Adrenalectomy reverses the impaired pyrogenic responses to interleukin-beta in obese Zucker rats

Interleukin-1 is an important endogenous pyrogen which stimulates thermogenesis in normal animals by a central action which is dependent on release of corticotrophin releasing factor (CRF). Central injection of murine recombinant interleukin-1 beta (IL-1 beta, 5 ng) in conscious lean (+/?) Zucker rats produced significant increases in resting oxygen consumption (VO2, 26 per cent), colonic temperature (1.3 degrees C) and thermogenic activity (mitochondrial GDP binding) of brown adipose tissue (BAT, 24 per cent). In contrast, genetically obese (fa/fa) Zucker rats showed nonsignificant changes in VO2 (4 per cent), temperature (0.5 degrees C) and BAT activity (0 per cent). Bilateral surgical adrenalectomy (ADX) dramatically enhanced the effects of IL-1 beta on VO2 (45 per cent) body temperature (1.8 degrees C) and BAT activity (44 per cent) in obese mutants, but only slightly increased responses in lean rats. These data suggest that impaired responses to IL-1 beta in obese mutants may be due to inhibitory actions of glucocorticoids on either prostaglandin synthesis or CRF release within the hypothalamus.     

Influence of sodium intake on thermogenesis and brown adipose tissue in the rat

Presenting rats with a 0.9 per cent sodium chloride solution to drink instead of water had little or no effect on body weight gain and food intake, but resting oxygen consumption and total energy expenditure (corrected for body size) were elevated, and thermogenic responses to both noradrenaline and a meal were enhanced. Brown adipose tissue (BAT) mass and protein content were significantly elevated in saline treated rats, but mitochondrial GDP-binding capacity was depressed. Basal Na+, K+-ATPase activity was slightly increased in BAT homogenates from rats given saline, but noradrenaline-stimulated enzyme activity was much greater than control values. In rats drinking 1.8 per cent saline, energy intake, body weight gain and the efficiency of gain (g gain/MJ eaten) were all markedly depressed. BAT mass, corrected for differences in body size, was slightly greater than controls and the protein content of BAT was increased by 45 per cent. Rats allowed 0.9 per cent saline to drink for 7 d, and then presented with a palatable cafeteria diet, showed a more rapid rise in metabolic rate than cafeteria-fed animals drinking water. This difference was apparent only over the first 3-4 d of cafeteria feeding, and energy balance over 14 d was similar for both groups. These data show that increasing sodium intake with isotonic saline has very little effect on food intake or resting metabolic rate, but causes a marked increase in thermogenic capacity and responses to food or noradrenaline, probably because of an increase in active BAT mass. Changes in plasma ion concentrations or osmolarity, therefore, could be involved in the thermogenic response to food.     

The effect of vigorous treadmill exercise on adipose tissue development in the Zucker rat

Four-week-old male lean and obese Zucker rats were subjected to intense daily exercise for a 10-week period. The exercise regimen used (running 6 days/week for 90 min/day on a treadmill at 1.3 Km/h at an 8 per cent grade) was designed to maximize the amount of exercise performed. Lean and obese runners (LR and OR) gained significantly less weight than sedentary controls (LS and OS). Food intake was lower in LR and unchanged in OR compared with control animals. Exercise increased adrenal weight in runners of both phenotypes. Gastrocnemius muscle weight was significantly higher in OR compared to OS. Despite the intense exercise regimen, carcass fat of OR was reduced only 12 per cent versus OS. In contrast, exercise decreased carcass fat by 32 per cent in LR versus LS. This decrease in body fat of LR was due to smaller adipocytes. Exercise did not affect adipocyte size in obese rats. However, OR had fewer carcass adipocytes. These results indicate that exercise had substantially different effects on adipose tissue cellularity of lean and obese rats. The results of the present study indicate that a program of intense treadmill exercise initiated immediately post weaning only modestly reduced adipose tissue growth in obese Zucker rats. Furthermore, it did not normalize body composition.     

Acute effects of fat and carbohydrate on metabolic rate in normal, cold-acclimated and lean and obese (fa/fa) Zucker rats

The rise in metabolic rate after intragastric feeding with fat and carbohydrate was enhanced in cold-acclimated (5 degrees C) rats and diminished in warm-acclimated (30 degrees C) rats compared to controls (24 degrees C), but the response was largest in cold-acclimated animals intubated with fat. These acute effects of nutrients were almost completely abolished by beta-adrenergic blockade with propranolol in all groups, while the parasympathetic antagonist atropine sulphate enhanced the responses in control rats, but had little effect in cold-acclimated animals. Feeding carbohydrate produced similar increases in interscapular brown adipose tissue (BAT) temperature in control and cold-acclimated rats, but fat caused a much greater rise in the latter group. The thermic effects of both nutrients were lower in genetically obese Zucker rats than in their lean littermates. Atropine slightly increased the thermic responses to fat and carbohydrate in the lean Zucker rats and caused marked potentiation in obese rats intubated with fat, but did not alter the effect of carbohydrate in the obese animals These data suggest that the size of the acute rise in metabolic rate after fat and carbohydrate is dependent on the thermogenic capacity of the animal. The response to fat was particularly large in cold-acclimated rats, where BAT activity is high, possibly due to a direct action of fat on the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of limit feeding on thermogenesis and thermoregulation in genetically obese (ob/ob) mice during cold exposure

Thermogenesis and thermoregulation in ad-lib-fed and limit-fed lean (+/ob or +/+) and obese (ob/ob) mice during acute cold exposure were studied by measuring oxygen consumption and body temperature. No significant differences in oxygen consumption were found between the lean ad-lib, obese ad-lib- or obese limit-fed groups. The oxygen consumption of the lean-limit-fed group was decreased by 25-30 per cent compared with the other groups. The body temperature of the obese ad-lib-fed group fell at a rate of at least twice that of any other group. The weight, total cytochrome c oxidase activity and protein content of the brown adipose tissue (BAT) of the lean groups was similar, and there appeared to be little difference in cell size or fat content. The BAT of both obese groups showed a several-fold increase in weight, and a 50 per cent increase in total protein, compared with the lean groups. The limit-fed obese group showed a significant increase in cytochrome c oxidase activity compared with all other groups. The BAT cells of both obese groups were much enlarged and contained considerable amounts of fat. These observations indicate that the susceptibility of obese mice to hypothermia is not due to a reduced capacity for thermogenesis, but to a failure to conserve heat. Failure of thermoregulation in obese animals may be due to postural constraints that result in increased heat loss by radiation. The results are discussed in relation to the accredited role of BAT thermogenesis in rodents exposed to the cold.     

Effects of age on diet-induced thermogenesis and brown adipose tissue metabolism in the rat

Measurements of energy balance, thermogenic responses to noradrenaline and brown adipose tissue (BAT) activity were performed in male Lister-hooded rats aged 3.5 and 6.5 months, and fed either a pelleted control diet or a palatable cafeteria diet for 15 d. Cafeteria feeding produced increases in energy intake of 34 and 30 per cent in 3.5 and 6.5-month-old rats respectively, and energy expenditure was elevated by 25 and 10 per cent in these groups. Three-and-a-half-month-old cafeteria-fed rats gained more energy than their controls, but net energetic efficiency was significantly reduced, while in the older cafeteria rats, body energy gain was markedly increased without any apparent effect on net efficiency. The thermogenic response to noradrenaline was enhanced by cafeteria feeding at both ages. The younger cafeteria-fed rats showed significant increases in the mass, protein content and mitochondrial yield of BAT, and the activity of the mitochondrial proton conductance pathway, assessed from GDP-binding, was greater than their controls. The 6.5-month-old cafeteria group also showed hypertrophy of BAT and small, but not significant, increases in the protein content of the tissue and mitochondrial GDP-binding. These results demonstrate that rats aged 3.5 months can exhibit diet-induced thermogenesis and activate BAT in response to overfeeding, but the capacity for thermogenesis declines with age and was virtually absent in 6.5-month-old rats.     

Impaired effects of interleukin-1 beta on fever and thermogenesis in genetically obese rats

Interleukin-1 beta (IL-1 beta) is an endogenous peptide which induced fever (1.8 degrees C rise in colonic temperature) when injected interacerebroventricularly (i.c.v., 80ng human recombinant IL-1 beta) into conscious lean rats. IL-1 beta also stimulated resting oxygen consumption (VO2) by 38 percent, in vitro thermogenic activity (mitochondrial GDP binding) of brown adipose tissue (BAT) by almost two-fold, and blood flow to brown fat (assessed from the distribution of radiolabelled microspheres) by nine-fold in lean animals. Genetically obese Zucker rats showed only small increases in temperature (0.5 degrees C), VO2 (15 percent) and blood flow to BAT (less than two-fold), and no change in GDP binding, but exhibited normal thermogenic responses to i.c.v. injection of corticotrophin releasing factor (GRF). The results indicate that the obese Zucker is insensitive to the central effects of interleukin; this may explain the reduced febrile responses to endotoxin which have previously been reported.     

Diazoxide enhances basal metabolic rate and fat oxidation in obese Zucker rats

Persistent suppression of hyperinsulinemia in genetically obese (fa/fa) Zucker rats by diazoxide (DZ) reduces food intake and weight gain; improves insulin sensitivity, glycemic control, and lipid profile; and enhances β₃-adrenergic function and lipolysis in adipose tissue. The aim of this study was to elucidate the effects of DZ on basal metabolic rate (BMR), fat oxidation, and adrenergic function of lean and obese Zucker rats. Diazoxide (150 mg/kg/d) or vehicle (control) was administered for 4 weeks in 7-week-old obese and lean Zucker rats (n = 8-9 per subgroup). Animals underwent indirect calorimetry, body composition analysis, and determination of uncoupling proteins (UCPs) messenger RNA (mRNA) in brown and white adipose tissues (BAT and WAT) and skeletal muscle (SM), β₃-adrenergic receptor (AR) mRNA in BAT and WAT, β₂-AR in SM as well as WAT, and SM adenylate cyclase (AC) activity at the completion of study. Diazoxide treatment decreased food intake, weight gain, and body fat in obese rats (P < .01). Although DZ treatment lowered fasting plasma glucose, insulin, leptin, adiponectin, and lipids in obese rats (P < .01), it increased adiponectin-leptin ratio (P < .01). Plasma adiponectin-leptin ratio was inversely correlated with fat mass in obese and lean rats (r = −0.86, P < .0001). Diazoxide treatment resulted in higher BMR and fat oxidation rate in obese compared with control animals (P < .01), without any effect in lean animals. Furthermore, plasma adiponectin was inversely correlated with BMR (−0.56, P < .001) and lipid oxidation rate (−0.61, P < .0005) and was positively correlated with nonprotein respiratory quotient (r = 0.41, P < .01) in obese and lean rats. This was associated with increased β₃-AR mRNA expression in BAT and WAT (P < .01), UCP-1 and UCP-3 in BAT and AC activity in WAT (P < .02), and AC activity in SM of DZ obese rats compared with controls (P < .01), without significant change in SM β₂-AR mRNA expressions. Diazoxide attenuation of hyperinsulinemia decreased the rate of weight gain but enhanced insulin sensitivity, BMR, and fat oxidation in obese rats. This was associated with increased receptor- and non-receptor-mediated adrenergic function in adipose and muscle tissues in obese rats, respectively. These metabolic changes in obese Zucker rats suggest that antiobesity effects of DZ appear to be not only through its anorectic effect, modification of disturbed insulin metabolism, and inhibition of lipogenesis, but also due to augmentation of adrenergic function, energy expenditure, and fat utilization.     

Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control

Melatonin limits obesity in rodents without affecting food intake and activity, suggesting a thermogenic effect. Previously we demonstrated that melatonin browns subcutaneous fat in Zücker diabetic fatty (ZDF) rats. Other works pointed to melatonin as a signal that increases brown adipose tissue (BAT) mass and function in rodents. However, direct proof of thermogenic properties (uncoupled mitochondria) of the newly recruited BAT in response to melatonin is still lacking. Therefore, in this work, we investigated if melatonin recruits thermogenic BAT in ZDF rats. Zücker lean (ZL) and ZDF animals were subdivided into two groups, control (C) and treated with oral melatonin (M) for 6 weeks. Mitochondrial mass, activity of citrate synthase (CS), and respiratory chain complexes I and IV were lower in C‐ZDF than in C‐ZL animals (P < .001). Melatonin treatment increased BAT weight in ZDF rats (P < .001). Also, it rose mitochondrial mass (P < .01) and activities of CS and complexes I and IV (P < .001) in both, ZDF and ZL rats. Uncoupling protein 1 (UCP1) mRNA and protein were 50% lower in BAT from obese rats. Also, guanosine diphosphate (GDP) binding was lower in ZDF than in lean rats (P < .01). Melatonin treatment of obese rats restored the expression of UCP1 and GDP binding to levels of lean rats and sensitized the thermogenic response to cold exposure. These data demonstrated that melatonin recruits thermogenic BAT in ZDF rats. This may contribute to melatonin's control of body weight and its metabolic benefits.     

Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin

Obese (fa/fa) Zucker rat is a spontaneous genetic obesity model and, by comparison with lean Zucker rat, exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia. The aim of this study was to examine the physiological difference concerning adiponectin between obese (fa/fa) Zucker rats and control lean Zucker rats. We therefore measured plasma adiponectin level and analyzed adiponectin and adiponectin receptor 1 mRNA expression in retroperitoneal white adipose tissue (RT WAT), brown adipose tissue (BAT), liver, and soleus muscle. We also examined the tissue mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR delta, and PPAR gamma, which regulate adiponectin expression sensitivity to a PPAR gamma agonist shown by brown adipocytes from obese (fa/fa) Zucker rats and lean Zucker rats, by measuring adiponectin release from these cells. Plasma adiponectin levels of obese (fa/fa) Zucker rats were significantly higher than those of lean Zucker rats. Adiponectin mRNA expression levels in RT WAT were lower in obese (fa/fa) Zucker rats than in lean Zucker rats, but those in BAT were higher. Adiponectin receptor 1 expression levels in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats were lower than in lean Zucker rats. The expression level of PPAR alpha, PPAR delta, and PPAR gamma in BAT was lower in obese (fa/fa) Zucker rats than in lean Zucker rats. Moreover, the PPAR gamma agonist increased adiponectin release only from the brown adipocytes isolated from lean Zucker rats. It is the conclusive difference between obese (fa/fa) Zucker rats and lean Zucker rats that plasma adiponectin levels of obese (fa/fa) Zucker rats are significantly higher than those of lean Zucker rats. Moreover, we clarified that mRNA expression level of adiponectin receptor 1 in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats is low despite high plasma adiponectin level, and low expression of PPARs in BAT leads to less sensibility of adiponectin release from brown adipocytes to a PPAR gamma agonist in obese (fa/fa) Zucker rats.     

Lipoprotein lipase activity and cellularity in brown and white adipose tissue in Zucker obese rats

The genetically obese adult Zucker rat (fafa) exhibits reduced thermogenesis when stimulated by physiological agents (cold, catecholamines). Recent evidence suggests that this thermogenic defect may be important in the manifestation of the animal's obesity and that it reflects a reduced thermogenic contribution from brown adipose tissue, the major nonshivering thermogenic site in many mammals. The present study describes the effects of the obese genotype on brown (and white) adipocyte size, number, and lipid content and tissue lipoprotein lipase (LPL) activity. In the obese rats, brown fat depots were increased in mass. This increase could be accounted for by brown fat hypertrophy (due primarily to an increase in the amount of triglyceride present in each cell) rather than hyperplasia (there being no increase in the number of brown fat cells). In addition, unlike the situation in white fat, the brown fat from the obese rats did not exhibit higher LPL activity than did the brown fat from their lean littermates. This absence of an increased capacity for triglyceride uptake, coupled with the greater amount of triglyceride per brown adipocyte, is consistent with a reduction of triglyceride oxidation (and, thus, heat production) in the cells from the obese (v the lean) rats.     

Effects of palatable diets on body weight and adipose tissue cellularity in the adult obese female Zucker rat (fa/fa)

Obese 7–8 mo-old female Zucker rats (fa/fa) and their lean littermates (Fa/?) exhibited the same percentage increase in body weight during a 50-day period when both groups of animals were fed a highly palatable snack food diet (SF). A subsequent 50-day period of refeeding with standard laboratory chow caused rats of both genotypes to shed the excess weight gained on SF. These findings suggest that lean and obese Zucker female rats are comparably responsive to a highly palatable diet. When a second group of female fa/fa rats were fed either SF or another palatable, semipurified high fat diet for 135 days, beginning at 2–3 mo of age, they were found to have substantially more fat cells in all depots studied that did female (fa/fa) rats that had been fed only chow. Thus, the obese Zucker rat is also comparable to normal rats with respect to the phenomenon of diet-induced adipocyte hyperplasia.     

Adrenalectomy reduces but does not reverse obesity in ob/ob mice

Bilateral adrenalectomy (ADX) of 4-month-old ob/ob mice led to reduced rates of body weight gain, a complete cessation of fat deposition and increased percentage carcass protein and ash during a 2-month observation period after surgery. However, ADX obese mice were still heavier and had more body fat and lower concentrations of carcass protein and ash than intact sex-matched littermate lean mice at the end of the experiment. When adrenalectomy was performed in younger obese mice before the syndrome was fully expressed (23 +/- 2 days of age), body weight gain was reduced by 40 per cent and fat deposition by 50 per cent during the next 3.5 months, but each was still greater than that of littermate lean mice. Despite the lower rate of weight gain after adrenalectomy, the skeletal and lean body growth of the early ADX obese mice equalled that of both obese and lean mice fed ad libitum. When the carcass composition of early ADX obese mice was compared with that of intact obese mice which were calorically restricted to the same rate of body weight gain, the ADX group had significantly less carcass fat (28 per cent) and more protein (50 per cent) and ash (20 per cent) than the dieted obese mice. In both experiments adrenalectomy led to reduced circulating immunoreactive insulin levels, although hyperinsulinemia persisted. The present results show that adrenalectomy is an effective tool for ameliorating the severity of many aspects of the ob/ob syndrome, particularly when compared with caloric restriction, but the procedure does not entirely reverse the deranged metabolism or abnormal carcass composition of these mice.     

Thermogenic drugs for the treatment of obesity: screening using obese rats and mice

The thermogenic activity of ephedrine, ethinyloestradiol and triiodothyronine were compared by incorporating the drugs into the diets fed to groups of adult rats and mice. The animals used were normal lean mice, hypothalamic obese mice, dietary-induced obese mice and rats, and genetically obese mice and rats. Food intake and body weight were monitored throughout and oxygen consumption measurements were made. Finally, the animals were killed and their carcasses analysed. Generally, ethinyloestradiol reduced body weight by causing anorexia. Triiodothyronine increased oxygen consumption but also increased food intake such that in most cases body weight did not change; it killed the genetically obese animals, but reduced fat in the hypothalamic and dietary induced obese animals. The animals treated with ephedrine lost body weight and body fat without increasing food intake, and had elevated oxygen consumptions. This experiment not only demonstrated marked differences between the various laboratory animal models of obesity, but also that ephedrine is a potential slimming agent. It is relatively safe and has been used by us to obtain successful breeding using the genetically obese male animals which are normally sterile.     

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

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

Exercise training improves insulin sensitivity in the obese Zucker rat

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

Anti-obesity effect of two different levels of dehydroepiandrosterone in lean and obese middle-aged female Zucker rats

Dehydroepiandrosterone has previously been shown to prevent weight gain in growing lean and obese mice and rats. In the present study, lean and obese female Zucker rats were treated with either 0.6 or 1.0 percent DHEA in the diet from 8 until 14 months of age. In lean rats, 0.6 percent DHEA prevented weight gain and 1.0 percent DHEA resulted in significant weight loss compared to initial body weight. Control lean rats had a significant weight gain. Both 0.6 and 1.0 percent DHEA obese rats lost weight over the experimental period while control obese rats gained weight. Food intake of DHEA-treated obese rats was lowered compared to control obese rats but was similar to that of all lean groups. DHEA lowered serum insulin levels in both lean and obese rats relative to control groups. Both 0.6 and 1.0 percent DHEA lean rats had elevated hepatic G6PD activity compared to control lean rats. DHEA obese rats had lowered G6PD activity compared to the control obese rats. Hepatic malic enzyme was elevated by DHEA treatment in both lean and obese Zucker rats. Adipose tissue weights were lowered substantially in DHEA treated lean and obese rats versus their control groups. These data indicate that DHEA treatment in adult rats has an anti-obesity effect.     

Testosterone supplementation in male obese Zucker rats reduces body weight and improves insulin sensitivity but increases blood pressure

Androgen levels are lower in obese men as compared with normal weight individuals. However, there are no safety data regarding the chronic use of androgen supplements in middle-aged men. The present study was undertaken to determine the cardiovascular and metabolic effects of chronic (10 weeks) testosterone treatment in male obese Zucker rats, starting at 22 weeks of age, when testosterone levels were significantly decreased. Testosterone supplements increased plasma levels, 10-fold in both obese Zucker rats and lean Zucker rats. In obese Zucker rats, testosterone supplements reduced body weight, plasma insulin, and cholesterol levels and improved the oral glucose tolerance test. None of these parameters were affected in lean Zucker rats. Mean arterial pressure was significantly increased in obese Zucker rats but not lean Zucker rats. Testosterone supplements increased proteinuria and accelerated renal injury in lean Zucker rats only. Thus, treatment of obese men with chronic testosterone supplements should be done with careful monitoring of blood pressure.     

Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity in the obese Zucker rat

This study was designed to assess the contribution of hyperinsulinemia to the maintenance of high adipose and low muscle lipoprotein lipase (LPL) activity in the obese Zucker fa/fa rat. Insulinemia in obese Zucker rats was reduced for 4 days with a single injection of low-dose streptozotocin (STZ). Saline-injected intact obese (obese-INT) and STZ-injected obese (obese-STZ) rats were compared with a lean Fa/? reference group. LPL activity was assessed after a 12-hour fast, with or without a 1-hour refeeding period. Fasting serum insulin levels were 17-fold higher in obese-INT versus lean rats and were reduced to 60% of obese-INT levels in obese-STZ animals. In the postprandial state, serum insulin levels remained low in obese-STZ rats and were similar to the values in lean animals, whereas insulinemia increased in the obese-INT group to 18-fold the levels in lean rats. Serum glucose, nonesterified fatty acid (NEFA), and triglyceride levels, which were higher in obese-INT versus lean rats, were further increased in the obese-STZ group. Tissue weights of obese rats were unaffected by STZ treatment. Fasting LPL specific activity was higher in white adipose tissue ([WAT] +87%) and brown adipose tissue ([BAT] +167%) of obese-INT versus lean rats. Reducing the insulinemia in obese-STZ rats reduced fasting enzyme activity to the levels in lean animals in both WAT and BAT. Insulinemia and adipose LPL activity were positively correlated in the fasted state. Acute food intake increased WAT LPL activity in lean animals, but not in obese animals. Soleus LPL activity was lower in obese-INT compared with lean rats and was further decreased in obese-STZ animals. Heart LPL was decreased only in obese-STZ rats compared with the lean group. LPL in muscle tissue was not correlated with insulinemia, but an inverse relationship was found between serum NEFA levels and enzyme activity. It is concluded that in the obese Zucker rat, hyperinsulinemia is responsible for the maintenance of elevated basal LPL activity in adipose tissue independently of fat mass, whereas muscle enzyme activity appears to be more strongly and inversely related to the availability or tissue utilization of lipid substrates.     

The effects of 2-deoxy-D-glucose on brown adipose tissue of lean and obese Zucker rats

The response of brown adipose tissue (BAT) thermogenesis, as measured by mitochondrial GDP binding, of lean and obese Zucker fa/fa rats to 2-deoxy-D-glucose (2-DOG) has been investigated. 2-DOG reduced BAT mitochondrial GDP binding of lean rats but had no effect in obese rats. Adrenalectomy increased BAT GDP binding in obese rats and restored the 2-DOG inhibitory effect. Corticosterone inhibited GDP binding in lean rats and abolished the 2-DOG inhibitory effect. 2-DOG induced hyperphagia and hyperglycaemia in lean rats, but these effects were either absent or attenuated in the obese. The possibility that a glucocorticoid inhibition of glucose metabolism impairs sympathetic activity in the obese rats is discussed.