guanosine-diphosphate and Obesity

Topics: Adipocytes, Brown; Adipose Tissue, Brown; Animals; Diet; Disease Models, Animal; Gene Expression Regulation; Guanosine Diphosphate; History, 20th Century; History, 21st Century; Humans; Mice; Mitochondria; Mitochondrial Membranes; Obesity; Oxidative Phosphorylation; Oxygen Consumption; Thermogenesis; Uncoupling Protein 1

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Central Nervous System; Cold Temperature; Diet; Fatty Acids; Food Deprivation; Glucagon; Glucocorticoids; Gonadal Steroid Hormones; Guanosine Diphosphate; Humans; Insulin; Light; Melatonin; Norepinephrine; Obesity; Oxygen Consumption; Periodicity; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Sodium-Potassium-Exchanging ATPase; Sympathetic Nervous System; Thyroid Hormones; Triglycerides

Topics: Guanosine Diphosphate; Humans; Obesity; Prevalence; Socioeconomic Factors

The explanation of obesity as a simple result of positive energy balance fails to account for the scope of variable responses to diets and lifestyles. It is postulated that individual physiological and anatomical variation may be responsible for developing obesity. Girls in poor families develop greater adiposity than their male siblings, a trend not present in richer environments. This indicates strong influence of estrogen on fat accumulation irrespective of poor socioeconomic conditions. Obesity rates in males and females of developed nations are similar, while in poorer nations obesity is much more prevalent in females. Female to male ratio of obesity correlates inversely with gross domestic product. Therefore, the parity of male and female obesity in developed countries may result from male exposure to environmental estrogen-like substances associated with affluence. These hormonally driven mechanisms may be equally active within both sexes in more developed areas, thereby increasing overall obesity.

Topics: Developed Countries; Developing Countries; Estrogens; Female; Guanosine Diphosphate; Humans; Male; Models, Biological; Obesity; Rural Population; Siblings; Skinfold Thickness; Urban Population

Sympathetic nerve activity is increased in obesity-related hypertension. However, the central mechanisms involved in the increased sympathetic outflow remain unclear. The hypothalamic melanocortin system is important for regulating energy balance and sympathetic outflow. To understand the mechanisms by which the melanocortin systems regulates sympathetic outflow, we investigated the role of melanocortin 4 receptors (MC4R) in regulating presympathetic paraventricular nucleus (PVN) neurons. We performed whole-cell patch-clamp recordings on retrogradely labeled PVN neurons projecting to the rostral ventrolateral medulla in brain slices from obese zucker rats (OZRs) and lean zucker rats (LZRs). The MC4R agonists melanotan II (MTII) and α-melanocyte-stimulating hormone (α-MSH) increased the firing activity and depolarized the labeled PVN neurons from both LZRs and OZRs in a concentration-dependent manner. MTII produced significant greater increase in the firing activity in OZRs than in LZRs. Blocking MC4R with the specific antagonist SHU9119 had no effect on the basal firing rate but abolished the MTII-induced increase in the firing rate in both OZRs and LZRs. Furthermore, intracellular dialysis of guanosine 5'-O-(2-thodiphosphate), but not bath application of kynurenic acid and bicuculline, eliminated the MTII-induced increase in firing activity. In addition, MTII had no effect on the frequency and amplitude of glutamatergic excitatory postsynaptic currents and GABAergic inhibitory postsynaptic currents in labeled PVN neurons. Collectively, our findings suggest that MC4R contributes to the elevated excitability of PVN presympathetic neurons, which may be involved in obesity-related hypertension.

Topics: alpha-MSH; Animals; Bicuculline; Guanosine Diphosphate; Kynurenic Acid; Male; Melanocyte-Stimulating Hormones; Neurons; Obesity; Paraventricular Hypothalamic Nucleus; Patch-Clamp Techniques; Peptides, Cyclic; Rats; Rats, Zucker; Receptor, Melanocortin, Type 4; Thionucleotides

It has been suggested that increased dietary calcium intake can attenuate obesity. Calcium antagonists, such as benidipine, also have been shown to have an anti-obesity effect. However, the mechanism for calcium-related anti-obesity effect has not yet been established. A defective brown adipose tissue thermogenesis has been shown in obese rodents. This study was designed to examine the direct effects of calcium channel blocker benidipine and calmodulin antagonist W7 administration on the adaptive thermogenesis in brown adipose tissue taken from the genetically obese mice and their lean controls. The GDP binding to brown-fat cell mitochondria was used as a brown adipose tissue thermogenic index. The results show that benidipine treatment had no marked effect on brown-fat cell GDP-binding capacities in both obese and lean mice. However, GDP-binding capacities were significantly reduced in both obese and lean mice after the W7 administration. The results of this study support the previous finding that benidipine did not have direct thermogenic effect on brown adipose tissue and suggest that the change in intracellular calmodulin availability might contribute to the adaptive thermogenesis in brown adipose tissue.

Topics: Adipose Tissue, Brown; Animals; Calcium Channel Blockers; Calmodulin; Dihydropyridines; Enzyme Inhibitors; Female; Guanosine Diphosphate; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Sulfonamides; Thermogenesis

We investigated the relative importance of overeating, thermogenesis, and uncoupling protein (UCP) expression in determining the severity of obesity in male Wistar rats fed a highly palatable diet. After 2 wk of feeding, body weight did not differ significantly from controls (248 +/- 4 vs. 229 +/- 3 g; P > 0.3), but rectal temperature, brown adipose tissue (BAT) mass, UCP3 expression in gastrocnemius muscle, and UCP2 expression in white adipose tissue (WAT) were all elevated in diet-fed animals. In a further study, rats fed a palatable diet for 8 wk exhibited higher energy intake and rectal temperature than controls. Dietary-obese rats were divided into high (427-490 g; n = 8) and low (313-410 g; n = 10) weight gainers. The high gainers ate significantly more than the low gainers, and energy intake was positively correlated with weight gain (r(2) = 0.72, P < 0.01). UCP2 and UCP3 mRNA levels in gastrocnemius muscle were significantly increased above lean controls in all diet-fed animals, whereas UCPs in WAT and BAT did not differ significantly from controls. Whereas rats fed palatable food exhibited a thermogenic response, there was no significant difference in core temperature between high and low gain groups (37. 5 +/- 0.1 vs. 37.6 +/- 0.1 degrees C; P > 0.5). We conclude that a higher energy intake is the critical factor determining susceptibility to dietary obesity in unselected Wistar rats.

Topics: Adipose Tissue, Brown; Animals; Body Composition; Body Temperature; Body Weight; Carrier Proteins; Diet; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Guanosine Diphosphate; Hyperphagia; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondria; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Protein Biosynthesis; Rats; Rats, Wistar; Triglycerides; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3

To test if mitochondrial uncoupling in white adipocytes is responsible for obesity resistance of the aP2-Ucp transgenic mice expressing ectopic uncoupling protein 1 (UCPI) in white fat, mitochondrial membrane potential (delta psi(m)) was estimated by flow cytometry in adipocytes isolated from gonadal fat. Ectopic UCP1 (approximately 0.8 mol UCP1/mol respiratory chain) decreased the delta psi(m) and rendered the potential sensitive to GDP and fatty acids. These ligands of UCP1 had no effect on delta psi(m) in white adipocytes from non-transgenic mice, suggesting that the function of endogenous UCP2 in adipocytes was not affected. The results support the hypothesis that mitochondrial uncoupling in white fat may prevent development of obesity.

Topics: Adipocytes; Animals; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Carrier Proteins; Cell Membrane Permeability; Fatty Acids; Female; Flow Cytometry; Fluorescent Dyes; Guanosine Diphosphate; Ion Channels; Membrane Potentials; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Proteins; Obesity; Proteins; Uncoupling Protein 1; Uncoupling Protein 2

The mitochondrial uncoupling protein (UCP) has usually been found only in brown adipose tissue. We recently observed that a chronic administration of the beta 3-adrenergic agonist CL-316,243 (CL) induced the ectopic expression of UCP in white fat and skeletal muscle in genetic obese yellow KK mice. The aim of the present study was to examine whether UCP could be induced in nongenetic obese animals produced by neonatal injections of monosodium L-glutamate (MSG). The daily subcutaneous injection of CL (0.1 mg/kg) to MSG-induced obese mice for 2 wk caused significant reductions of body weight (15%) and white fat pad weight (58%). Northern and Western blot analyses showed that CL induced significant expressions of UCP in the white fat and muscle, as well as in brown fat. Immunohistochemical observations revealed that the UCP stains in white fat were localized on multilocular cells and that those in muscle were localized on slow-twitch fibers rich in mitochondria. Immunoelectron microscopy confirmed the mitochondrial localization of UCP in the myocytes. The guanosine 5'-diphosphate (GDP) binding to mitochondria in brown fat doubled after the CL treatment. Moreover, significant GDP binding was detected in the white fat and muscle of the CL-treated mice, at about one-fourth and one-thirteenth the activity of brown fat, respectively, suggesting that ectopically expressed UCP is functionally active. We concluded that the beta 3-adrenergic agonist CL can induce functionally active UCP in white fat and slow-twitch muscle fibers of obese mice.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Carrier Proteins; Dioxoles; Female; Food Additives; Guanosine Diphosphate; Ion Channels; Membrane Proteins; Mice; Mice, Obese; Microscopy, Immunoelectron; Mitochondria, Muscle; Mitochondrial Proteins; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Obesity; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; RNA, Messenger; Sodium Glutamate; Uncoupling Protein 1

Brown adipose tissue (BAT) of obese animals is generally in a relatively atrophied and thermogenically quiescent state. The aim of the current study was to investigate the effect of swimming training on BAT activity in lean and obese (ob/ob) mice. The trained mice underwent a 6-week endurance swimming training (1 h/day, 5 days/week) in water at 35-36 degrees C. The swimming training significantly increased BAT mass and its protein content in both the lean and obese mice, suggesting hypertrophy. After swimming training, the amounts of protein and guanosine 5'-diphosphate binding in the mitochondria recovered from BAT of both mice increased significantly as compared with the respective sedentary groups, whereas the uncoupling protein (UCP) content increased significantly only in lean mice. After swimming training, the level of UCP mRNA expression did not change substantially in lean mice but appeared to increase in obese mice. The results obtained here suggest that swimming training leads to an increase in the nonshivering thermogenesis of obese mice in addition to lean mice.

Topics: Adipose Tissue, Brown; Animals; Blotting, Northern; Blotting, Western; Body Weight; Carrier Proteins; Gene Expression Regulation; Guanosine Diphosphate; Ion Channels; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Organ Size; Protein Binding; Rats; RNA, Messenger; Uncoupling Protein 1

The anti-obesity and anti-diabetic effects of a highly specific beta 3-adrenoceptor agonist, CL316,243 (CL; beta 1: beta 2: beta 3 = 0:1:100,000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and Long-Evans Tokushima Otsuka (control) rats. Daily injection of CL (0.1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27%; control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5'-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic beta-Agonists; Analysis of Variance; Animals; Blotting, Northern; Blotting, Western; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dioxoles; Eating; Glucose Transporter Type 4; Guanosine Diphosphate; Hypoglycemic Agents; Immunohistochemistry; Ion Channels; Male; Membrane Proteins; Mitochondrial Proteins; Monosaccharide Transport Proteins; Muscle Proteins; Obesity; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; RNA, Messenger; Uncoupling Protein 1; Weight Gain

MPV-1743 A III ((+/-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation.

Topics: Adipose Tissue, Brown; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Anti-Obesity Agents; Binding Sites; Cell Line; Cerebral Cortex; Eating; Female; Guanosine Diphosphate; Imidazoles; In Vitro Techniques; Indenes; Male; Mydriatics; Obesity; Protein Binding; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; RNA, Messenger; Weight Gain

In this study, we investigate the in vitro effect of zinc addition on guanosine diphosphate (GDP) binding to mitochondria in brown adipocytes of genetically obese (ob/ob) mice. Interscapular brown adipocytes of male mice (obese; lean) at 4 and 12 wk of age were incubated with 0, 50, 100, or 200 microM zinc sulfate. Mitochondria were then isolated and their GDP binding capacities were measured. The GDP-binding capacities of ob/ob mice were lower than lean mice, with or without zinc addition, in both age groups (p < 0.05). Zinc addition did not have any significant effect on GDP binding in lean mice. GDP binding decreased with increasing zinc addition in ob/ob mice, and this attenuation was more predominant in 12-wk old ob/ob mice. Moreover, we found that high magnesium addition (5 mM) increased GDP binding in lean mice, but this effect was not significant in ob/ob mice. This study reveals that brown adipose tissue thermogenesis in ob/ob mice could be greatly attenuated by zinc addition, suggesting that zinc may play a regulatory role in obesity.

Topics: Adipocytes; Adipose Tissue, Brown; Animals; Binding Sites; Body Temperature Regulation; Guanosine Diphosphate; Magnesium; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria; Obesity; Zinc

This study was undertaken to determine whether administration of a thermogenic beta-agonist drug to Zucker fatty rats could correct some of the earliest metabolic defects detectable in brown adipose tissue (BAT). Fa/fa and fa/fa littermates were given oral administration of BRL-35135 from 8 to 16 days of age. In fa/fa rats, the lipid content of white and brown adipose tissues was significantly reduced. In the BAT of fa/fa rats, thermogenic capacity was restored to the level observed in Fa/fa rats, whereas hyperactivity of fatty acid synthetase was abolished, and a deficit in lipoprotein lipase (activity and mRNA) was partly corrected. Hyperinsulinemia in fa/fa pups was significantly reduced. The decreased content of GLUT-4 mRNA that characterized BAT of fa/fa pups was also restored to normal. At variance with observations in preobese rats, BRL had very little or no effect on lean Fa/fa rats. The present study reveals that chronic administration of a beta-agonist drug early in life prevents emergence of most of the metabolic abnormalities that characterize fa/fa rats at the onset of obesity. This suggests that impaired sympathetic activity may play a role in the development of this genetic obesity.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Base Sequence; Body Temperature Regulation; Carrier Proteins; Fatty Acid Synthases; Fatty Acids, Nonesterified; Female; Gene Expression; Glucose Transporter Type 4; Guanosine Diphosphate; Ion Channels; Lipid Metabolism; Lipoprotein Lipase; Male; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Molecular Sequence Data; Monosaccharide Transport Proteins; Muscle Proteins; Obesity; Oligodeoxyribonucleotides; Phenethylamines; Rats; Rats, Zucker; RNA, Messenger; RNA, Ribosomal, 18S; Thinness; Uncoupling Protein 1

The effects of dietary mineral levels on caloric intake, nutrient choice, body weight, adipose tissue weight, interscapular brown adipose tissue (IBAT) weight, and thermogenic capacity, and plasma insulin and glucose levels were examined in adult male Sprague-Dawley rats. In Experiments 1 and 2, rats were fed a purified diet with zinc (Zn), chromium (Cr), and selenium (Se) added, or the same diet without the addition of these minerals. In Experiment 3, the effects of Zn and Cr were examined separately. In all experiments, half of the rats in each diet group were given a 32% sucrose solution in addition to their standard diet and water. Rats given sucrose consumed more calories and gained more weight than rats not given sucrose. However, mineral levels altered the effects of sucrose on these measures. Added minerals increased percent sucrose intake, reduced weight gain and feed efficiency, increased GDP binding in IBAT mitochondria, improved glucose tolerance, and reduced plasma insulin levels. The reduction in weight gain and increased feed efficiency found when Zn alone was added to the diet was independent of sucrose condition. In comparison, the alterations observed in these measures when Cr alone was added to the diet varied as a function of sucrose availability.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Chromium; Diet; Drinking; Eating; Glucose Tolerance Test; Guanosine Diphosphate; Insulin; Male; Minerals; Obesity; Organ Size; Rats; Rats, Sprague-Dawley; Selenium; Sucrose; Weight Gain; Zinc

To investigate the hypothesis that anti-obesity action of bofu-tsusho-san (TJ-62) works via activating the brown adipose tissue thermogenesis and inhibiting the phosphodiesterase activity.. MSG obese mice and lean controls were fed a diet including 1.4% or 4.7% TJ-62 of weight of food for 8 weeks. Another group of MSG obese mice were fed with 1-ephedrine (1-E) + d-pseudoephedrine (d-PE) of equivalent amounts as contained in TJ-62 (4.7%) for 8 weeks. Yet another group of MSG obese mice were further supplemented with Glycyrrhizae Radix (GR) extract + Forsythiae Fructus (FF) extract + Schizonepetae Spica (SS) extract (that inhibited phosphodiesterase activity) of amounts contained in TJ-62 (4.7%) for 8 weeks.. The following were measured: The concentration of ephedrine and its congeners in TJ-62; the inhibitory effect of TJ-62 on phosphodiesterase activity; body weight; food intake; retroperitoneal white adipose tissue (RWAT) weight; interscapular brown adipose tissue (IBAT) weight; mitochondrial protein content in IBAT; cytochrome c oxidase activity in IBAT; guanosine-5'-diphosphate (GDP) binding in IBAT mitochondria.. One gram of TJ-62 contained 3.33 mg of 1-E and 0.73 mg of d-PE. One mg of TJ-62 was equivalent to 2.5 mg of caffeine in the inhibitory effect on phosphodiesterase activity. After feeding with TJ-62, GDP binding was significantly increased in a dose dependent manner. Body weight and RWAT weight decreased in both MSG obese mice and lean controls. Food intake was not changed by TJ-62. Feeding with 1-E + d-PE produced responses of about 70% of those of TJ-62. These responses were, furthermore, enhanced by the addition of the three extracts to the levels that were similar to those produced by TJ-62.. Bofu-tsusho-san (TJ-62) works via activating the BAT thermogenesis and inhibiting the phosphodiesterase activity in mice.

Topics: Adipose Tissue; Animals; Body Composition; Body Temperature Regulation; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Eating; Electron Transport Complex IV; Energy Metabolism; Ephedrine; Female; Glycyrrhiza; Guanosine Diphosphate; Japan; Mice; Mice, Inbred ICR; Mice, Obese; Mitochondria; Obesity; Phosphodiesterase Inhibitors; Plants, Medicinal; Sodium Glutamate; Time Factors

1. The effects of chronic treatments with a selective beta 3-adrenoceptor agonist and a selective alpha 2-adrenoceptor antagonist and their interactions with physical exercise training were studied in experimental obesity. 2. BRL 35135 (beta 3-agonist, 0.5 mg kg-1 day-1 p.o.), atipamezole (alpha 2-antagonist, 4.0 mg kg-1 day-1 p.o.) and placebo were given to genetically obese male Zucker rats. Half of the rats were kept sedentary whereas the other half were subjected to moderate treadmill exercise training. Body weight gain, cumulative food intake, the neuropeptide Y content of the hypothalamic paraventricular nucleus, brown adipose tissue thermogenic activity (measured as GDP binding), plasma insulin and glucose levels were measured after 3 weeks' treatment and exercise. 3. Treatment with BRL 35135 reduced weight gain by 19%, increased brown adipose tissue thermogenic activity 45-fold and reduced plasma insulin by 50%. Atipamezole slightly increased food intake and neuropeptide Y content in the paraventricular hypothalamic nucleus but had no effect on the other measured parameters. Exercise alone had no effect on weight gain, food intake or thermogenic activity, whereas it reduced plasma insulin and glucose levels. 4. The effect of BRL 35135 on weight gain and thermogenic activity was significantly potentiated by exercise; the reduction in weight gain was 56% in comparison with 19% in sedentary animals. Food intake was significantly reduced in the BRL 35135-treated-exercise-trained animals, although neither beta 3-agonist nor exercise alone affected it. 5. Based on the present results in genetically obese Zucker rats, combination of 03-agonist treatment with a moderate physical training may offer a new feasible approach to the therapy of obesity.-. BRL 35135; atipamezole; P3-adrenoceptor agonism; M2-adrenoceptor antagonism; brown adipose tissue; thermogenesis;genetic obesity; Zucker rat; exercise; neuropeptide Y

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Temperature Regulation; Feeding Behavior; Guanosine Diphosphate; Imidazoles; Insulin; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Phenethylamines; Physical Conditioning, Animal; Rats; Rats, Zucker; Weight Gain

A single intracerebroventricular injection of dexamethasone rapidly (within 30 min) decreases brown adipose tissue thermogenesis by 25% as assessed by GDP binding and increases plasma insulin twofold in adrenalectomized ob/ob mice. The present study investigated the type of corticoid receptor(s) that mediate these effects and determined whether protein synthesis was necessary for expression of these glucocorticoid actions in ob/ob mice. Intracerebroventricular injection of aldosterone (a type I-corticoid receptor agonist) was ineffective in altering peripheral metabolism in adrenalectomized ob/ob mice, whereas RU-486 (a type II-corticoid receptor antagonist) abolished the effects of dexamethasone. Thus type II-like corticoid receptors, not type I receptors, mediated the rapid effects of dexamethasone in adrenalectomized ob/ob mice. Anisomycin (0.5 mg) administered subcutaneously almost completely suppressed (-92%) cerebral protein synthesis, but anisomycin did not abolish the rapid effects of dexamethasone in adrenalectomized ob/ob mice. Thus protein synthesis is not a prerequisite for rapid effects of dexamethasone in adrenalectomized ob/ob mice.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Anisomycin; Brain; Dexamethasone; Guanosine Diphosphate; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mifepristone; Obesity; Oxygen Consumption; Protein Biosynthesis; Receptors, Glucocorticoid

Brown adipose tissue (BAT) thermogenesis is an uncoupled ATPase-independent thermogenic mechanism. Ion transport by the Na,K pump is an ATPase-dependent thermogenic mechanism. Both have been proposed as mechanisms of altered energy expenditure during states of dietary energy surfeit and deficit. Our aim was to study these mechanisms during diet-induced obesity and weight loss. Over 36 weeks rats were fed lard- or tallow-based diets (63% energy as fat), or a control diet (12% energy as fat). During periods of restriction rats were fed 50% of the energy intake of controls in the form of a control diet. Several components of thermogenic response increased in rats eating high fat diets and decreased following dietary restriction. BAT activation occurred, particularly with a lard-based diet, as indicated by increased GDP binding and uncoupling protein (UCP) content. Na,K pump activity in thymocytes increased with the feeding of both high fat diets at some time points. Plasma T3 level increased in rats eating the lard-based diet and decreased with dietary restriction regardless of previous diet. Resting metabolic rate (RMR) of the animals was unchanged despite increases in these thermogenic components and was decreased in all groups following dietary restriction. Our results indicate a lack of any major role for activated BAT thermogenesis in mitigating the extent of the obesity induced by the high fat diets. The reasons for the differences in response to the two different sources of saturated fat, lard, and tallow, are not clear.

Topics: Adenosine Triphosphatases; Adipose Tissue; Adipose Tissue, Brown; Animals; Body Composition; Body Weight; Carrier Proteins; Diet; Energy Intake; Energy Metabolism; Guanosine Diphosphate; Ion Channels; Male; Membrane Proteins; Mitochondrial Proteins; Obesity; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Thermogenesis; Thymus Gland; Thyroxine; Time Factors; Triiodothyronine; Uncoupling Protein 1; Weight Loss

The metabolic properties of brown adipose tissue (BAT), liver, and skeletal muscles were compared in lean and obese diabetic SHR/N-cp rats (a new model of type II diabetes) to test whether the severe insulin resistance of obese animals is specifically associated with a thermogenic defect in BAT. The respiratory response of brown adipocytes to norepinephrine and to agents bypassing the adenylate cyclase complex (dibutyryl cyclic AMP and palmitate) was decreased by two-thirds in obese rats, thereby indicating the presence of a major postreceptor defect. Significantly, total BAT cytochrome oxidase activity, uncoupling protein content, and mitochondrial guanosine 5'-diphosphate binding (3 indexes of BAT thermogenic capacity) were also decreased by two-thirds. The specific activities of these parameters expressed per total BAT mitochondrial protein were not altered either. This indicates that the total number of mitochondria per cell is decreased in BAT of obese rats. In contrast, total tissue cytochrome oxidase activity, protein content, and DNA content all increased by two to three times in the liver of obese SHR/N-cp rats, but these parameters remained unchanged in skeletal muscles (vastus lateralis and soleus). Such a remarkable liver hypertrophy may have occurred as a consequence of the persistent hyperphagia-hyperinsulinemia of obese rats that induced a hyperplasia and/or a hepatocyte polyploidization. This observation together with the fact that daily energy expenditure associated with food intake was markedly increased in obese rats (representing as much as 25% of the total energy expenditure) strongly suggests that the liver plays a major role in energy balance in these animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Bucladesine; Crosses, Genetic; DNA; Electron Transport Complex IV; Energy Metabolism; Female; Guanosine Diphosphate; Kinetics; Mitochondria; Mitochondria, Liver; Mitochondria, Muscle; Norepinephrine; Obesity; Organ Specificity; Oxygen Consumption; Palmitic Acid; Palmitic Acids; Rats; Rats, Inbred SHR; Rats, Mutant Strains; Thinness

d-Fenfluramine is an appetite suppressant drug that acts by releasing serotonin from axon terminals and inhibiting its reuptake. S 5B/P1 rats, which are resistant to dietary-fat induced obesity, and Osborne-Mendel rats, which are sensitive, were adapted to ad lib feeding of either a low- or high-fat diet. d-Fenfluramine (10 mg/kg, IP) was injected daily for 12 days. Other than a slightly greater suppression of food intake in Osborne-Mendel rats, there was little difference in response to d-fenfluramine between S 5B/P1 and Osborne-Mendel rats eating the low-fat diet. However, in Osborne-Mendel rats d-fenfluramine completely abolished the excess food intake and weight gain associated with the high-fat diet. Purine nucleotide (GDP) binding on day 13 was higher in S 5B/P1 rats than in Osborne-Mendel rats and was increased by d-fenfluramine in animals of both strains eating the low-fat diet. The high-fat diet increased GDP binding only in S 5B/P1 rats and blocked the fenfluramine-induced increase in GDP binding in both strains. We speculate that d-fenfluramine blocks a feeding reward system stimulated by the high-fat diet.

Topics: Animals; Dietary Fats; Disease Models, Animal; Eating; Fenfluramine; Guanosine Diphosphate; Hypothalamus; Male; Obesity; Rats; Serotonin; Species Specificity; Sympathetic Nervous System; Weight Gain

The effect of chronic metformin treatment on brown adipose tissue thermogenetic activity was investigated in young genetically obese Zucker rats. The binding of [3H]GDP to brown adipose tissue mitochondria, expression of uncoupling protein mRNA in brown adipose tissue, weight gains and cumulative food intakes were measured in metformin (320 mg/kg orally for 12 days)-treated obese Zucker rats as well as in pair-fed--and in ad libitum--fed control obese rats. The weight gains were identically reduced in the metformin- and pair-fed control group compared to the ad libitum--fed rats. Metformin also significantly reduced cumulative food intake. The binding of [3H]GDP to brown adipose tissue mitochondria and the expression of uncoupling protein mRNA in brown adipose tissue were not modified by metformin. It is concluded that the weight gain reducing effect of metformin in obese Zucker rats is mainly due to reduced food intake and does not involve an effect of metformin on brown adipose tissue thermogenetic activity.

Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Body Temperature Regulation; Carrier Proteins; Eating; Guanosine Diphosphate; Insulin; Ion Channels; Male; Membrane Proteins; Metformin; Mitochondria; Mitochondrial Proteins; Obesity; Rats; Rats, Zucker; RNA, Messenger; Uncoupling Protein 1; Weight Gain

A single intracerebroventricular (icv) injection of dexamethasone (250 ng) lowers brown adipose tissue (BAT) thermogenesis and whole body metabolic rates and raises plasma insulin concentrations within 30 min in adrenalectomized ob/ob mice with minimal effects in adrenalectomized lean mice. The present study was conducted to determine if intracerebroventricular neuropeptide Y (NPY), a neuropeptide regulated in part by glucocorticoids, would mimic effects of dexamethasone in these mice. NPY lowered BAT metabolism and whole body oxygen consumption and raised plasma insulin concentrations within 30 min in adrenalectomized ob/ob mice similarly to dexamethasone; but, unlike dexamethasone, NPY was as effective in modulating these metabolic responses in adrenalectomized lean mice as in ob/ob mice. Further, intracerebroventricular NPY increased food intake equally in both ob/ob and lean mice, whereas dexamethasone did not alter food intake during the 30 min postinjection period. These data are consistent with the hypothesis that NPY mediates some of the effects of intracerebroventricular dexamethasone action in ob/ob mice and that the divergence between ob/ob and lean mice lies in glucocorticoid control of NPY release/synthesis rather than in NPY action mechanisms.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Dexamethasone; Eating; Energy Metabolism; Guanosine Diphosphate; Injections, Intraventricular; Insulin; Male; Mice; Mice, Inbred C57BL; Mitochondria; Neuropeptide Y; Obesity; Reference Values

The effects of fasting and refeeding on interscapular brown adipose tissue (IBAT) in normal rats and in those made obese by cafeteria feeding was investigated in order to evaluate the sequential feeding responses relating to the IBAT facultative thermogenesis. The thermogenic activity (GDP binding) and related parameters such as IBAT mass, tissue protein, mitochondrial protein and cytochrome c oxidase (COX) activity were compared in fed, fasted and refed situations in controls and in rats made obese by cafeteria feeding. The IBAT mass, tissue protein content, mitochondrial protein content, total COX activity and specific GDP binding were significantly increased by the cafeteria diet. The thermogenic response to fasting and refeeding was different between control and cafeteria obese rats. Thus, in control rats, the loss of mitochondrial protein as well as total COX activity are probably the main responses to fasting, whereas in cafeteria obese rats no changes in mitochondrial protein and total COX activity occur during fasting. Furthermore mitochondrial protein and total COX activity were not recovered during refeeding in control rats, and no changes occurred in cafeteria fed rats. However, the proton conductance pathway (measured by GDP binding) is inactivated in control and cafeteria fed rats on fasting. In conclusion, these results indicate different responses during fasting in the mitochondrial protein between control and dietary obese rats, suggesting a possible activated mitochondrial proteolysis in the control rats only.

Topics: Adipose Tissue, Brown; Analysis of Variance; Animals; Carrier Proteins; Eating; Electron Transport Complex IV; Female; Food Deprivation; Guanosine Diphosphate; Ion Channels; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Obesity; Rats; Rats, Inbred Strains; Uncoupling Protein 1

Adrenalectomy stimulates depressed brown adipose tissue (BAT) metabolism and decreases hyperinsulinemia in ob/ob mice, with minimal effects in lean mice. A single intracerebroventricular injection of dexamethasone (250 ng) into adrenalectomized ob/ob mice completely reversed the effects of adrenalectomy on BAT thermogenesis as assessed by mitochondrial GDP binding, approximately doubled plasma insulin, lowered whole body metabolic rates by 17%, and increased food intake by 19%. These responses were rapid in onset, with changes in BAT metabolism and plasma insulin occurring within 30 min of dexamethasone injection. Adrenalectomized lean mice were much less responsive to dexamethasone than their ob/ob counterparts. The dexamethasone-induced decrease in BAT thermogenesis in adrenalectomized ob/ob mice was associated with an organ-specific decrease in BAT sympathetic nerve activity as assessed by norepinephrine turnover, whereas the dexamethasone-induced increase in plasma insulin was blocked by atropine, suggesting involvement of the parasympathetic nervous system. Intracerebroventricular injection of corticotropin-releasing hormone did not affect BAT thermogenesis in dexamethasone-injected adrenalectomized ob/ob mice but markedly lowered plasma insulin concentrations, possibly by suppression of the parasympathetic nervous system. In conclusion, dexamethasone alters regulation of the autonomic nervous system in ob/ob mice.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Brain; Corticotropin-Releasing Hormone; Dexamethasone; Glucocorticoids; Guanosine Diphosphate; Injections, Intraventricular; Insulin; Male; Mice; Mitochondria; Obesity

The anti-obesity and anti-diabetic actions of BRL 26830A, beta 3-adrenoceptor agonist, (2 mg/kg administered intramuscularly daily for 2 weeks) were evaluated in obese diabetic Yellow KK mice and C57B1 control mice. The following parameters were compared in the treated vs. control animals: brown adipose tissue (BAT) thermogenesis, resting metabolic rate (RMR), insulin receptors in adipocytes, and blood glucose and serum insulin levels during a glucose overloading test. BRL 26830A significantly increased BAT thermogenesis and RMR but it decreased the amount of white adipose tissue without affecting food intake. Those actions contributed to the mitigation of obesity in Yellow KK mice. BRL 26830A also increased the concentration of insulin receptors and decreased the levels of serum insulin and blood glucose during the glucose overloading test in Yellow KK mice. In the glucose overloading test performed one hour after BRL 26830A injection, insulin secretion was significantly increased and the blood glucose level was markedly decreased in both groups. These observations suggest that BRL 26830A possesses anti-obesity and anti-diabetic actions and consequently may be useful for treating obesity as well as non-insulin-dependent diabetes mellitus with obesity.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Ethanolamines; Guanosine Diphosphate; Insulin; Male; Mice; Mice, Inbred Strains; Mitochondria; Obesity; Organ Size; Oxygen Consumption; Proteins

To clarify whether reduced brown adipose tissue (BAT) thermogenesis and resting metabolic rate (RMR) are the cause or the consequence of obesity in monosodium-L-glutamate (MSG)-treated mice, we measured guanosine-5'-diphosphate (GDP) binding, and oxygen consumption in the interscapular BAT (IBAT) mitochondria, and the RMR in pre-obese (3-week-old) and obese (12-week-old) MSG-treated mice. Decreases in IBAT mitochondrial GDP binding and oxygen consumption as well as lowered RMR in MSG-treated mice were found even in the pre-obese stage as well as the obese stage, when compared to those in control mice. These findings suggest that reduced BAT thermogenesis may be one of the contributing factors in the development of obesity.

Topics: Adipose Tissue, Brown; Animals; Basal Metabolism; Body Temperature Regulation; Female; Guanosine Diphosphate; Insulin; Mice; Mice, Inbred ICR; Mitochondria; Obesity; Oxygen Consumption; Sodium Glutamate; Triiodothyronine

A specific immunoassay of uncoupling protein (UCP) and measurement of GDP binding were used to study the chronic responses of brown adipose tissue (BAT) mitochondria from rats made obese by dietary means (cafeteria rats) and from obese rats subsequently fed a standard diet (post-cafeteria rats). We studied the response to fasting in order to assess the masking/unmasking responses in these groups. These studies have shown the following. (1) In the obese rats (cafeteria and post-cafeteria) the chronic increase in mitochondrial UCP concentration compared with controls parallels the increase in GDP binding. (2) In 24 h-fasted control rats the decrease in GDP binding is associated with a change in UCP concentration, but in fasting cafeteria and post-cafeteria obese rats the decrease in GDP binding is not associated with any change in UCP concentration. (3) Post-cafeteria obese rats showed increased GDP binding and higher UCP concentrations than the controls, but these values were less than in cafeteria obese rats. (4) Control rats at 8 months old showed greater GDP binding and had a higher UCP concentration than 11-month-old control rats. (5) The responses of GDP binding and UCP concentration to fasting in post-cafeteria obese rats were similar to those in cafeteria obese rats, suggesting that such abbreviations are related to the obese status itself rather than to the composition of the cafeteria diet. The evidence supports the hypothesis that the response of the cafeteria and post-cafeteria obese rats to fasting is associated with a masking of UCP, whereas with chronic manipulation of diet changes in UCP concentration predominate.

Topics: Adipose Tissue, Brown; Animals; Binding Sites; Carrier Proteins; Diet; Energy Intake; Fasting; Female; Guanosine Diphosphate; Ion Channels; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Obesity; Rats; Rats, Inbred Strains; Uncoupling Protein 1

Half of the mice in both the monosodium-L-glutamate (MSG)-induced obesity and saline control groups were given BRL 26830A via a gastric tube at a daily dose of 5 mg/kg for 2 weeks, and the other half given distilled water. BRL 26830A administration significantly increased guanosine-5'-diphosphate (GDP)-binding in brown adipose tissue (BAT) and the resting metabolic rate (RMR), and significantly reduced retroperitoneal white adipose tissue (WAT) pads in both groups. It also markedly reduced body weight in MSG obese mice that had reduced BAT thermogenesis and decreased RMR. However, food intake was unchanged in both groups. Neither beta 1- nor beta 2-selective antagonists affected the increase of RMR induced by BRL 26830A, but a non-selective beta-antagonist completely inhibited its increase. These results suggest that BRL 26830A, which is a new beta-adrenoceptor agonist, stimulates BAT thermogenesis, increases RMR, and reduces WAT, thus contributing to the mitigation of obesity.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Basal Metabolism; Ethanolamines; Female; Guanosine Diphosphate; Mice; Mice, Obese; Obesity; Temperature

The effects of high fat feeding on brown fat thermogenesis in rodents are controversial. In this study, we examined the effects of 8 d of high fat feeding on brown fat mitochondrial GDP binding (an in vitro index of thermogenic activity) in lean (Fa/?) and obese (fa/fa) Zucker rats. Six-week-old female rats were fed a defined low fat control diet (9.5% of energy from fat) only during the dark cycle (1200-2400 h), and food intake was measured daily at 1200, 1600, 2300, and 2400 h for 7 d (the control period). For the next 8 d, half of the lean and obese rats were fed a high fat diet (65% of energy from fat), and the others remained on the low fat control diet. Each rat was fed the amount of energy equivalent to its average energy intake during the 7-d control period. Rats were killed at 0800-1000 h. In the lean rats, high fat feeding increased GDP binding. This increased binding in the lean rats appeared to reflect levels of dietary fat and carbohydrate and was independent of caloric intake. The blunted GDP binding of the obese rats failed to respond to dietary changes.

Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Dietary Fats; Disease Models, Animal; Eating; Energy Intake; Female; Guanine Nucleotides; Guanosine Diphosphate; Insulin; Obesity; Rats; Rats, Zucker; Weight Gain

To clarify whether nicotine stimulates the sympathetic nervous system (SNS) and thermogenesis in brown adipose tissue (BAT) and whether it promotes the resting metabolic rate (RMR), with resulting mitigation of obesity, we measured norepinephrine (NE) turnover (an indicator of SNS activity), guanosine-5'-diphosphate (GDP) binding (a thermogenic indicator), oxygen consumption in BAT, and RMR in monosodium-L-glutamate (MSG) obese and saline control mice after 2 weeks treatment with nicotine. Nicotine significantly increased NE turnover, GDP binding, oxygen consumption in BAT, and RMR, and significantly reduced body weight in MSG obese mice as well as in control mice without affecting food intake. These results suggest that nicotine stimulates NE turnover and thermogenesis in BAT, and promotes RMR, all of which contribute to the mitigation of obesity.

Topics: Adipose Tissue, Brown; Animals; Basal Metabolism; Body Temperature Regulation; Body Weight; Eating; Female; Guanosine Diphosphate; Mice; Mice, Inbred ICR; Mitochondria; Nicotine; Norepinephrine; Obesity; Organ Size; Oxygen Consumption; Proteins; Sodium Glutamate

Mice treated neonatally with monosodium-L-glutamate (MSG) are known to develop into obese adults without hyperphagia, which are characterized by the reduced levels in the resting metabolic rate (RMR) and the thermogenesis of brown adipose tissue (BAT) in the thermoneutral environment. The present study revealed that an acute cold-exposure (5 degrees C, 1 h) of these animals resulted in the increase in norepinephrine turnover and mitochondrial-5'-diphosphate (GDP) binding in the interscapular BAT as well as the guanosine RMR, suggesting a normal thermogenic responsiveness of BAT to cold.

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Cold Temperature; Energy Metabolism; Female; Guanine Nucleotides; Guanosine Diphosphate; Mice; Mice, Inbred ICR; Mice, Obese; Norepinephrine; Obesity; Sodium Glutamate; Time Factors

Brown adipose tissue (BAT) thermogenesis was assessed by measuring mitochondrial guanosine diphosphate (GDP) binding, cytochrome oxidase activity and oxygen consumption in ovariectomized (OVX) and sham-operated rats. The food intake and body weight of OVX rats increased more than those of controls and OVX rats became obese. Mitochondrial GDP binding, as an indicator of thermogenic activity, cytochrome oxidase activity, as a marker of mitochondrial abundance, and mitochondrial respiration of BAT in OVX rats were significantly reduced compared with those in controls. And, also, even when OVX rats were restricted in food intake (pair-gained) to produce comparable changes in body weight with sham-controls, or matched in food intake (pair-fed) with sham-controls, these parameters in both pair-gained and pair-fed OVX groups were decreased markedly compared to those in sham-controls. As expected, body weight in pair-fed OVX rats increased significantly more than that in sham-controls. In response to cold exposure, these parameters of OVX rats increased as much as those of controls did. These results suggest that reduced brown adipose tissue thermogenesis might be one of the important factors that are responsible for the development of obesity after OVX.

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Electron Transport Complex IV; Female; Guanosine Diphosphate; Mitochondria; Obesity; Ovariectomy; Oxygen; Rats; Rats, Inbred Strains

The effect of electrolytic lesions in the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN) has been compared during both the dynamic and static phase of weight gain. Hyperphagia and weight gain were greater in the VMH-lesioned rats than in the PVN-lesioned rats. Food intake increased at night after both lesions but increased in the daytime only in VMH-lesioned rats. During the dynamic phase of rapid weight gain, the diurnal pattern of corticosterone was blunted to a similar degree in both lesioned groups. The morning insulin concentrations were higher in both lesioned groups than in the sham-operated controls, but in the static phase only the VMH-lesioned rats had higher insulin levels. In the afternoon the insulin was higher in the VMH-lesioned rats than in either the sham-operated or PVN-lesioned rats. In the dynamic phase the weight of interscapular brown adipose tissue was significantly increased in the VMH-lesioned rats, but the specific GDP binding was depressed both in the morning and afternoon when compared with either the sham-operated or PVN-lesioned groups. In both the dynamic and static phases GDP binding was similar in sham-operated and PVN-lesioned animals. The differences in concentration of corticosterone in morning and afternoon were smaller in the lesioned groups than in the controls. These data are consistent with the hypothesis that animals with PVN lesions do not show the disturbances in food intake or in the autonomic nervous system that characterize the VMH-lesioned rats.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Circadian Rhythm; Corticosterone; Energy Intake; Female; Guanosine Diphosphate; Insulin; Mitochondria; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Time Factors; Ventromedial Hypothalamic Nucleus

Topics: Adipose Tissue, Brown; Animals; Glutamates; Guanine Nucleotides; Guanosine Diphosphate; Mitochondria; Obesity; Oxygen Consumption; Rats; Rats, Inbred Strains

The influence of diet on the response of lean and obese fa/fa rats to adrenalectomy has been studied. Adrenalectomized and sham-operated rats were fed either a semi-synthetic high-carbohydrate (HC) or high-fat (HF) diet for 13 days. Energetic efficiency, calculated for measurements of energy storage and energy intake, was increased in obese rats fed both HC and HF diets and reduced close to values of lean rats after adrenalectomy. Brown adipose tissue mitochondrial GDP binding and uncoupling protein concentration were reduced in control obese rats fed both HC and HF diets. After adrenalectomy the level of GDP binding and uncoupling protein concentration were increased to levels of lean rats. Molar ratios of GDP binding to uncoupling protein were similar in lean and obese rats, were unaffected by adrenalectomy, but were elevated in rats fed the HC diet (0.40 +/- 0.02 vs 0.28 +/- 0.03). The data suggests that diet, but not obese genotype, may influence the masking of mitochondrial uncoupling protein.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Body Composition; Body Weight; Carrier Proteins; Dietary Carbohydrates; Dietary Fats; Energy Intake; Energy Metabolism; Guanosine Diphosphate; Ion Channels; Male; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Obesity; Rats; Rats, Zucker; Uncoupling Agents; Uncoupling Protein 1

Daily injection of lean Zucker rats with a beta 2-adrenergic agonist (clenbuterol, 1 mg/kg) for 22 day increased weight gained by 38 per cent; there were significant increases in carcass protein and water, but fat content was unaltered. Clenbuterol did not affect energy intake or expenditure, the acute thermogenic response to food, or brown adipose tissue (BAT) activity (assessed from mitochondrial purine nucleotide (GDP) binding). In obese Zucker rats, clenbuterol significantly depressed energetic efficiency and increased the thermogenic response to food and BAT activity in these mutants. Body weight gain was not significantly affected by clenbuterol in obese Zucker rats but this was because of a 19 per cent reduction in fat content accompanied by a simultaneous 13 per cent increase in protein content. The ratio of protein/fat gained during the study was increased by 50 and 173 per cent by clenbuterol in lean and obese rats, respectively. Thus, clenbuterol exhibits potent anabolic effects on lean body mass in genetically obese as well as lean rats, but also increases thermogenesis and reduces body fat content in the obese mutants.

Topics: Adipose Tissue, Brown; Animals; Body Composition; Body Temperature Regulation; Body Weight; Clenbuterol; Eating; Energy Intake; Energy Metabolism; Ethanolamines; Food; Guanosine Diphosphate; Male; Mitochondria; Obesity; Oxygen Consumption; Rats; Rats, Zucker

Adrenalectomy normalizes many abnormalities of the obese (ob/ob) mouse. The high corticosterone concentration in blood may account in part for development of obesity and other abnormalities in the ob/ob mouse. Our objective was to determine dose-response relationships for the effect of corticosterone on the obesity. Lean and ob/ob mice were adrenalectomized or sham-operated at 4.5 wk of age. Adrenalectomized mice received 100 mg implants of cholesterol containing corticosterone (0, 2, 5, 20, or 50 mg) at 8.5 wk of age and were killed at 10.5 wk of age. In ob/ob mice, but not in lean mice, low physiological levels of serum corticosterone (up to 10 micrograms/dl) markedly increased body weight gain, food intake, and serum insulin. They also increased white and brown adipose tissue weights and decreased brown adipose tissue mitochondrial GDP binding. Higher levels of corticosterone (12-22 micrograms/dl) increased body weight gain, white and brown adipose tissue weights, and serum insulin and suppressed brown adipose tissue mitochondrial GDP binding in lean mice also, although in most cases to a lesser extent than in ob/ob mice, but were still without effect on food intake. Only very high levels of corticosterone (approximately 30 micrograms/dl) increased food intake in lean mice. Hyperglycemia was induced in ob/ob, but not lean, mice only at concentrations of corticosterone greater than 17 micrograms/dl. Thermoregulation was unaffected by serum corticosterone at levels from 0 to 30 micrograms/dl in both ob/ob and lean mice. Thus the ob/ob mouse is excessively sensitive and responsive to an effect of physiological levels of corticosterone that results in hyperphagia, hyperinsulinemia, and increased weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenalectomy; Animals; Blood Glucose; Body Temperature; Body Weight; Corticosterone; Dose-Response Relationship, Drug; Eating; Female; Guanosine Diphosphate; Insulin; Mice; Mice, Inbred C57BL; Mitochondria; Obesity; Organ Size

Rats with obesity-producing, hypothalamic knife cuts (KC) were fed a purified high fat diet for 9 wk. KC rats consumed more energy (+70-100%) and retained energy with a much higher efficiency than control rats. Adrenalectomy of KC rats 1 wk (before gross obesity was evident) or 5 wk (when KC rats were 70% overweight) after KC surgery caused a reduction in energy intake to levels approximating those of control rats. Furthermore, energy retention in adrenalectomized KC rats was depressed more than could be explained on the basis of the reduction in energy intake. Two factors associated with the reduction in energy retention, urinary excretion of norepinephrine, an indicator of sympathetic nervous system activity, and GDP binding to brown adipose tissue mitochondria, an indicator of the thermogenic capacity of the tissue, were higher in vadrenalectomized KC rats than in pair-fed KC rats. Removal of the adrenals not only suppressed hyperphagia in KC rats fed a high fat diet, but also increased energy expenditure per kilocalorie consumed.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Body Temperature Regulation; Energy Intake; Energy Metabolism; Female; Guanosine Diphosphate; Hypothalamus; Mitochondria; Norepinephrine; Obesity; Rats; Rats, Inbred Strains; Sympathetic Nervous System

Adrenalectomy prevents development of obesity in ob/ob mice fed high-carbohydrate stock diets partly by stimulating the low thermogenic capacity of their brown adipose tissue (BAT). Adrenalectomy, however, fails to prevent development of obesity in ob/ob mice fed a high-fat diet. Effects of adrenalectomy on BAT metabolism in ob/ob mice fed a high-fat diet were thus examined. ob/ob mice fed the high-fat diet developed gross obesity despite normal BAT metabolism, as assessed by rates of norepinephrine turnover in BAT, GDP binding to BAT mitochondria, and GDP-inhibitable, chloride-induced mitochondrial swelling. Adrenalectomy failed to arrest the development of obesity or to influence BAT metabolism in ob/ob mice fed the high-fat diet. Development of obesity in ob/ob mice fed a high-fat diet is not associated with low thermogenic capacity of BAT or with adrenal secretions, as it is in ob/ob mice fed high-carbohydrate stock diets.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Body Temperature Regulation; Dietary Fats; Female; Guanosine Diphosphate; Mice; Mice, Inbred C57BL; Norepinephrine; Obesity

The effects of chronic feeding of a high-fat diet or a cafeteria-type diet on weight gain and thermogenesis in brown adipose tissue as measured by the binding of a purine nucleotide (guanosine 5'-diphosphate, GDP) to mitochondria of brown adipose tissue have been studied in two strains of rats that differ in their susceptibility to dietary obesity. S 5B/Pl rats, which are resistant to developing obesity when eating a high-fat diet or drinking sucrose solutions, have greater specific GDP binding in interscapular brown adipose tissue (IBAT) than do Osborne-Mendel rats, which are sensitive to fat-induced obesity. A high-fat diet, fed isoenergetically to the low-fat diet, did not increase the growth of IBAT and decreased specific GDP binding in both strains. Feeding a cafeteria diet resulted in obesity and increased mass and protein content of the IBAT in both strains of rats. However, specific GDP binding increased in response to cafeteria feeding only in the Osborne-Mendel rats. These studies show that thermogenesis, as measured by GDP binding to mitochondria in brown adipose tissue, is suppressed by both isoenergetic and ad libitum feeding of a high-fat diet. The higher basal GDP binding in the brown fat of the S 5B/Pl rats suggests that higher thermogenesis of this tissue contributes to the resistance of this strain to fat-induced obesity. The inability of S 5B/Pl rats to further increase thermogenesis when eating a cafeteria diet may contribute to their becoming obese.

Topics: Adipose Tissue, Brown; Animals; Body Composition; Body Temperature Regulation; Body Weight; Dietary Fats; Disease Models, Animal; Disease Susceptibility; Guanosine Diphosphate; Obesity; Organ Size; Rats

Mice treated with glutamate in the neonatal period are known to develop into stunted obese adults, despite hypophagia. Our objective was to find out whether brown adipose tissue (BAT) thermogenic function might be abnormal in the glutamate-obese mouse. At 10 wk of age, group-housed glutamate-obese mice exhibited nocturnal and early diurnal torpor, i.e., they thermoregulated at a lower than normal body temperature. When exposed to 4 degrees C, they died in hypothermia within 24 h. They could adapt to living at 14 degrees C for up to 1 wk but failed to adjust their food intake sufficiently to maintain their body weight. Their fat stores were, nevertheless, conserved. BAT was present in increased amounts in glutamate-obese mice. Its thermogenic activity (as assessed by the level of mitochondrial GDP binding) was normal (male mice) or reduced (female mice). A normal thermogenic responsiveness of BAT to cold occurred. The thermogenic response of BAT to a cafeteria diet was normal (male mice) or reduced (female mice). Serum corticosterone concentration was increased in both male and female glutamate-treated mice particularly in the cold. We conclude that the high metabolic efficiency and obesity of the glutamate-obese mouse are principally a consequence of its maintenance of a hypothermic torpid state for more than 50% of the time. An additional deficit in energy expenditure in female, but not male, glutamate-obese mice is associated with suppressed responsiveness of the thermogenic function of BAT to diet and may account for the greater degree of obesity in female than in male glutamate-treated mice.

Topics: Acclimatization; Adipose Tissue, Brown; Animals; Body Temperature Regulation; Body Weight; Circadian Rhythm; Cold Temperature; Eating; Female; Glutamates; Glutamic Acid; Guanosine Diphosphate; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Sex Factors

This study was undertaken to examine whether adrenalectomy performed during the weaning period could correct some of the first metabolic abnormalities to develop in obese fa/fa rats: impaired thermogenesis in brown adipose tissue and hyperlipogenesis in interscapular brown and white (inguinal) adipose tissues. Pups were adrenalectomized or sham-operated at 23 days of age and studied at 30 days of age. Body weight, interscapular brown adipose tissue and inguinal white adipose tissue weight were decreased after adrenalectomy in Fa/fa and fa/fa pups. Adrenalectomy had no effect on the thermogenic capacity of brown adipose tissue (as assessed by GDP binding to mitochondria) which remained significantly lower in fa/fa than in Fa/fa rats. In both Fa/fa and fa/fa rats the lipogenic capacity of brown and white adipose tissues (as assessed by fatty acid synthetase activity) was dramatically reduced by adrenalectomy. However, in adrenalectomized rats, the fatty acid synthetase activity of brown and white adipose tissue remained 2 and 5-fold higher, respectively, in fa/fa than in Fa/fa rats. These results show that adrenalectomy at postweaning, did not affect specifically the rats bearing the fatty genotype but induced large alterations in both groups of rats. Adrenalectomized fa/fa animals remained obese as compared to the appropriate controls.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenalectomy; Animals; Body Temperature Regulation; Electron Transport Complex IV; Fatty Acid Synthases; Guanosine Diphosphate; Lipid Metabolism; Mitochondria; Obesity; Rats; Rats, Zucker; Weaning

Rats with obesity-producing, hypothalamic knife cuts were fed a high fat diet and placed in the cold (2 degrees C) for six days starting 3, 11, or 24 days after surgery. Between surgery and cold exposure, knife-cut rats consumed 90% to 122% more energy and gained more weight (32 +/- 4, 112 +/- 5, and 241 +/- 9 g) than sham-operated rats (15 +/- 2, 34 +/- 2, and 58 +/- 3 g). When exposed to cold, sham-operated rats increased (22% to 30%) energy intake whereas knife-cut rats decreased (5% to 51%) intake. After 24 hours at 2 degrees C body temperatures of knife-cut rats were 1.2, 0.7, and 0.7 degrees less than those of control rats; body temperatures continued to decrease to 2.9, 3.0 and 2.5 degrees less than control rats after six days at 2 degrees C. Fasting for 12 hours at 2 degrees C caused a further reduction in body temperature to 4.9, 4.8, and 5.9 degrees less than in control rats. Cold exposure increased urinary excretion of norepinephrine and epinephrine (indicators of sympathoadrenal activity) in all rats. Guanosine diphosphate (GDP) binding to brown adipose tissue (BAT) mitochondria (an indicator of the thermogenic capacity of the tissue) was similar in cold-exposed, knife-cut, and sham-operated rats. Cold acclimation before hypothalamic knife-cut surgery prevented the cold-induced decrease in body temperatures of knife-cut rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Cold Temperature; Dopamine; Electron Transport Complex IV; Fasting; Female; Guanosine Diphosphate; Hypothalamus; Norepinephrine; Obesity; Rats; Rats, Inbred Strains

Topics: Adipose Tissue, Brown; Adrenal Cortex Hormones; Animals; Body Temperature Regulation; Guanosine Diphosphate; Insulin; Insulin Resistance; Mice; Obesity; Sympathetic Nervous System

The effects of a lowered rearing temperature on body weight, core temperature (Tc) and norepinephrine(NE)-stimulated thermogenesis were investigated in 16- to 17-day-old Zucker rat pups. 16-day-old fatty pups were significantly heavier (9%) than lean littermates in litters reared at 18 degrees C ("cold-reared") but not in litters reared at 25 degrees C ("normally-reared"). After 2 h isolation at 25 degrees C, Tc of lean pups was slightly higher (37.1 degrees C) in cold-reared litters than in normally-reared litters (36.4 degrees C), while fatty pups reared at either temperature were severely hypothermic (Tc = 33 - 34 degrees C). At an ambient temperature of 25 degrees C Tc in fatty and lean cold-reared pups increased to 39.5 degrees C after subcutaneous injection of 800 micrograms/kg NE. Normally-reared lean pups reached the same peak Tc after NE injection, while their fatty littermates reached a significantly lower peak Tc of 38.4 degrees C. The hypothermia associated with the onset of excess fat deposition in suckling fatty Zucker rats is not caused by a reduced capacity for NE-stimulated thermogenesis.

Topics: Adipose Tissue, Brown; Animals; Body Temperature; Body Temperature Regulation; Body Weight; Cold Temperature; Guanosine Diphosphate; Norepinephrine; Obesity; Rats; Rats, Zucker

Measurements were made of cytochrome c oxidase activity and the GDP-binding capacity of mitochondria in brown adipose tissue of genetically obese mice and wild-type siblings, to estimate the thermogenic capacity of the tissue. The binding capacity was decreased in ad libitum fed obese animals compared with wild-type animals. Limited feeding of obese animals to restrict their body weight caused a large increase in the binding capacity of the tissue, which was greater than that in wild-type animals fed either ad limitum or on a limited diet. The decreased binding capacity of brown adipose tissue mitochondria in obese mice appears to be a consequence of ad libitum feeding and therefore not a cause of the obesity. Limit feeding of obese animals also corrected their characteristic hypothermia at low ambient temperature. The large increase in the thermogenic capacity of brown adipose tissue in obese animals, induced by limited feeding, may account for the vital improvement of their thermoregulation. However, close similarities were found between obesity hypothermia and hypothermia induced in wild-type animals by restraint. It is suggested that changes in posture caused by obesity, resulting in increased loss of body heat, may be important in the development of obesity hypothermia. Obese animals fed less than wild-type grained more weight than wild-type animals, indicating that the high thermogenic capacity of their brown adipose tissue did not function to regulate their calorie intake.

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Electron Transport Complex IV; Female; Food Deprivation; Guanosine Diphosphate; Male; Mice; Mice, Obese; Mitochondria; Obesity

The concentration of the 'uncoupling protein' in brown adipose tissue mitochondria has been measured in lean and obese (ob/ob) mice and Zucker (fa/fa) rats at different ages using a specific radioimmunoassay. During the suckling period the concentration of the protein was similar in normal and mutant animals of both types, despite the decrease in mitochondrial GDP binding observed in the obese. The concentration of uncoupling protein was, however, decreased in adult ob/ob mice and adult Zucker rats compared with their respective lean siblings, in parallel with the decrease in GDP binding. It is concluded that there is a 'masked', or inactive, form of uncoupling protein in young ob/ob mice and fa/fa rats.

Topics: Adaptation, Physiological; Adipose Tissue, Brown; Aging; Animals; Carrier Proteins; Cold Temperature; Guanosine Diphosphate; Ion Channels; Male; Membrane Proteins; Mice; Mice, Obese; Mitochondria; Mitochondrial Proteins; Obesity; Rats; Rats, Zucker; Uncoupling Protein 1

The number of high affinity [3H]GDP binding sites in brown adipose tissue mitochondria is normal in obese (fa/fa) 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.

Topics: Adipose Tissue, Brown; Animals; Binding Sites; Guanine Nucleotides; Guanosine Diphosphate; Kinetics; Mitochondria; Obesity; Rats; Rats, Zucker

The lipogenic capacity and thermogenic activity (assessed by GDP binding to mitochondrial) of brown adipose tissue was studied in lean (Fa/fa) and obese (fa/fa) suckling Zucker rat pups 2 and 10 days old. By 10 days of age, fat deposition, lipogenesis in vivo and fatty acid synthetase activity were 1.5 to 2-fold higher, whereas GDP binding to mitochondria was 40% lower in pre obese than in lean pups. Compared with lean pups, 2-day old fa/fa pups showed a 60% increase in triglyceride accumulation in interscapular brown adipose tissue and a 30% decrease in GDP binding to mitochondria, while no change occurred in fatty acid synthetase activity. These results strongly suggest that an impaired thermogenic activity in the brown adipose tissue of fa/fa pups could play a key role in the development of obesity. However, the concomitant increase in fat content in the brown adipose tissue of 2-day old pre-obese pups raises the question of the causal relationship between these two disorders.

Topics: Adipose Tissue, Brown; Aging; Animals; Body Temperature Regulation; Fatty Acid Synthases; Female; Guanosine Diphosphate; Lipids; Male; Mitochondria; Obesity; Rats; Rats, Zucker; Triglycerides

Norepinephrine concentration and turnover (measured by the time-dependent loss of tissue [3H]norepinephrine specific activity) were reduced in the brown adipose tissue (BAT) of obese Zucker rats but were normal in the heart. After acclimation to a 4 degrees C environment for 7 days, BAT norepinephrine turnover was increased to similar levels in lean and obese rats. After overfeeding with sucrose BAT norepinephrine turnover increased in lean rats but was unaffected in obese rats. Propranolol prevented the normalization of BAT mitochondrial GDP binding that followed adrenalectomy of obese rats. Adrenalectomy of obese rats restored BAT norepinephrine turnover to levels observed in lean rats. However, the increase in BAT GDP binding associated with sucrose overfeeding of adrenalectomized lean and obese rats was neither prevented by propranolol nor associated with a stimulation of norepinephrine turnover. The results suggest that the pituitary-adrenal endocrine axis may influence diet-related BAT thermogenesis and that this influence is only partially mediated by the sympathetic nervous system.

Topics: Acclimatization; Adipose Tissue, Brown; Adrenalectomy; Animals; Body Temperature Regulation; Cold Temperature; Guanosine Diphosphate; Kinetics; Norepinephrine; Obesity; Propranolol; Rats; Rats, Zucker; Sympathetic Nervous System

Restricting the food intake of the genetically obese (ob/ob) mouse is known to ameliorate its cold intolerance. Cold intolerance of the ob/ob mouse is associated with defective thermogenesis in its brown adipose tissue. The objective of the experiments was to find out whether food restriction could increase the thermogenic function of brown adipose tissue of the ob/ob mouse. Obese and lean mice were fed a restricted amount of chow in one meal per day for 3-7 mo. Both lean and ob/ob mice were torpid (rectal temperature of approximately 32 degrees C) in the early morning and aroused spontaneously to a normal body temperature before the anticipated meal time. Obese mice were also torpid during the dark phase, whereas lean mice were active and had a normal body temperature at this time. Brown adipose tissue was in a thermogenically inactive state (low level of mitochondrial GDP binding) in torpid lean and ob/ob mice but became thermogenically active (increase in mitochondrial GDP binding) during stimulated arousal when body temperature increased by 6-7 degrees C in 15-30 min. Ad libitum-fed ob/ob mice had a normal diurnal rhythm in a rectal temperature that was at a lower level than in lean ad libitum-fed mice. They did not raise their rectal temperatures when stimulated and no activation of brown adipose tissue thermogenesis occurred under these conditions. Food restriction increased the capacity of both lean and ob/ob mice to raise their metabolic rate in response to injection of noradrenaline, indicating an increased capacity for thermogenesis in their brown adipose tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue, Brown; Animals; Basal Metabolism; Body Temperature; Body Weight; Circadian Rhythm; Energy Metabolism; Fatigue; Female; Food Deprivation; Guanosine Diphosphate; Mice; Mice, Obese; Norepinephrine; Obesity; Triiodothyronine

Corticotropin stimulated brown adipose tissue mitochondrial GDP binding of young obese rats to the levels seen in lean rats. This effect was attenuated by chronic increases in corticosterone. The stimulatory response to corticotropin was absent from lean rats unless endogenous secretion of corticosterone was prevented.

Topics: Adipose Tissue, Brown; Adrenalectomy; Adrenocorticotropic Hormone; Animals; Corticosterone; Guanine Nucleotides; Guanosine Diphosphate; Male; Mitochondria; Obesity; Rats; Rats, Zucker

GDP binding to brown-adipose-tissue mitochondria of obese Zucker-rat (fa/fa) pups aged 2-14 days was significantly less than in lean control rats. Scatchard analysis in 10-day-old pups suggests that there was a large decrease in GDP-binding sites. However, a significant increase in fat content in brown adipose tissue of 2-day-old pre-obese pups raised the question of the sequential order and causal relationship between these two derangements.

Topics: Adipose Tissue, Brown; Animals; Animals, Newborn; Animals, Suckling; Binding Sites; Guanine Nucleotides; Guanosine Diphosphate; Mitochondria; Obesity; Rats; Rats, Zucker

The suggestion that defective thermoregulatory thermogenesis in the genetically obese (ob/ob) mouse is due to a low thermic response to noradrenaline has been investigated using both noradrenaline and the longer-acting sympathomimetic compounds, ephedrine and BRL 26830A. Below thermoneutrality (23.5 degrees C) the metabolic rate of obese mice was lower than that of their lean littermates, whereas at a thermoneutral temperature (31 degrees C) the metabolic rate of the obese mice was as high as that of lean mice. This confirms the view that the ob/ob mouse has defective thermoregulatory thermogenesis. However, in C57BL/6 mice, this defect is not due to a failure to respond to noradrenaline, because at 31 degrees C the maximum thermic effects of noradrenaline, ephedrine and BRL 26830A were as high in obese as in lean mice and at 23.5 degrees C they were higher in obese than in lean mice. Furthermore, the response of brown adipose tissue to beta-adrenoceptor stimulation appears normal since noradrenaline caused a normal rise in brown adipose tissue temperature, and treatment with noradrenaline or BRL 26830A in vivo caused a normal increase in GDP binding by brown adipose tissue mitochondria. At 31 degrees C propranolol depressed metabolic rate equally in lean and obese C57BL/6 mice, whereas at 23.5 degrees C it depressed metabolic rate more in lean than obese mice. In contrast to C57BL/6 mice, Aston ob/ob mice showed a reduced thermic response to noradrenaline. These results suggest that defective thermoregulatory thermogenesis in the ob/ob mouse is primarily due to a reduced ability to raise sympathetic tone, but in some strains an additional failure in the thermic response to noradrenaline may develop.

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Energy Metabolism; Ephedrine; Ethanolamines; Female; Guanosine Diphosphate; Kinetics; Metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Norepinephrine; Obesity; Propranolol; Sympathomimetics

Young genetically obese (fatty, fa/fa) rats (7-8 wk old) maintained on a chow diet at 28 degrees C have a relatively normal amount of brown adipose tissue (BAT) (normal protein content, normal noradrenaline content, normal or slightly reduced cytochrome oxidase content, 30% reduction in DNA content) with cells grossly hypertrophied by accumulation of lipid. The binding of purine nucleotides by BAT mitochondria is lower in fa/fa rats than in lean rats, suggesting a lesser thermogenic activation of this tissue. Acute exposure to cold (24 h at 4 degrees C) activates BAT thermogenesis (visible hyperemia, marked increase in mitochondrial binding of purine nucleotides, depletion of noradrenaline content) in fa/fa rats as in lean rats. In contrast, feeding a cafeteria diet to young fa/fa rats fails to activate BAT (no increase in mitochondrial binding of purine nucleotides) as it does in lean rats, and these rats accumulate more extra fat (increase in weight of gonadal white adipose tissue) than do cafeteria diet-fed lean rats. It is concluded that the young fa/fa rat has normal cold-induced nonshivering thermogenesis in BAT but defective diet-induced thermogenesis in BAT and that the consequent reduction in energy expenditure, coupled with hyperphagia, contributes to the development of its obesity. The most probable location for the defect is suggested to be associated with the hypothalamus.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Cold Temperature; Diet; DNA; Electron Transport Complex IV; Female; Guanosine Diphosphate; Male; Mitochondria; Norepinephrine; Obesity; Proteins; Rats; Rats, Zucker

The specific binding capacity for purine nucleotides in brown-adipose-tissue mitochondria is thought to indicate the capacity of the proton-conductance pathway which leads to uncoupled respiration. This functional relationship was investigated in studies measuring initial Ca2+-uptake rates and membrane potential in the presence or absence of GDP in brown-adipose-tissue mitochondria with different GDP-binding capacities. The mitochondria from pre-obese and obese ob/ob mice were less able than those from lean control mice to dissipate membrane potential in the absence of GDP. Mitochondria from the obese animals also maintained a higher Ca2+-uptake rate without GDP in comparison with the rate found with mitochondria from the lean mice. The GDP-dependence of Ca2+ uptake was greater in brown-adipose-tissue mitochondria from cold-adapted animals than in those from animals kept at 22 degrees C or at thermoneutrality (33 degrees C). It is concluded that Ca2+-uptake rate and membrane-potential values are depressed in the absence of GDP and indicate indirectly the influence of purine nucleotides on maintaining the proton electrochemical gradient in brown-adipose-tissue mitochondria. It is also apparent that the lower GDP-binding capacity in mitochondria from ob/ob mice is related to a decreased ability to dissipate the proton electrochemical gradient.

Topics: Adipose Tissue, Brown; Animals; Biological Transport; Calcium; Female; Guanine Nucleotides; Guanosine Diphosphate; In Vitro Techniques; Membrane Potentials; Mice; Mice, Obese; Mitochondria; Obesity; Temperature

GDP binding to brown-adipose-tissue mitochondria was decreased in obese Zucker rats. Adrenalectomy restored both GDP binding and serum tri-iodothyronine of obese rats to values observed in lean rats. The effects of adrenalectomy on GDP binding and serum tri-iodothyronine were reversed by corticosterone. Decreasing food intake had no effect on brown-adipose-tissue GDP binding in obese rats. Young (5-week-old) obese rats showed a normal increase in brown-adipose-tissue mitochondrial GDP binding after housing at 4 degrees C for 7 days, but this response was attenuated in 10-week-old obese rats. Overfeeding with sucrose increased brown-adipose-tissue thermogenesis in lean, but not in obese, rats. After adrenalectomy, overfeeding with sucrose enhanced brown-adipose-tissue mitochondrial GDP binding in obese rats.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Cold Temperature; Corticosterone; Guanosine Diphosphate; Male; Microscopy, Electron; Obesity; Rats; Rats, Zucker; Sucrose; Triiodothyronine

The effect of 120 hours' (five days) fasting on the activity of some enzymes of energy metabolism in skeletal muscles was investigated in six obese young men. The results revealed a significant decline in the activity of the following enzymes: triosophosphate dehydrogenase (by 20%), glycerol-3-phosphate dehydrogenase (by 24%), lactate dehydrogenase (by 13%), citrate synthase (by 20%), hydroxyacyl-CoA dehydrogenase (by 40%), while the hexokinase and malate dehydrogenase activities were not significantly altered. Contrary to muscles of non-obese healthy men (Vondra, Bass, Brodan, Kuhn, Andĕl, Veselková and Vítek 1982), a smaller decline of activities of the investigated enzymes occurred together with a paradoxical change of the enzyme pattern, namely a predominance of carbohydrate catabolism and a decline of the role of fatty acids in muscle energy metabolism.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Adult; Citrate (si)-Synthase; Energy Metabolism; Fasting; Glyceraldehyde-3-Phosphate Dehydrogenases; Guanosine Diphosphate; Humans; L-Lactate Dehydrogenase; Male; Muscles; Obesity

GDP binding to brown-adipose-tissue mitochondria of young obese Zucker rats (fa/fa) was significantly lower than in lean control rats, as a result of a decrease in the number of binding sites. Adrenalectomy of fa/fa rats restored GDP binding to control values. Corticosterone replacement suppressed GDP binding in adrenalectomized obese rats.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Binding Sites; Guanine Nucleotides; Guanosine Diphosphate; In Vitro Techniques; Kinetics; Male; Mitochondria; Obesity; Rats; Rats, Zucker

GDP binding to brown-adipose-tissue mitochondria from adult diabetic--obese (db/db) mice was significantly less than with lean siblings. Binding was also decreased in the mutant mice before obesity had begun to develop. Decreased GDP binding was found to result from a decrease in the number of binding sites.

Topics: Adipose Tissue, Brown; Animals; Binding Sites; Diabetes Mellitus; Guanine Nucleotides; Guanosine Diphosphate; In Vitro Techniques; Kinetics; Mice; Mice, Obese; Mitochondria; Obesity

Topics: Acclimatization; Adipose Tissue, Brown; Animals; Cold Temperature; Female; Guanosine Diphosphate; Mice; Mice, Inbred C57BL; Microscopy, Electron; Mitochondria; Obesity