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.     

Chlorogenic acid modifies plasma and liver concentrations of: cholesterol,triacylglycerol, and minerals in (fa/fa) Zucker rats

Chlorogenic acid, a phenolic compound found ubiquitously in plants, is an in vitro antioxidant and metal chelator. Some derivatives of chlorogenic acid are hypoglycemic agents and may affect lipid metabolism. Concentrations of cholesterol and triacylglycerols are of interest due to their association with diseases such as non-insulin-dependent-diabetes- mellitus and obese insulin resistance. As little is known about the effects of chlorogenic acid in vivo, studies using obese, hyperlipidemic, and insulin resistant (fa/fa) Zucker rats were conducted to test the effect of chlorogenic acid on fasting plasma glucose, plasma and liver triacylglycerols and cholesterol concentrations. Aditionally, the effects of chlorogenic acid on selected mineral concentrations in plasma, spleen, and liver were determined. Rats were implanted with jugular vein catheters. Chlorogenic acid was infused (5 mg/Kg body weight/day) for 3 weeks via intravenous infusion. Chlorogenic acid did not promote sustained hypoglycemia and significantly lowered the postprandial peak response to a glucose challenge when compared to the same group of rats before Chlorogenic acid treatment. In Chlorogenic acid-treated rats, fasting plasma cholesterol and triacylglycerols concentrations significantly decreased by 44% and 58% respectively, as did in liver triacylglycerols concentrations (24%). We did not find differences (p > 0.05) in adipose triacylglycerols concentration. Significant differences (p < 0.05) in the plasma, liver, and spleen concentration of selected minerals were found in chlorogenic acid-treated rats. In vivo, chlorogenic acid was found to improve glucose tolerance, decreased some plasma and liver lipids, and improve mineral pool distribution under the conditions of this study.     

Impaired FAD-glycerophosphate dehydrogenase activity in islet and liver homogenates of fa/fa rats

The mitochondrial FAD-linked enzyme glycerophosphate dehydrogenase plays a key role in the pancreatic B-cell glucose sensing device. In the present study, the activity of this enzyme was examined in islets of fa/fa rats in which inherited diabetes mellitus is associated with obesity, hyperinsulinism and severe insulin resistance. The specific activity of both FAD-linked glycerophosphate dehydrogenase and glutamate dehydrogenase were decreased in islet and liver homogenates prepared from fa/fa, as compared to Fa/Fa, rats, this coinciding with a low ratio between glutamateoxalacetate and glutamate-pyruvate transaminase activity in both islet and liver extracts, islet hyperplasia, hyperinsulinemia and hepatic steatosis in the hyperglycemic fa/fa rats. It is speculated that a low activity of FAD-linked glycerophosphate dehydrogenase in the pancreatic B-cell may participate to the perturbation of glucose homeostasis in fa/fa rats, like in other animal models of non-insulin-dependent diabetes mellitus.     

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.     

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.     

Xanthohumol lowers body weight and fasting plasma glucose in obese male Zucker fa/fa rats

Obesity contributes to increased risk for several chronic diseases including cardiovascular disease and type 2 diabetes. Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus), was tested for efficacy on biomarkers of metabolic syndrome in 4 week old Zucker fa/fa rats, a rodent model of obesity. Rats received daily oral doses of xanthohumol at 0, 1.86, 5.64, and 16.9 mg/kg BW for 6 weeks. All rats were maintained on a high fat (60% kcal) AIN-93G diet for 3 weeks to induce severe obesity followed by a normal AIN-93G (15% kcal fat) diet for the last 3 weeks of the study. Weekly food intake and body weight were recorded. Plasma cholesterol, glucose, insulin, triglyceride, and monocyte chemoattractant protein-1 (MCP-1) levels were assessed using commercial assay kits. Plasma and liver tissue levels of XN and its metabolites were determined by liquid–chromatography tandem mass spectrometry. Plasma and liver tissue levels of xanthohumol were similar between low and medium dose groups and significantly (p < 0.05) elevated in the highest dose group. There was a dose-dependent effect on body weight and plasma glucose levels. The highest dose group (n = 6) had significantly lower plasma glucose levels compared to the control group (n = 6) in male but not female rats. There was also a significant decrease in body weight for male rats in the highest dose group (16.9 mg/kg BW) compared to rats that received no xanthohumol, which was also not seen for female rats. Plasma cholesterol, insulin, triglycerides, and MCP-1 as well as food intake were not affected by treatment. The findings suggest that xanthohumol has beneficial effects on markers of metabolic syndrome.     

Leptin receptor-deficient Zucker (fa/fa) rat retards the development of pig serum-induced liver fibrosis with Kupffer cell dysfunction

The aim of this study was to investigate the role of leptin in the development of liver fibrosis with Kupffer cell function using leptin receptor deficient rats. Male Zucker (fa/fa) and control (fa/-) rats received pig serum for 8 weeks. Animals were sacrificed to estimate the degree of liver fibrosis and stellate cell activation with the expression of alpha smooth muscle actin (alphaSMA). Microarray analysis was performed. Isolated Kuppfer cells of Zucker and control rats were treated with LPS. LPS uptake and TNF-alpha production were examined. Stellate cells were also isolated from Zucker and control rats. The expression of procollagen type I mRNAs was examined. Control rats developed liver fibrosis 8 weeks after injection of pig serum and showed an increased liver hydroxyproline content of 348 +/- 34 microg/g (n = 10) compared with Zucker rats (225 +/- 13, n = 10, P < 0.01). The procollagen type I mRNA level and alphaSMA expression of Zucker rats were also significantly reduced. Microarray analysis indicated significantly reduced expression of TNF-alpha, LPS-binding protein, urokinase-type plasminogen activator (uPA), IGF, IGF-binding protein (IGFBP)-3,5, and increased expression of apolipoprotein IV. Isolated Kupffer cells of Zucker rats showed significantly reduced LPS uptake as well as TNF-alpha production compared with control rats. However, no significant change was observed in procollagen type I mRNA levels of isolated stellate cells after 4 days of culture on plastic dishes. These results suggest that leptin receptor deficiency retards the development of liver fibrosis due to the dysfunction of Kuppfer cells.     

Hepatic glycogen synthase phosphatase and phosphorylase phosphatase activities are increased in obese (fa/fa) hyperinsulinemic Zucker rats: effects of glyburide administration

The chronically hyperinsulinemic Zucker fatty rat, with peripheral insulin resistance and glucose intolerance, represents a model of noninsulin dependent diabetes mellitus (NIDDM). These animals have elevated hepatic glycogen levels. Hepatic levels of synthase phosphatase and phosphorylase phosphatase, which are diminished in the IDDM rat, were markedly increased in the obese rats. Glyburide, a sulfonylurea used in treatment of NIDDM, resulted in reduced levels of glycemia and increased insulin levels in Zucker rats. Hepatic glycogen levels were increased, as was the activation of glycogen synthase, although there were no effects of drug administration on synthase phosphatase or phosphorylase phosphatase activities. G6P levels were increased by glyburide in lean rats but not in obese animals. These effects of glyburide on liver glycogen metabolism are accounted for via potentiation of the glycogenic effects of insulin.     

Reduced sensitivity to dexamethasone of pancreatic islets from obese (fa/fa) rats.

The direct effects of dexamethasone exposure on insulin secretion from islets of fa/fa rats and their lean littermates (Fa/?) were compared. After 72 h culture in 1 nM dexamethasone, glucose (27.5 mM)-stimulated insulin secretion over 90 min from islets of lean rats was significantly decreased compared with islets cultured without dexamethasone (12.9 +/- 1.4 vs. 5.7 +/- 1.0% of total islet content, p < 0.05). Higher doses of dexamethasone for 24-48 h culture produced similar effects. For islets of fa/fa rats, the minimum inhibitory concentration of dexamethasone was 10-fold higher, and islets required at least 48 h exposure for inhibitory effects to be observed. Dexamethasone also decreased the insulin response by islets to glybenclamide, indicating that dexamethasone effects were not specific to glucose transport or metabolism. The results suggest that islets of fa/fa rats may be less sensitive to direct inhibitory effects of glucocorticoids on glucose-stimulated insulin release than islets of lean animals.     

Insulin receptor exon 11+/- is expressed in Zucker (fa/fa) rats, and chlorogenic acid modifies their plasma insulin and liver protein and DNA

In vivo studies confirmed that chlorogenic acid (CGA) improved glucose tolerance and mineral pool distribution in obese Zucker (fa/fa) rats. We found a significant decrease (P<.05) in postprandial blood glucose concentrations, which may have been due to an improved sensitivity to insulin. Impaired glucose tolerance and insulin resistance have been associated with differences in the hepatic mRNA expression of the spliced variants of the insulin receptor at exon 11. Spliced variants of the insulin receptor have not been studied in obese Zucker (fa/fa) rats, and no information exists about the effects of CGA in vivo as a possible insulin sensitizer. Thus, we studied the in vivo effect of CGA on plasma insulin concentrations during a glucose tolerance test, liver protein and DNA concentrations, the hepatic activity of glucose-6-phosphatase (G-6-PASE) and the mRNA expression of the two variants of the insulin receptor at exon 11. Zucker (fa/fa) rats were implanted with jugular vein catheters. Chlorogenic acid was administered (5 mg/kg body weight per day) for 3 weeks via intravenous infusion. In the CGA-treated group, areas under the curve (AUC) for blood glucose and plasma insulin improved (P<.005), and the protein and DNA concentrations in the liver increased (P<.05). No significant differences (P>.05) were found between groups for the hepatic G-6-PASE activity. The insulin receptor exon 11(+) and the exon 11(-) variants were expressed in the liver of Zucker (fa/fa) rats without significant changes (P>.05). Chlorogenic acid improved some cellular mechanisms that are stimulated by insulin.     

Decreased responsiveness of gluconeogenesis to the modulation by sulfonylureas in hepatocytes isolated from obese (fa/fa) Zucker rats

The influence of the hypoglycemic agent glipizide (0-100 microM) on the rate of gluconeogenesis from lactate, as well as on the levels of fructose 2,6-bisphosphate, has been investigated in hepatocytes isolated from genetically obese (fa/fa) Zucker rats and from their corresponding lean (Fa/-) littermates. As compared to lean rat hepatocytes, liver cells isolated from obese animals showed a lower rate of basal gluconeogenesis (0.9 +/- 0.2 vs 5.4 +/- 0.5 micromol of lactate converted to glucose/g cell x 30 min, n=4) and higher levels of fructose 2,6-bisphosphate (11.5 +/- 1.0 vs 5.9 +/- 0.4 nmol/g cell, n=8-9). In lean rat hepatocytes, the presence of glipizide in the incubation medium caused a dose-dependent inhibition of the rate of lactate conversion to glucose (maximal inhibition=46%; EC50 value=26 microM), and simultaneously raised the cellular content of fructose-2,6-bisphosphate (maximal increment=40%; EC50 value=10 microM). In contrast, in hepatocytes isolated from obese rats, the inhibition of gluconeogenesis and the increment in fructose-2,6-bisphosphate levels elicited by glipizide were significantly reduced (maximal effects of 22 and 13%, respectively). Similarly, the activation of glycogen phosphorylase and the increase in hexose 6-phosphate levels in response to glipizide were less marked in obese rat hepatocytes than in liver cells isolated from lean animals. These results demonstrate that the efficacy of sulfonylureas as inhibitors of hepatic gluconeogenesis is reduced in the genetically obese (fa/fa) Zucker rat.     

Effects of Ellagic Acid on Copper,Zinc, and Biochemical Values in Serum and Liver of Experimental Cholestatic Rats

Ellagic acid (EA) is a natural polyphenolic compound. Although, modulator effects of EA on copper (Cu) and zinc (Zn) levels in some liver diseases have been reported in experimental animals, its effects in obstructive jaundice (OJ) has not been clarified. We aimed to evaluate potential effects of EA on Cu and Zn levels in liver and serum of cholestatic rats. Forty Wistar albino rats were equally divided into four groups. First group was used as controls. Second group received EA (60 mg⁻¹ kg⁻¹ day⁻¹) for 8 days. Third was OJ group, and fourth group was OJ plus EA group. After 8 days, blood and liver samples were obtained. Higher serum and liver Cu and lower serum and liver Zn levels were found in OJ group (p < 0.05) compared with other groups. However, these differences reached to significant levels for Cu in serum and for Zn in lever. Higher serum copper levels were decreased, and lower liver Zn levels were increased by EA treatment in cholestatic rats (p < 0.05). Also, higher Cu/Zn ratio in OJ group was decreased by EA treatment both in liver (p < 0.05) and in serum (p < 0.05). Significantly higher serum bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase values were found in OJ and OJ + EA groups compared with the control and EA groups (p < 0.05). In conclusion, result of the current study indicated that ellagic acid has modulator effects on Cu and Zn levels in liver and serum of cholestatic rats.     

Effects of thioacetamide on protein and ribonucleic acid metabolism of rat liver cells. A radioautographic study

Summary Injections of thioacetamide (T.A.) were given to rats and its effects on protein and RNA metabolism of liver cells was studied. Through the radioautographic method it was possible to observe the effects of T.A. on cytoplasm, chromatin, and nucleolus.The results show that T.A., when injected into rats, increases the amino acid incorporation into liver cell cytoplasm, chromatin, and nucleolus. This was observed by injecting either leucine-H³ or phenylalanine-H³ into rats previously treated with T.A., or by incubating liver slices with phenylalanine-H³.The effects of T.A. on RNA synthesis were studied by incubating liver slices of T.A. injected and control rats with adenine-H³. T.A. was also added to some flasks and incubated with liver slices from control and T.A. injected rats. The effect of the drug, when injected, was to increase the uptake of adenine-H³. Added to the incubation medium in the concentration of 10^–3 M, T.A. decreased the incorporation of adenine-H³. Ribonuclease digestion permitted to separate adenine-H³ incorporation into RNA, from the incorporation into DNA, which was very low in these experiments.     

Efficiency of intermittent exercise on adiposity and fatty liver in rats fed with high-fat diet

Objective: This study aimed to examine and compare the effects of continuous or intermittent exercises on adiposity and fatty liver in rats fed with high‐fat diet. Methods and Procedures: Wistar rats were divided according to diet composition—chow diet (C) or high‐fat diet (H)—and kinds of exercise—sedentary (S), continuous (CE), or intermittent (IE) exercises. The CE group swam 90 min/day, and the IE group swam 3 × 30 min/day (at 4‐h intervals between sessions); both groups exercised 5 days/week during 8 weeks. Body weight and food intake were recorded daily. Lipogenesis rate in vivo was determined by the incorporation of ³H₂O into saponified lipids in retroperitoneal (RET), epididymal (EPI), and visceral (VIS) white adipose tissues, brown adipose tissue (BAT), liver (L), and gastrocnemius muscle (GAST) using the gravimetric method. Total cholesterol, high‐density lipoprotein (HDL)‐cholesterol, and triacylglycerol (TG) were analyzed. Results: The major finding of this study is that IE was more efficient than CE in reducing the adverse effects of high‐fat diet and sedentarism. There was an improvement in the lipid profile and a reduction in food intake, body weight gain, visceral and central adiposity, and fatty liver, contributing to the control of obesity and other comorbidities, including nonalcoholic fat liver diseases. Discussion: Earlier studies have discussed the effects of diet consumption on adiposity and their relation to chronic diseases and obesity. This study discusses the effects of high‐fat diet consumption and the different kinds of exercise on weight gain, adiposity, fatty liver, and lipid profile in rats. The results may depend on the exercise, time of each session, age, gender, and experimental period.     

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.     

High affinity GDP binding sites on brown adipose tissue mitochondria of genetically obese ‘fa/fa’ rats

The number of high affinity [³H]GDP binding sites in brown adipose tissue mitochondria is normal in obese ( f a / f a ) rats in contrast to the reduced number of low affinity GDP binding sites. Adrenalectomy corrected the loss of low affinity binding sites in fa/fa rats but had no effect on the number of high affinity sites in either lean or obese rats. Equilibrium dialysis was used to show the presence of both high and low affinity binding sites on the purified 32 kdalton protein.     

Modulation of gluconeogenesis by epinephrine in hepatocytes isolated from genetically obese (fa/fa) Zucker rats

The obese (fa/fa) Zucker rat shows an impaired sympathetic tone which is accompanied by an altered thermogenesis and changes in both lipid and carbohydrate metabolism. In this work, we have investigated the regulatory effects of epinephrine on the rate of gluconeogenesis from a mixture of [(14)C]lactate/pyruvate, in hepatocytes isolated from obese (fa/fa) rats and their lean (Fa/-) littermates. Epinephrine caused a dose-dependent stimulation of the rate of [(14)C]glucose formation in both obese and lean rat hepatocytes, the maximal rates being five- and twofold higher than the corresponding basal values (0.50 +/- 0.06 and 1.96 +/- 0.15 micromol of lactate converted to glucose/g of cell x 20 min, respectively). No significant differences were found between the calculated half-maximal effective concentrations (EC(50)) for epinephrine in obese and lean rat liver cells. The stimulation of gluconeogenesis by epinephrine was accompanied by a decrease in the cellular concentration of fructose 2,6-bisphosphate, and an inactivation of both pyruvate kinase and 6-phosphofructo 2-kinase, to similar extents in both types of hepatocytes. Epinephrine also significantly raised the hepatocyte content of cyclic AMP, with about a twofold increase at a saturating concentration of the catecholamine (1 microM), in both lean and obese rat liver cells. However, at suboptimal concentrations of epinephrine, the rise in cyclic AMP levels was significantly less marked in obese than in lean rat hepatocytes. Nevertheless, no significant differences were found in either the affinity or the number of beta-adrenergic receptors, in radioligand binding studies carried out in liver plasma membranes obtained from obese and lean Zucker rats. In conclusion, compared to the corresponding basal values, the response of gluconeogenesis from lactate to the stimulatory effect of epinephrine is higher in obese (fa/fa) than in lean (Fa/-) Zucker rat hepatocytes, with no significant differences in the calculated EC(50) values for this hormone. This occurs in spite of an apparent decreased sensitivity of the adenylate cyclase system to the stimulatory effect of epinephrine in obese rat liver cells.     

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.