levels declined significantly as they matured, it remained significantly higher in fatty rats than in lean rats. On the other hand, levels of ovarian adiponectin and its receptors were significantly lower in mature fatty rats than in lean mature rats or immature fatty rats.

Conclusions

Our findings indicate that ovarian morphology and hormone profiles are significantly altered by the continuous insulin resistance in Zucker fatty rats. Simultaneously, abrupt reductions in serum and ovarian adiponectin also likely contribute to the infertility seen in fatty rats.     

Dietary Fat Is Shunted Away from Oxidation,Toward Storage in Obese Zucker Rats

BESSESEN, DANIEL H, CONNIE L RUPP AND ROBERT H ECKEL. Dietary fat is shunted away from oxidation, toward storage in obese zucker rats. Obes Res. 1995;3:179–189. Previous measurements of lipoprotein lipase (LPL) activity in adipose tissue (ATLPL) of lean and obese Zucker rats have consistently documented increased activity in obese rats relative to lean. Since LPL is considered to be rate limiting for the delivery of triglyceride fatty acids (TGFA) to muscle and adipose tissue, these data have been used to suggest that the metabolic partitioning of TGFA favors storage over oxidation in obese rats. To document the partitioning of TGFA directly, the fate of ¹⁴C labeled oleic acid (42nmols) was fed to lean, obese, and obese Zucker rats fed a hypocaloric diet designed to chronically reduce weight 25% below that of obese controls (reduced-obese). The amount of ¹⁴C recovered in CO₂ over 6 hours following ingestion was significantly less in obese rats compared to lean (0.45 ± 0.06 vs. 0.88 ± 0.09nmols, p=.0004) and less still in the reduced obese group (0.34 ± 0.06nmols p=.00003). Six hours after ingestion, the quantity of label found in adipose tissue was significantly greater in the obese rats compared to lean (14.51 ± 1.92 vs. 1.38 ± 0.29nmols p<.00001), but was intermediate in the reduced-obese group (9.23 ± 0.98nmols p=.0003). At 2.2 hours there was significantly more label in skeletal muscle of lean rats compared to either obese or reduced-obese (2.33 ± 0.24; 1.35 ± 0.04nmols p=.01; 1.41 ± 0.27nm p=.02). However, at 6 hours these differences between groups were no longer present. These findings Indicate that dietary fat is shunted away from oxidation toward storage in obese Zucker rats. Additionally it appears that there may be a relative block in the oxidation of TGFA that is taken up by skeletal muscle in obese rats. Finally the relative normalization of this partitioning defect in reduced-obese rats is at variance with what was suggested by previous measurements of tissue specific levels of LPL, and suggests an enhanced recirculation of fatty acids from adipose tissue to muscle in reduced-obese rats. This could occur through increased delivery of non-esterified fatty acids (NEFA) to muscle as a result of an increase in net lipolysis.     

Copper absorption,endogenous excretion,and distribution in Sprague-Dawley and lean (Fa/Fa) Zucker rats

We previously observed a rapid reduction in plasma ceruloplasmin activity in lean Zucker (Fa/Fa) rats fed a marginal copper (Cu)-deficient diet compared to similarly fed obese Zucker (fa/fa) and lean Sprague-Dawley rats. In an effort to understand the mechanisms underlying this response, we utilized the isotope dilution method to investigate the absorption and excretion of Cu in lean Zucker rats fed control and marginal Cu diets. Sprague-Dawley (SD) and homozygous lean Zucker rats were fed either a Cu-adequate (Cont; 7.5 μg Cu/g diet) or a low Cu (Low; 1.1 μg Cu/g diet) casein-based diet for 23 d. Two weeks following initiation of the dietary treatment, each rat was injected intramuscularly (im) with 11.2 μCi of⁶⁷Cu. Urine and feces were collected daily. On the 9th d following isotope injection, rats were killed and tissues collected. Significant dietary effects were observed in the relative absorption and endogenous fecal excretion of⁶⁷Cu. The tissue distributions of nonisotopic Cu and⁶⁷Cu activity were also different between dietary treatments. Tissues from rats fed the low-Cu diet typically had high concentrations of⁶⁷Cu and low concentrations of nonisotopic Cu compared to controls. An increase in relative⁶⁷Cu absorption was evident for rats fed the low-Cu diet (57.2 and 39.3%, for SD Low, Zucker Low, respectively, and 17.9, and 28.5% SD Cont and Zucker Cont, respectively). Rats fed the low-Cu diet also had reductions in endogenous fecal excretion of⁶⁷Cu compared to their respective controls. Although strain effects were not evident for either percent Cu absorption or endogenous fecal Cu excretion, the relative adaptive changes appeared more marked for the Sprague-Dawley rats compared to the lean Zucker rats.