The Male Obese Wistar Diabetic Fatty Rat Is a New Model of Extreme Insulin Resistance

The male obese Wistar Diabetic Fatty (WDF) rat is a genetic model of obesity and non-insulin dependent diabetes (NIDDM). The obese Zucker rat shares the same gene for obesity on a different genetic background but is not diabetic. This study evaluated the degree of insulin resistance in both obese strains by examining the binding and post binding effects of muscle insulin receptors in obese, rats exhibiting hyperinsulinemia and/or hyperglycemia. Insulin receptor binding and affinity and tyrosine kinase activity were measured in skeletal muscle from male WDF fa/fa (obese) and Fa/? (lean) and Zucker fa/fa (obese) and Fa/Fa (homozygous lean) rats. Rats were fed a high sucrose (68% of total Kcal) or Purina stock diet for 14 weeks. At 27 weeks of age, adipose depots were removed for adipose cellularity analysis and the biceps femoris muscle was removed for measurement of insulin binding and insulin-stimulated receptor kinase activity. Plasma glucose (13.9 vs. 8.4 mM) and insulin levels (14,754 vs. 7440 pmoI/L) were significantly higher in WDF obese than in Zucker obese rats. Insulin receptor number and affinity and TK activity were unaffected by diet. Insulin receptor number was significantly reduced in obese WDF rats (2.778 ± 0.617 pmol/mg protein), compared to obese Zucker rats (4.441 ± 0.913 pmol/mg potein). Both obese strains exhibited down regulation of the insulin receptor compared to their lean controls. Maximal tyrosine kinase (TK) activity was significantly reduced in obese WDF rats (505 ± 82 fmol/min/mg protein) compared to obese Zucker rats (1907 ± 610 fmol/min/mg protein). Only obese WDF rats displayed a decrease in TK activity per receptor. These observations establish the obese WDF rat as an excellent model for exploring mechanisms of extreme insulin resistance, particularly post-receptor tyrosine kinase-associated defects, in non-insulin dependent diabetes.     

Characteristics of the Obesity Syndrome in Zucker-Brown Norway (ZBN) Hybrid Rats

The existence of a restriction fragment length polymorphism (RFLP) closely linked to the fatty locus between the Zucker (Z) and Brown Norway (BN) rat strains allows evaluation of early effects of the fatty (fa) gene using offspring of back-crosses (N₂) between F₁ females and Zucker obese males. We examined several metabolic characteristics of N₂ animals to determine if these hybrid animals exhibited similar characteristics of the obese syndrome to those of Zucker rats. Females from crosses of obese male Zucker (fd/fa) and lean female BN (+/+) rats were back-crossed to their sires, resulting in twelve N₂ litters. At 9 weeks of age, liver, spleen, interscapular brown fat (IBAT), and gonadal, retroperitoneal (RP), and inguinal fat depots were removed and weighed. Samples of the RP depot were analyzed for cell size and number. Obese N₂ rats were hyperphagic, with body weights in the range of those of obese Zucker rats. Obese N₂ rats were also hyperinsulinemic [mean f SEM, pU/ml: females, 7.9 ± 0.6 vs. 82.1 f 8.4 (lean vs. obese); males, 10.5 ± 1.6 vs. 128.5 ± 13.4 (lean vs. obese)] and mildly hyperglycemic [mean ± SEM, mg/dl: females, 104.1 ± 2.0 vs. 139.0 ± 14.7 (lean vs. obese); males, 100.9 ± 2.6 vs. 132.0 ± 2.8 (lean vs. obese) p ≤ 0.05]. White fat depots in obese tats were 3 to 7 times heavier than those in lean rats; adipocyte numbers in RP depots were 50% greater in obese than in lean rats; and cell size was more than 3 times larger. IBAT, liver, and spleen were also heavier in obese vs. lean rats, while tail lengths were shorter. Percent lean carcass mass and % carcass protein were about 30% greater in lean vs. obese rats, while % carcass fat in obese rats was 5 times greater than that of lean rats. Thus, phenotypic expression of the fa gene in ZBN hybrid animals, with approximately 25% of their genetic background coming from the BN strain, appears to be similar to that in Zucker rats. Given the similarity of phenotypic expression of the fa gene between the Zucker strain and ZBN hybrids, it is plausible to consider using ZBN hybrids for studies of early manifestations of fa gene action prior to onset of detectable obesity .     

Regional Fat Pad Growth and Cellularity in Obese Zucker Rats: Modulation by Caloric Restriction

Objective : To investigate, in young obese male Zucker rats, the effects of chronic food restriction and subsequent refeeding on: 1) parameters of nonadipose and adipose growth, 2) regional adipose depot cellularity [fat cell volume (FCV) and number], and 3) circulating leptin levels. Research Methods and Procedures : Obese (fa/fa) and lean (Fa/?) male Zucker rats were studied from age 5 to 19 weeks. After baseline food intake monitoring, 10 obese rats were subjected to 58 days of marked caloric restriction from ad libitum levels [obese‐restricted (OR)], followed by a return to ad libitum feeding for 22 days. Ten lean control rats and 10 obese control rats were fed ad libitum for the entire experiment. All rats were fed using a computer‐driven automated feeding system designed to mimic natural eating patterns. Results : After food restriction, OR rats weighed significantly less than did lean and obese rats and showed a significant diminution in body and adipose growth as compared with obese rats. Relative adiposity was not different between obese and OR rats and was significantly higher than that of lean rats. The limitation in growth of the adipose tissue mass in OR rats was due mostly to suppression of fat cell proliferation because the mean FCV in each of the four depots was not affected. Serum leptin levels of OR and obese rats were not different from each other but were significantly higher than those of lean rats. Discussion : Marked caloric restriction affects obese male Zucker rats in a manner different from that of nongenetic rodent models (i.e., Wistar rats). In comparison with the response to caloric deprivation of Wistar rats, these calorically restricted obese male Zucker rats appeared to defend their relative adiposity and mean FCV at the expense of fat cell number. These findings indicate that genetic and/or tissue‐specific controls override the general consequences of food restriction in this genetic model of obesity.     

Gastrin release in obese Zucker rats

In this study, gastrin release in the obese Zucker rat was investigated by in vivo and in vitro experiments. Obese rats exhibited normal plasma gastrin levels at 3 weeks (preobese), were moderately hypergastrinemic at 3 months and severely hypergastrinemic at 5 months, compared to lean littermates. Following oral peptone, plasma gastrin levels doubled in both lean and obese rats. Basal and vagally stimulated gastrin release from perfused stomachs was greater in obese compared to lean rats and atropine had no effect on basal gastrin release in either group. Basal somatostatin release from the perfused stomach was found not to differ in both groups of animals. Morphological studies revealed an increase in the number of gastrin-containing G-cells in adult obese rats compared to lean littermates, but not in 3-week-old pups compared to lean littermates, indicating a strong correlation between cell number and plasma gastrin levels. These data indicate that the obese Zucker rat exhibits fasting hypergastrinemia in vivo, a condition which appears after weaning and increases in severity with age. Gastrin hypersecretion persists from the vascularly perfused stomach preparation. The basal hypergastrinemia of the obese Zucker rat is independent of a hyperactive postganglionic cholinergic drive but is associated with and probably causally related to an increase in antral G-cell numbers.     

Altered Kidney CYP2C and Cyclooxygenase‐2 Levels Are Associated with Obesity‐Related Albuminuria

Objective: To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity‐related hypertension and diabetes. Research Methods and Procedures: Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured. Results: Body weight and blood glucose averaged 432 ± 20 grams and 105 ± 5 mg/dl, respectively, in obese Zucker rats as compared with 320 ± 8 grams and 91 ± 5 mg/dl, respectively, in age‐matched 10‐ to 12‐week‐old lean Zucker rats. Renal microvascular CYP4A and COX‐2 protein levels were increased 2.3‐ and 17.0‐fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0‐fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B₂ was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 ± 1.8 vs. 13.4 ± 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age. Discussion: These results suggest that increased CYP4A and COX‐2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity‐related hypertension and type 2 diabetes.     

Pepsin Egg White Hydrolysate Ameliorates Obesity-Related Oxidative Stress,Inflammation and Steatosis in Zucker Fatty Rats

The aim of this work was to evaluate the effect of the administration of egg white hydrolysates on obesity-related disorders, with a focus on lipid metabolism, inflammation and oxidative stress, in Zucker fatty rats. Obese Zucker rats received water, pepsin egg white hydrolysate (750 mg/kg/day) or Rhizopus aminopeptidase egg white hydrolysate (750 mg/kg/day) for 12 weeks. Lean Zucker rats received water. Body weight, solid and liquid intakes were weekly measured. At the end of the study, urine, faeces, different organs and blood samples were collected. The consumption of egg white hydrolysed with pepsin significantly decreased the epididymal adipose tissue, improved hepatic steatosis, and lowered plasmatic concentration of free fatty acids in the obese animals. It also decreased plasma levels of tumor necrosis factor-alpha and reduced oxidative stress. Pepsin egg white hydrolysate could be used as a tool to improve obesity-related complications.     

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.     

Changes of Islet Size and Islet Size Distribution Resulting from Protein-Malnutrition in Lean (Fa/Fa) and Obese (fa/fa) Zucker Rats

TSE, ELIZABETH O, FRANCINE M GREGOIRE, BRIGITTE REUSENS, CLAUDE REMACLE, JOSEPH J HOET, PATRICIA R JOHNSON, JUDITH S STERN. Changes of islet size and islet size distribution resulting from protein malnutrition in lean (Fa/Fa) and obese (fa/fa) Zucker rats. Potential alterations in islet size and islet size distribution resulting from protein malnutrition were studied in lean (Fa/Fa) and obese (fa/fa) Zucker rats. The purpose was to investigate whether the distribution of enlarged islets in obese rats was altered by low-protein feeding. Four-week-old, male, lean and obese Zucker rats were fed either a diet containing 20% (w/w) protein (control diet) or a diet containing 5% (w/w) protein (low-protein diet) for 3 weeks. Pancreata were dissected at autopsy and immunostained for insulin. Islet size and distribution were determined by morphometric analysis. Body-weight gain, food intake, and serum insulin and glucose were also measured. After 3 weeks on the diets, serum insulin was significantly lower in both lean (-75%) and obese (-54%) rats fed low protein compared with that in controls. However, obese rats were still hyperinsulinemic compared with lean rats. Protein malnutrition resulted in a shift in distribution of islets to smaller size both in lean and in obese rats, with an increase in the population of small islets (100 μm²) and a decrease in the population of large islets (>20,000 μ;m²). In lean and obese rats fed low protein, β-cell weight was significantly lower, B cell volume fraction tended to decrease, and islet number per section area was significantly elevated when compared with controls. Taken together, these results show that protein deficiency alters the endocrine pancreas in both lean and obese Zucker rats. Although the decrease in islet size and the shift in distribution to smaller islets most likely contribute to the decrease in serum insulin concentration, these changes appear insufficient to normalize hyperinsulinemia in the obese Zucker rat.     

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

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

Alpha 1- and beta-adrenergic receptors in brown adipose tissue of lean (Fa/?) and obese (fa/fa) Zucker rats. Effects of cold-acclimation,sucrose feeding and adrenalectomy.

1. The populations of alpha 1- and beta-adrenergic receptors in brown adipose tissue (BAT) of genetically obese Zucker rats (fa/fa) were studied with [3H]prazosin and [3H]CGP-12177 respectively. 2. The density of alpha 1-adrenergic receptors in BAT was significantly lower in obese than in lean Zucker rats, both at 2-4 months of age and at 6 weeks of age. The density of beta-adrenergic receptors was identical in BAT of lean and obese 6-week-old Zucker rats. 3. Cold-acclimation increased the alpha 1-receptor density significantly in BAT of both lean and obese Zucker rats, and the number of beta-receptors was also somewhat increased. 4. Sucrose feeding did not affect the density of alpha 1-receptors in BAT of lean or obese Zucker rats, but it increased beta-receptor density. 5. Adrenalectomy restored the density of alpha 1-adrenergic receptors in BAT of obese Zucker rats to the value observed in lean rats. 6. It is concluded that there is a direct correlation between alpha 1-receptor density and tissue recruitment, and that alpha 1-receptor density is thus positively correlated with sympathetic activity. beta-Receptor density is apparently better correlated with feeding conditions.     

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

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

Augmented Insulinotropic Action of Arachidonic Acid through the Lipoxygenase Pathway in the Obese Zucker Rat

Objective: The metabolism of arachidonic acid (AA) has been shown to be altered in severe insulin resistance that is present in obese (fa/fa) Zucker rats. We examined the effects and mechanism of action of AA on basal and glucose‐stimulated insulin secretion in pancreatic islets isolated from obese (fa/fa) Zucker rats and their homozygous lean (Fa/Fa) littermates. Research Methods and Procedures: Islets were isolated from 10‐ to 12‐week‐old rats and incubated for 45 minutes in glucose concentrations ranging from 3.3 to 16.7 mM with or without inhibitors of the cyclooxygenase or lipoxygenase pathways. Medium insulin concentrations were measured by radioimmunoassay, and islet production of the 12‐lipoxygenase metabolite, 12‐hydroxyeicosatetraenoic acid (12‐HETE), was measured by enzyme immunoassay. Results: In islets from lean animals, AA stimulated insulin secretion at submaximally stimulatory glucose levels (< 11.1 mM) but not at 16.7 mM glucose. In contrast, in islets derived from obese rats, AA potentiated insulin secretion at all glucose concentrations. AA‐induced insulin secretion was augmented in islets from obese compared with lean rats at high concentrations of AA in the presence of 3.3 mM glucose. Furthermore, the inhibitor of 12‐lipoxygenase, esculetin (0.5 μM), inhibited AA‐stimulated insulin secretion in islets from obese but not lean rats. Finally, the islet production of the 12‐HETE was markedly enhanced in islets from obese rats, both in response to 16.7 mM glucose and to AA. Discussion: The insulin secretory response to AA is augmented in islets from obese Zucker rats by a mechanism related to enhanced activity of the 12‐lipoxygenase pathway. Therefore, augmented action of AA may be a mechanism underlying the adaptation of insulin secretion to the increased demand caused by insulin resistance in these animals.     

Genotype and diet effects in lean and obese Zucker rats fed either safflower or coconut oil diets

Previously we reported that suckling lean heterozygous (FA/fa) Zucker rats had a number of adipose tissue measurements intermediate between those of homozygous lean (FA/FA) and obese (fa/fa) rats. However, in young adult male rats maintained on a low-fat diet, these differences were no longer apparent (i.e., values for the two lean genotypes were similar). In the present study we determined whether the heterozygous effect of the "fa" gene was dependent on the consumption of a high-fat diet. Mother rats were fed high-fat diets containing either safflower (SOD) or coconut (COD) oil throughout mating and lactation. Homozygous lean male and female rats were bred, as well as obese male and lean heterozygous female rats. Suckling rats were studied at 17 days of age. Additional male rats were maintained on the same diet as their mothers until 11-12 weeks of age. Obese suckling rats had higher body weights than lean pups. Inguinal fat pad weights and pad-to-body weight ratios followed the pattern of obese greater than lean (FA/fa) pups that were greater than lean (FA/FA) pups. A similar relationship was found for adipose tissue lipogenic enzyme activities. At 11-12 weeks of age, measurements followed the general pattern of obese rats having greater values than lean rats (i.e., FA/fa = FA/FA). SOD-fa/fa rats had higher hepatic lipogenic enzyme activities than COD-fa/fa rats. In addition, SOD rats had higher fat cell numbers than COD rats. These results suggest that specific fatty acids can alter adipocyte proliferation and/or differentiation in vivo. In addition, there appears to be a defect of fatty acid regulation in livers of genetically obese rats. The heterozygous effect of the "fa" gene in suckling Zucker rats was confirmed. However, high-fat feeding did not result in a heterozygous effect in young adult lean male rats. We will next evaluate the role of sex on this effect.     

Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats

Ghrelin is a new orexigenic and adipogenic peptide primarily produced by the stomach and the hypothalamus. In the present experiment, we determined the circulating ghrelin levels in 60-week old fa/fa Zucker rats with a well-established obesity (n = 12) and in their lean (FA/FA) counterparts (n = 12). We also tested the feeding response of both groups to intra-peritoneal (I.P.) injection of ghrelin agonist and antagonist. Obese rats ate significantly more than the lean rats (21.7 +/- 1.1 vs. 18.3 +/- 0.3 g/day; p < 0.01). Their plasma ghrelin concentration was 35% higher than that in the lean homozygous rats (p < 0.025). GHRP-6 (1 mg/kg I.P, a GHS-R agonist) stimulated food intake in lean but not in obese rats (p < 0.01), whereas [D-Lys)]-GHRP-6 (12 mg/kg I.P., a GHS-R antagonist) decreased food intake in both groups (p < 0.0001). These results indicate that the obese Zucker rat is characterized by an increase in plasma ghrelin concentrations and by an attenuated response to a GHS-R agonist. They support a role for ghrelin in the development of obesity in the absence of leptin signaling.     

Integrin expression and H2O2 production in circulating and splenic leukocytes of obese rats

Objective: Obesity is associated with oxidative stress and inflammation. We hypothesized that the pro‐inflammatory state in obesity may result in spontaneous activation and, hence, increased generation of reactive oxygen species (ROS) and integrin expression in the circulating leukocytes. Methods: Flow cytometry was used to determine integrin expression (immunostaining) as well as superoxide and hydrogen peroxide productions (fluorescent probes) in the peripheral blood and splenic leukocyte of 24‐week‐old male obese normotensive and not‐as‐yet diabetic Zucker rats (n = 6) and their lean counterparts (n = 6). Results: Obese rats had hyperlipidemia and normal arterial pressure, plasma glucose, and creatinine concentrations. Nevertheless, obese rats exhibited increased hydrogen peroxide production by circulating and splenic CD4+ and CD8+ T lymphocytes and by splenic macrophages. This was accompanied by up‐regulations of CD11a expression in the peripheral blood and splenic CD4+ T cells, CD11b in circulating macrophages, and CD11a and CD18 in circulating granulocytes. Conclusion: The study revealed direct evidence of spontaneous leukocyte activation and increased ROS generation by T lymphocytes and monocytes in the peripheral blood of obese Zucker rats before the development of diabetes or hypertension. These findings illustrate the link between obesity, oxidative stress, and inflammation.     

Positive Modulation of the Adipoconversion of Adipoblasts Derived from Genetically Obese Rats by Sodium Butyrate

Using a new serum-free primary culture system, we have previously reported genotypic differences between adipoblasts derived from the epididymal adipose deposit of lean and obese 8-week-old Zucker and Wistar Diabetic Fatty (WDF) rats (15). In these strictly controlled culture conditions, obese-derived adipoblasts expressed low levels of the late markers of differentiation (lipid accumulation, GPDH). In order to further characterize obese-derived adipoblasts and analyze the critical relationship between growth and differentiation, growth arrest was induced in leanand obese-derived cultures using sodium butyrate treatment. Addition of 2.5 mM sodium butyrate to the serum-free medium from day 1 reduced markedly the growth of lean as well as obese-derived cells. Adipoconversion of lean-derived adipoblasts was not altered, similar levels of LPL and GPDH activities being obtained in control and butyrate-treated groups. By contrast, a marked increase in both activities was observed in obese-derived cultures, restoring the level of both markers of differentiation to the lean level. Similar results were obtained with adipoblasts derived from subcutaneous inguinal (ING) fat pad of obese Zucker as well as adipoblasts derived from ING and EPI fat deposits from obese WDF rats. Taken together, these results suggest that adipose deposits of these genetically obese rats contain a specific adipoblast population which differs from lean-derived adipoblasts in respect to its adipoconversion capacity andlor its stage of commitment to differentiation.     

Comparison of Tissue Metal Concentrations in Zucker Lean, Zucker Obese, and Zucker Diabetic Fatty Rats and the Effects of Chromium Supplementation on Tissue Metal Concentrations

Diabetes results in several metabolic changes, including alterations in the transport, distribution, excretion, and accumulation of metals. While changes have been examined in several rat models of insulin resistance and diabetes, the metal ion concentrations in the tissues of Zucker lean, Zucker obese (an insulin resistance and early stage diabetes model), and Zucker diabetic fatty (ZDF, a type 2 diabetes model) have not previously been examined in detail. The concentration of Cu, Zn, Fe, Mg, and Ca were examined in the liver, kidney, heart and spleen, and Cr concentration in the liver and kidney of these rats were examined. Zucker obese rats have a reduction in the concentration of Cu, Zn, Fe, Mg in the liver compared to ZDF and/or lean Zucker rats, presumably as a result of the increased fat content of the liver of the obese rats. ZDF rats have increased concentrations of kidney Cu compared to the lean rats, while kidney Ca concentrations are increased in the Zucker obese rats. Spleen Fe concentrations are decreased in Zucker obese rats compared to the lean rats. No effects on metal concentrations in the heart were observed between the lean, obese, and ZDF rats, and no effects on Cr concentrations were identified. Cr(III) complexes have previously been shown to have beneficial effects on the signs of insulin resistance in Zucker obese and ZDF rats. The effects of daily gavage administration of chromium picolinate ([Cr(pic)₃]) (1 mg?Cr/kg body mass), CrCl₃ (1 mg?Cr/kg body mass), and Cr3 ([Cr₃O(propionate)₆(H₂O)₃]⁺) (33 μg and 1 mg?Cr/kg body mass) on metal concentrations in these tissues were examined. Treatment with CrCl₃ and Cr3, but not [Cr(pic)₃], at 1 mg?Cr/kg resulted in a statistically significant accumulation of Cr in the kidney of lean and obese but not ZDF rats but resulted in lowering the elevated levels of kidney Cu in ZDF rats, suggesting a beneficial effect on this symptom of type 2 diabetes.