Sympatho-adrenal activity and metabolic responses in fasted rats--the role of interscapular brown adipose tissue

1. Sympatho-adrenal (SA) and metabolic responses to fasting were studied in sham-operated (SHAM) rats and in those with interscapular brown adipose tissue (IBAT) removed. 2. Fasting significantly increased adrenaline (A) excretion and serum free fatty acids (FFA), but decreased noradrenaline (NA) excretion and blood glucose level in SHAM rats. 3. IBAT removal did not change metabolic responses while it markedly altered the SA activity. Fasting in animals void of IBAT potentiated the activity of adrenal medulla, inhibited the FFA rise and prevented glucose reduction, which is normally observed in SHAM-fasted rats. 4. Results suggest the significance of IBAT in the regulation of the blood level of energy substrates in fasted rats and in maintaining the basal level of NA excretion.     

Effect of fasting and refeeding on the activities of monoamine oxidase and antioxidant enzymes in rat hypothalamus and brown adipose tissue

Fasting for 48 h and the same period of recovery induced by 48 h refeeding increased rat hypothalamic monoamine oxidase (MAO) activity. However, in the interscapular brown adipose tissue (IBAT), only refeeding induced a significant elevation of the enzyme activity. As far as hypothalamic antioxidative enzymes are concerned, the copper zinc superoxide dismutase (CuZnSOD) activity was decreased in refed rats only. However, in the IBAT both food deprivation and refeeding induced a significant decrease in catalase (CAT) activity. Under the influence of fasting the adrenal glands were strongly activated as judged by the increased dopamine-beta-hydroxylase (DBH) activity and decreased cholesterol concentration. Refeeding brought both parameters to control levels indicating full recovery of these glands. As expected, fasting for 48 h induced a significant decrease in serum glucose but an increase in FFA concentrations. Thus, it can be concluded that both fasting and refeeding resulted in increased activation of hypothalamic MAO, whereas CuZnSOD activity was decreased only by refeeding. However, in the IBAT only refeeding increased MAO activity whereas both fasting and refeeding decreased that of CAT. In conclusion, it may be assumed that food deprivation for 48 h and the same duration of refeeding influenced MAO and antioxidative enzymes activities in the rat hypothalamus and IBAT in a tissue specific manner.     

Effects of diet and phenotype on adipose cellularity and 5'-deiodinase activity of liver and brown adipose tissue of diabetic SHR/N-cp rats.

1. Groups of lean and obese male SHR/N-cp rats were fed isoenergetic diets containing 54% carbohydrate as cornstarch (CS) or sucrose (SU) plus other nutrients from 5 weeks of age, and measures of adiposity, thyroxine 5' deiodinase (T4-5'DI) activity, and tissue and plasma triiodothyronine (T3) content determined at 9.5 months of age. 2. Body weights (BW) of obese greater than lean, and were greater when fed the SU than CS diet in both phenotypes. Phenotype effects (obese greater than lean) were present for fat pad weights and adipose cellularity in most primary adipose tissue depots, and diet effects (SU greater than CS) were present for epididymal and retroperitoneal depots in both phenotypes. 3. Interscapular brown adipose tissue (IBAT) and IBAT:BW ratios of obese greater than lean, and diet effects (SU greater than CS) were present for lean but not obese rats. Liver T4-5'DI activity and plasma and tissue T3 of lean greater than obese, while IBAT 5'DI activity of obese greater than lean in the CS diet. 4. These results indicate that obesity occurs in the SHR/N-cp rat as the result of hypertrophy and hyperplasia of adipose tissue, and that isoenergetic substitution of simple for complex carbohydrate exaggerates fat accretion in lean but not obese rats. Moreover, the obesity occurs in spite of greater mass, cellularity, and T4-5'DI activity of IBAT, consistent with a thermogenic defect in the obese phenotype of this strain.     

Effects of acute cold exposure on rectal temperature, blood glucose and plasma free fatty acids in alloxan-diabetic rats

These experiments were carried out to study the effects of acute cold exposure (0-2 degrees C/4 hr) on rectal temperature, blood glucose and plasma free fatty acids (FFA) in alloxan-diabetic rats. Male Wistar rats weighing 170-190 g were used and diabetes was induced by i.v. alloxan injection (40 mg/kg body wt). Cold exposure produced severe hypothermia in diabetic rats. After 4 hr of cold, blood glucose of diabetic rats was reduced from 296 +/- 16 to 86 +/- 12 mg/dl (P less than 0.01), and FFA increased slightly, but was not statistically different (P greater than 0.05) from the initial value. As expected, interscapular brown adipose tissue (IBAT) and retroperitoneal and epididymal white adipose tissues were significantly lower in diabetic than in control rats. Cold exposure reduced total IBAT lipids in control but not in diabetic animals. The results of this experiment suggest that diabetic rats were unable to maintain body temperature in the cold, probably because of a failure to generate an adequate amount of heat by nonshivering thermogenesis in brown adipose tissue.     

Lesions of the hypothalamic paraventricular nucleus and norepinephrine turnover in rats

The effects of bilateral lesions of the hypothalamic paraventricular nuclei (PVN), of rats with a mean weight of 260 g body, on eating habits and body weight, as well as on sympathetic nervous system (SNS) activity in interscapular brown adipose tissue (IBAT) were investigated. In 59 of 131 Sprague-Dawley female rats, PVN lesions resulted in hyperphagia and obesity. Although lesions were considered successful when more than 50% of the PVN was destroyed histologically, such lesions were observed in 35.9% (47/131) of all lesioned rats and all of these 47 rats were obese. Therefore, in this study, these 47 rats which were confirmed histologically, were designated as "PVN-lesioned rats". Plasma insulin levels in these 47 PVN-lesioned ats were more than double those of the controls. However, no significant differences were observed between plasma glucose levels in PVN-lesioned and control groups. Norepinephrine turnover, a reliable indicator of SNS activity, in IBAT, heart and pancreas was similar in PVN-lesioned and sham-operated control animals, even under contrasting conditions of feeding (ad libitum and fasting) and temperature (22 degrees C and 4 degrees C). It is concluded that PVN lesions produce hyperphagia, obesity and hyperinsulinemia in rats with an average body weight of 260g without affecting the SNS activity in IBAT, heart or pancreas.     

Running Exercise Improves Metabolic Abnormalities and Fat Accumulation in Sucrose-Induced Insulin-Resistant Rats

NARA, MAKOTO, MASAKI TAKAHASHI, TSUGIYASU KANDA, YOUNOSUKE SHIMOMURA, ISAO KOBAYASHI. Running exercise improves metabolic abnormalities and fat accumulation in sucrose-induced insulin-resistant rats. Insulin resistance and hyperinsulinemia are observed in rats fed a high sucrose diet. Insulin resistance is thought to be related to abnormal fat distribution. We previously reported the metabolic characteristics and the fat distribution in rats with sucrose-induced insulin resistance. This study was designed to examine the effects of exercise in these rats. The rats were divided into three groups: those receiving a starch-based diet (control), those receiving a high-sucrose diet (sucrose fed), and those receiving a high-sucrose diet and wheel-running exercise (exercised). Animals were killed after 4 weeks or 12 weeks. After 4 weeks, the three groups did not differ with respect to gain in adipose tissues. The portal vein (PV) insulin concentration was significantly increased in the sucrose-fed and the exercised rats compared with the control rats. The inferior vena cava (IVC) glucose concentration and the PV free fatty acid (FFA) were significantly lower in the exercised rats than in the sucrose-fed rats. After 12 weeks, the exercised rats had significantly lower mesenteric fat (MS) and subcutaneous fat (SC) and a lower MS:SC ratio than the sucrose-fed rats. The glucose levels in IVC, PV, and FFA in PV were significantly reduced in the exercised rats as compared with the sucrose-fed rats. These findings suggest that long-term exercise improves insulin resistance by reducing the accumulation of MS as well as SC. It is also suggested that short-term exercise improves glucose metabolism without change of fat accumulation.     

Effects of dietary carbohydrate and phenotype on thyroid hormones and brown adipose tissue locularity in adult LA/N-cp rats

1. Groups of lean and corpulent LA/N-cp rats were fed isoenergetic diets containing, 54% carbohydrate as maize starch (MS) or sucrose (SU), 20% protein, 16% mixed fats, plus other essential nutrients and fiber from 1.5-9 months of age. Final body weights of corpulent rats were 2-3 times those of their lean littermates, and were greater with SU than MS diet in both phenotypes. 2. Interscapular brown adipose tissue (IBAT) mass was greater in corpulent than lean and was greater with SU than MS diet in lean but not corpulent rats. IBAT cell diameters and adipocyte volumes were generally similar in both phenotypes, and were not markedly affected by dietary carbohydrate type. 3. Brown adipocyte locularity profiles were qualitatively similar in both phenotypes, and were morphologically indicative of thermogenic activity in both phenotypes. Locule profiles of corpulent animals contained a greater proportion of thermogenically less active types IV and V brown adipocytes than similarly fed lean animals, however, and locule distribution profiles were not influenced by diet. 4. Serum T3 concentrations were similar in both phenotypes, were greater in SU than MS lean rats and were not influenced by diet in the corpulent phenotype. In contrast, serum thyroxine concentrations and percent thyroxine uptake were not influenced by diet or phenotype. 5. These results are consistent with a partial impairment in BAT-mediated thermogenic activity in the corpulent phenotype and suggest that obesity in this strain may be due to factors other than biochemically defective brown adipose tissue thermogenesis.     

Changes in fructose-induced production of glucose in the rat liver following partial hepatectomy.

The fructose-induced production of glucose in the liver after partial hepatectomy (PH) was evaluated by using the liver-perfusion system. There was no significant difference in plasma glucose level between hepatectomized (HX) and sham-operated (SO) rats at 24 h after surgery, and, thereafter, almost similar levels were obtained in both groups. However, the level of serum free fatty acids (FFA) was significantly higher in HX rats than that in SO rats at 24 and 48 h after surgery. When both groups of rats were given fructose by gavage, the increment of plasma glucose was significantly larger in HX rats than in SO rats. Lactate infusion failed to increase the rate of glucose production in perfused livers of both HX and SO rats and there was no significant difference in the activity of hepatic phosphoenolpyruvate carboxykinase. By contrast, fructose infusion elicited a large increase in glucose production in the perfused livers of HX rats at 24 and 48 h after PH. The increase was closely associated with not the change in fructose 2,6-bisphosphate levels but the increment of the intracellular levels of citrate. Treatment of octanoate or oleate, which supplies acetyl-CoA via fatty acid oxidation, mimicked the fructose-induced increase in glucose production in SO rats with a concomitant increase in hepatic levels of citrate. These results suggest that the oxidation of FFA may play an important role in glucose production induced by fructose administration during the early phase of liver regeneration.     

Role of SCN in daily rhythms of plasma glucose, FFA, insulin and glucagon

The daily changes in plasma glucose, FFA, insulin and glucagon concentrations in rats under 12 hr-12 hr light-dark conditions, and the role of the suprachiasmatic nucleus (SCN) of the hypothalamus in these changes were examined. In sham-operated rats, the four parameters showed significant daily rhythms. However, after bilateral lesions of the SCN, daily rhythms could not be detected in these parameters under the present experimental conditions. Furthermore, after the SCN lesions the plasma glucose concentration remained at the minimum level of that in sham-operated rats, while the plasma insulin and glucagon concentrations reduced to approximately the mean level and about half the minimum level of sham-operated rats, respectively, and the FFA concentration lowered to somewhat below the minimum level. Gradual increase in the plasma insulin concentration at the end of the light period was observed in intact rats even after starvation for 24 hr. These findings suggest that the SCN is essential for generation of the daily changes in the plasma glucose, FFA, insulin and glucagon concentrations and also that it plays critical roles in regulation of the secretion of pancreatic hormones. The gradual increase in the plasma insulin level observed at the end of the light period is discussed in connection with initiation of spontaneous feeding behaviour.     

Role of SCN in Daily Rhythms of Plasma Glucose,FFA, Insulin and Glucagon

The daily changes in plasma glucose, FFA, insulin and glucagon concentrations in rats under 12 hr-12 hr light-dark conditions, and the role of the suprachiasmatic nucleus (SCN) of the hypothalamus in these changes were examined. In sham-operated rats, the four parameters showed significant daily rhythms. However, after bilateral lesions of the SCN, daily rhythms could not be detected in these parameters under the present experimental conditions. Furthermore, after the SCN lesions the plasma glucose concentration remained at the minimum level of that in sham-operated rats, while the plasma insulin and glucagon concentrations reduced to approximately the mean level and about half the minimum level of sham-operated rats, respectively, and the FFA concentration lowered to somewhat below the minimum level. Gradual increase in the plasma insulin concentration at the end of the light period was observed in intact rats even after starvation for 24 hr. These findings suggest that the SCN is essential for generation of the daily changes in the plasma glucose, FFA, insulin and glucagon concentrations and also that it plays critical roles in regulation of the secretion of pancreatic hormones. The gradual increase in the plasma insulin level observed at the end of the light period is discussed in connection with initiation of spontaneous feeding behaviour.     

Dietary n‐3 long‐chain polyunsaturated fatty acids modify phosphoenolpyruvate carboxykinase activity and lipid synthesis from glucose in adipose tissue of rats fed a high‐sucrose diet

Long‐chain polyunsaturated n‐3 fatty acids (n‐3 LCPUFAs) have hypolipidemic effects and modulate intermediary metabolism to prevent or reverse insulin resistance in a way that is not completely elucidated. Here, effects of these fatty acids on the lipid profile, phosphoenolpyruvate carboxykinase (PEPCK) activity, lipid synthesis from glucose in epididymal adipose tissue (Ep‐AT) and liver were investigated. Male rats were fed a high‐sucrose diet (SU diet), containing either sunflower oil or a mixture of sunflower and fish oil (SU–FO diet), and the control group was fed a standard diet. After 13 weeks, liver, adipose tissue and blood were harvested and analysed. The dietary n‐3 LCPUFAs prevented sucrose‐induced increase in adiposity and serum free fat acids, serum and hepatic triacylglycerol and insulin levels. Furthermore, these n‐3 LCPUFAs decreased lipid synthesis from glucose and increased PEPCK activity in the Ep‐AT of rats fed the SU–FO diet compared to those fed the SU diet, besides reducing lipid synthesis from glucose in hepatic tissue. Thus, the inclusion of n‐3 LCPUFAs in the diet may be beneficial for the prevention or attenuation of dyslipidemia and insulin resistance, and for reducing the risk of related chronic diseases. Copyright © 2013 John Wiley & Sons, Ltd.     

Influence of fasting and dopamine on the tissue catecholamines diurnal variations

To define the role of catecholamines (CA) in the metabolic adaptation to fasting we examined the effect of exogenous dopamine(DA) on heat production(HP) and CA content in the interscapular brown adipose tissue(IBAT) and adrenals of control-fed and 2-day fasted rats in the morning(M) and in the evening(E). DA stimulates HP in fed rats in the M by 45% but the thermogenic effect of this CA is markedly higher in the E. However, DA had no thermogenic effect in fasted rats. The tissue CA in fed rats fluctuates diurnally: in the IBAT noradrenaline(NA) was much higher in the E while adrenaline(A) in adrenals was lower. DA in fed rats did not change the adrenal A but reduced NA content both in the adrenals and in the IBAT all over the day. Fasting depleted A from adrenals but increased NA content both in the M and in the E. Unlike the adrenals in the IBAT fasting did not affect NA content. In the adrenal gland of fasted rats DA significantly increased the A content to the equal degree during the day, while this CA had no effect on NA content of the IBAT.     

Effect of parathyroid hormone on the increase in serum glucose and insulin levels after a glucose load to thyroparathyroidectomized rats.

Thyroparathyroidectomy (TPTX) caused a significant increase in serum glucose and a corresponding fall in serum calcium in both fed and fasted rats. The increase in serum glucose, induced by TPTX, was markedly potentiated by a single intraperitoneal administration of calcium (2 mg/100 g BW) which caused a significant elevation of serum calcium in thyroparathyroidectomized rats. Parathyroid hormone (PTH; 20 U/100 g BW) administered subcutaneously to thyroparathyroidectomized rats, caused a significant decrease in serum glucose (0.1 g/100 g BW) to sham-operated rats significantly increased both serum glucose and insulin. The rise of serum glucose produced by a glucose load was markedly potentiated by TPTX, but the increase in serum insulin was not promoted significantly. The administration of PTH decreased both serum glucose and insulin levels increased by a glucose load to thyroparathyroidectomized rats, in a dose-dependent manner. The administration of calcitonin (80 MRC mU/100 g BW) significantly prevented the effect of PTH to decrease serum glucose after a glucose load to thyroparathyroidectomized rats, and calcitonin increased serum insulin. These results suggest that the effect of PTH on serum glucose does not involve insulin secretion.     

The longitudinal effect of inhibiting fatty acid oxidation in diabetic rats fed a high fat diet.

This study was designed to examine the time-course of response to inhibition of fatty acid (FA) oxidation in rats rendered mildly diabetic with streptozotocin and fed a high fat diet (50% of energy derived from fat). Etomoxir, a specific carnitine palmitoyltransferase (CPT-1) inhibitor, was administered subcutaneously (12.5 mg/kg) to inhibit long chain fatty acid oxidation. Diabetic and non-diabetic control rats were maintained on the high fat diet. Following an overnight fast, glucose, free fatty acid (FFA) and triglyceride (TG) concentrations were determined after three days, one week and four weeks of treatment. The effect of Etomoxir treatment in reducing fasting glucose concentrations was not evident until after one week, while fasting FFA and TG concentrations were already reduced after three days treatment. All of these changes were maintained over the four week period (P less than 0.001), resulting in reduced levels of fasting plasma glucose (17.6 +/- 2.4 vs 22.3 +/- 1.9 mmol/l), fasting plasma TG (0.32 +/- 0.07 vs 0.98 +/- 0.14 mmol/l) and fasting serum FFA (1.52 +/- 0.26 vs 3.51 +/- 0.69 mEq/l). In addition, the improvements in glucose and lipid levels were accompanied by restored rates of growth towards that of non-diabetic control rats. These results suggest that the short term inhibition of FA oxidation improves fasting glucose, FFA and TG concentrations in diabetic rats fed a high fat diet.     

Dysregulated pyruvate dehydrogenase complex in Zucker diabetic fatty rats

The mitochondrial pyruvate dehydrogenase complex (PDC) is inactivated in many tissues during starvation and diabetes. We investigated carbohydrate oxidation (CHO) and the regulation of the PDC in lean and obese Zucker diabetic fatty (ZDF) rats during fed and starved conditions as well as during an oral glucose load without and with pharmacologically reduced levels of free fatty acids (FFA) to estimate the relative contribution of FFA on glucose tolerance, CHO, and PDC activity. The increase in total PDC activity (20-45%) was paralleled by increased protein levels ( approximately 2-fold) of PDC subunits in liver and muscle of obese ZDF rats. Pyruvate dehydrogenase kinase-4 (PDK4) protein levels were higher in obese rats, and consequently PDC activity was reduced. Although PDK4 protein levels were rapidly downregulated (57-62%) in both lean and obese animals within 2 h after glucose challenge, CHO over 3 h as well as the peak of PDC activity (1 h after glucose load) in liver and muscle were significantly lower in obese rats compared with lean rats. Similar differences were obtained with pharmacologically suppressed FFA by nicotinic acid, but with significantly improved glucose tolerance in obese rats, as well as increased CHO and delta increases in PDC activity (0-60 min) both in muscle and liver. These results demonstrated the suppressive role of FFA acids on the measured parameters. Furthermore, the results clearly demonstrate a rapid reactivation of PDC in liver and muscle of lean and obese rats after a glucose load and show that PDC activity is significantly lower in obese ZDF rats.     

Triiodothyronine deiodinating activity in brown adipose tissue after short cold stimulation test in trained and untrained rats

Interscapular brown adipose tissue (IBAT) activity is controlled by sympathetic nervous system, and factors that influence thermogenesis appear to be centrally connected to the sympathetic outflow to IBAT. Cold exposure produces a rise in BAT temperature, which is associated with an increased thyroid activity, elevated serum levels of 3,5,3'-triiodothyronine (T3), and an increased rate of T3 production. This study evaluated the effect of swimming training on 5'-triiodothyronine deiodinase (5'-D) activity in IBAT under normal environmental conditions and after short (30 min) cold exposure (TST stimulation test). 5'-D activity is lower in trained rats at basal condition, and TST increases 5'-D in IBAT of both untrained and trained rats. However, this increase is lower in trained rats. Training reduces the deiodinating activity in normal environmental conditions as well as after short cold exposure. Probably, other compensatory mechanisms of heat production are active in trained rodents.     

The activity of antioxidant enzymes and the content of uncoupling protein-1 in the brown adipose tissue of hypothyroid rats: comparison with effects of iopanoic acid

The activity of antioxidant enzymes, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and catalase (CAT), as well as that of the mitochondrial FAD-dependent alpha-glycerophosphate dehydrogenase (alpha-GPD) in the rat interscapular brown adipose tissue (IBAT) were studied after the treatment with methimazole (MMI) for three weeks or with iopanoic acid (IOP) for five days. Besides, the mitochondrial concentration of uncoupling protein-1 (UCP-1) and the activity of catecholamine degrading enzyme monoamine oxidase (MAO) in the IBAT as well as the activity of the catecholamine synthesizing enzyme, dopamine beta-hydroxylase (DBH) in rat serum were examined. Judging by the significantly enhanced level of serum DBH, which is an index of sympathetic activity, and that of IBAT MAO, the increase in MnSOD and CAT activities in the IBAT of hypothyroid (MMI-treated) rats seems to be due to elevated activity of sympathetic nervous system (SNS). However, CuZnSOD activity is not affected by SNS. On the contrary, IOP, which is a potent inhibitor of T4 deiodination into T3 producing "local" hypothyroidism, did not change either SNS activity or activities of IBAT antioxidant enzyme. However, both treatments significantly decreased IBAT UCP-1 content and alpha-GPD activity suggesting that the optimal T3 concentration in the IBAT is necessary for maintaining basal levels of these key mitochondrial parameters.     

Reciprocal changes of plasma glucose and ketone bodies in fasted and acutely diabetic rats after CNS stimulation

To assess the effect of chemical stimulation of the central nervous system (CNS) on ketogenesis, we injected neostigmine (5 x 10(-8)mol) into the third cerebral ventricle in normal rats fasted for 48 h and fed rats with diabetes induced by streptozotocin (STZ, 80 mg/kg). The hepatic venous plasma levels of ketone bodies (3-hydroxybutyrate and acetoacetate), free fatty acids (FFA), and glucose were measured for 120 min after the injection of neostigmine under pentobarbital anesthesia. In the normal rats, plasma glucose levels were significantly increased but neither ketone bodies nor FFA were affected by CNS stimulation with neostigmine. In contrast the plasma levels of ketone bodies and FFA were significantly increased in STZ-diabetic rats, while glucose levels remained unchanged. The intravenous infusion of somatostatin (1.0 microgram/kg/min) suppressed the increase in plasma ketone bodies following CNS stimulation in STZ-diabetic rats. These findings suggest that CNS stimulation with neostigmine may accelerate ketogenesis by promoting the lipolysis, which may be induced by glucagon, in fed diabetic rats but not in normal fasted rats.     

NO-1886改善糖尿病小型猪的糖代谢

合成化合物NO-1886是一种脂蛋白脂酶活化剂,已被证明其可降低血浆TG并能升高HDLC的浓度．后又发现其还有降低高脂高蔗糖诱发糖尿病兔血浆葡萄糖浓度的作用．对高脂高蔗糖饲料喂养的小型猪脂肪细胞大小、血浆TNF—α和FFA的水平以及NO-1886对其影响进行了研究,结果发现,脂肪细胞明显肥大．血浆TNF-α和FFA以及空腹血糖水平均增高,且引起胰岛素抵抗．添加了l％NO-1886后．脂肪细胞增大被抑制,血浆TNF—α、FFA和空腹血糖的浓度均显著降低,血浆葡萄糖清除率和胰岛素分泌急性相都有了明显改善．以上结果说明,NO-1886可能通过抑制脂肪蓄积、降低血浆TNF-α和FFA的浓度而改善高脂高蔗糖饲料引起的小型猪的糖代谢紊乱．     

PPARgamma agonists diminish serum VEGF elevation in diet-induced insulin resistant SD rats and ZDF rats

We investigated the effect of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on serum vascular endothelial growth factor (VEGF) in diet-induced insulin resistant SD rats and ZDF rats. SD rats fed a high fat/sucrose diet showed increases in serum insulin and VEGF (both p < 0.01). Treatment with a PPARgamma agonist GI262570 normalized the diet-elevated insulin and VEGF (both p < 0.01). There was a positive correlation between serum insulin and VEGF (p < 0.05) in SD rats. ZDF rats had higher serum glucose, insulin, and VEGF than Zucker lean rats (all p < 0.01). Treatment of ZDF rats with PPARgamma agonist pioglitazone decreased serum glucose and VEGF (both p <0.01). There was a positive correlation between glucose and VEGF in ZDF rats (p < 0.05). In 3T3-L1 adipocytes, GI262570 did not affect insulin-stimulated VEGF secretion. These studies demonstrated that hyperinsulinemia in SD rats and hyperglycemia in ZDF rats were associated with increased serum VEGF; PPARgamma agonists normalized serum insulin, glucose, and VEGF, but did not affect VEGF secretion in vitro.