Biomedical subjects

M J Stock

Publications and source records attributed to M J Stock.

At least 91 records · Page 5Linked to original sources

PubMed1988

Thermogenic effects of dihydrocodeine in the rat.

The object of this study was to assess the effects of dihydrocodeine on thermogenesis and brown adipose tissue activity in the rat from measurements of oxygen consumption and blood flow. Acute injection of dihydrocodeine tartrate (s.c.) stimulated resting oxygen consumption (VO2) in Sprague-Dawley rats in a dose-dependent manner (0.5-50 mg/kg), with a peak response (40-45% increase) occurring at 10-25 mg/kg. This effect was also observed in urethane-anaesthetized rats (although the effect was reduced) and in conscious animals following gastric intubation with the drug. Pretreatment of rats with either a beta-adrenergic antagonist (propranolol, 20 mg/kg), ACTH (4 g/kg), or an opiate antagonist (WIN44441-1, 2 mg/kg) significantly reduced the response to dihydrocodeine, whereas corticosterone injection (5 mg/kg) enhanced the effect. Surgical adrenalectomy or hypophysectomy (HYPX) almost completely abolished the thermogenic effect of dihydrocodeine. Dihydrocodeine also stimulated VO2 in lean (58% increase) and genetically obese Zucker rats (69% increase), and in both Zucker genotypes these responses were only slightly affected by HYPX, but enhanced in HYPX rats treated daily with corticosterone (1 mg/kg). Tissue blood flow, assessed from the distribution of radiolabelled microspheres, was unaffected in white adipose tissue, skeletal muscle, testes, kidney, brain, and liver (arterial supply) after a single injection of dihydrocodeine (25 mg/kg), but flow to interscapular and perirenal brown adipose tissue was increased by 9- to 10-fold. Surgical sympathectomy of brown adipose tissue prevented the increase in blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗

PubMed1988

Effect of hypophysectomy on energy balance and brown fat activity in obese Zucker rats.

Hypophysectomy (HYPX) in genetically obese (fa/fa) Zucker rats significantly reduced body weight and energy gains and stimulated energy expenditure (by 34%), the thermic response to food (by 144%), and brown adipose tissue (BAT) mitochondrial GDP-binding capacity (by 190%) compared with pair-fed, sham-operated obese rats. These changes in energy balance in obese HYPX rats were reversed by corticosterone replacement (1 mg/day), but the increased BAT activity was only partly restored to normal. HYPX had only small effects on energy balance in lean Zucker rats compared with pair-fed, sham-operated lean controls but increased the acute thermic response to food and BAT mitochondrial GDP-binding capacity; these effects were inhibited by replacement of HYPX rats with corticosterone. The results suggest that alterations in the hypothalamic-pituitary-adrenal axis play a fundamental role in the development and maintenance of genetic obesity.

Adipose Tissue, Brown↗

PubMed1988

Involvement of sympathetic nervous system and brown fat in endotoxin-induced fever in rats.

The object of this study was to assess the role of brown adipose tissue (BAT) and the sympathetic nervous system in the rise in heat production associated with endotoxin-induced fever. Oxygen consumption (VO2) was found to be significantly increased (28%) over a 4-h period after two doses of endotoxin (Escherichia coli lipopolysaccharide, 0.3 mg/100 g body wt) given 24 h apart. Injection of a mixed beta-adrenoceptor antagonist (propranolol) reduced VO2 by 14% in endotoxin-treated rats, whereas the selective beta 1- (atenolol) or beta 2- (ICI 118551) antagonists suppressed VO2 by 10%. These drugs did not affect VO2 in control animals. BAT thermogenic activity assessed from measurements of in vitro mitochondrial guanosine 5'-diphosphate (GDP) binding was elevated by 54% in interscapular BAT and by 171% in other BAT depots. Surgical denervation of one lobe of the interscapular depot prevented these responses. Endotoxin failed to stimulate GDP binding in rats fed protein-deficient diets. This may have been because BAT thermogenic activity was already elevated in control rats fed these diets or because endotoxin caused a marked suppression of food intake in the protein-deficient animals. The results indicate that sympathetic activation of BAT is involved in the thermogenic responses to endotoxin and that these can be modified by dietary manipulation.

Adipose Tissue, Brown↗

PubMed1988

Insulin and thermogenesis.

The evidence reviewed here indicates that insulin can increase sympathetically-mediated thermogenesis, probably via its central actions. However, since hypoglycaemia appears to inhibit thermogenesis, the interpretation of data and design of the experiments to study this phenomenon are highly problematic and further confounded by marked changes in insulin sensitivity. This review has purposely concentrated on work performed on experimental animals without directly referring to man. This is because of the very limited number of studies carried out in man, and the fact that difficulties of interpretation discussed above are multiplied many-fold by the limitations of human studies. The evidence to support a role for DIT in energy balance regulation and the importance of brown fat in man has been reviewed elsewhere. A limited number of studies have reported increases in metabolic rate in human subjects infused with glucose and insulin. This response is partially inhibited by the beta-adrenergic antagonist propranolol, and the effects diminished in some grossly obese subjects (e.g. Pima Indians). Landsberg has recently presented and discussed data which indicate that insulin can stimulate thermogenesis in man, and concluded that 'insulin is a major signal that relates dietary intake to sympathetic activity'.

Adipose Tissue, Brown↗

PubMed1987

Changes in thermogenesis and brown fat activity in response to tumour necrosis factor in the rat.

A single intravenous injection of recombinant human tumour necrosis factor (TNF) resulted in significant, but transient (24-48 hr) reductions in food intake and body weight, and increases in rectal temperature, resting oxygen consumption (VO2) and brown adipose tissue (BAT) thermogenic activity (mitochondrial GDP-binding). The increased VO2 was inhibited by beta-adrenergic blockade (propranolol), and activation of BAT was prevented by denervation of the tissue. In adult (4-month old) animals, TNF induced greater reductions in food intake and body weight, caused general malaise and some fatalities, but did not significantly alter VO2 or BAT activity. However, the reduction in VO2 following beta-adrenergic blockade was greater in TNF-treated rats and BAT activity was enhanced when compared to pair-fed controls. Injection of adult rats with gamma-interferon induced small changes in body weight and temperature which were slightly potentiated when injected with a low dose of TNF. The results indicate that TNF stimulates sympathetic outflow to BAT. This effect may be partly responsible for the increases in body temperature and metabolic rate associated with TNF treatment and with cancer cachexia.

Adipose Tissue, Brown↗

PubMed1987

Effect of a selective beta 2-adrenergic agonist (clenbuterol) on energy balance and body composition in normal and protein deficient rats.

In rats fed a normal (22% protein) diet, injection of clenbuterol (1 mg/kg/d for 21 d) did not affect energy intake, energy expenditure or weight gain, but reduced energetic efficiency, and fat and energy gains and increased body protein content. Presenting a low-protein (8%) diet reduced energy intake, gain and efficiency, body protein content and the mass of the gastrocnemius muscle when compared to rats fed the control diet. Injection of the protein-deficient rats with clenbuterol (1 mg/kg/d for 21 d) caused hypophagia and reduced body weight and energy gains, energy expenditure and total body fat. However, the total body content of protein was not significantly reduced and the percentage of body protein in this protein deficient, clenbuterol-treated group was greater than that of untreated rats on both the high- and low-protein diets. The ratio of body protein to fat following clenbuterol treatment was increased by over 50% in both normal and protein-deficient rats. The results show that in protein deficient animals, clenbuterol treatment may help conserve body protein at the expense of fat, resulting in a smaller, but leaner body mass.

Animals↗

PubMed1987

Stimulation of thermogenesis and brown fat activity in rats fed medium chain triglyceride.

Gastric intubation of young male rats with 100 kJ/d of medium chain (C8 and C10) triglyceride (MCT) reduced their voluntary intake of stock diet such that total metabolizable energy intake was similar to that of rats intubated with water, and 41% of their energy intake was derived from MCT. Body weight, energy gain, and energetic efficiency were all markedly suppressed in MCT-fed rats, but energy expenditure over the 14-day experiment was significantly increased. Resting oxygen consumption, measured at thermoneutrality, was also enhanced in MCT-fed rats, but this difference was abolished by injection of the animals with the beta-adrenergic antagonist, propranolol. Brown adipose tissue mass was similar for both groups, but the activity of the mitochondrial proton conductance pathway, assessed from the binding of purine nucleotides, was increased by over 70%. These data indicate that the reduced weight gains of animals fed MCT are due to elevated rates of energy expenditure, possibly resulting from sympathetic activation of brown fat thermogenesis.

Adipose Tissue, Brown↗

PubMed1987

Activation of brown fat thermogenesis in response to central injection of corticotropin releasing hormone in the rat.

Injection of CRF-41 (2-5 nmol) into the third ventricle, or the paraventricular nucleus of anaesthetized rats caused a marked rise in the temperature of the interscapular brown adipose tissue (BAT) depot (peak rise 0.8-1 degree C) which was inhibited by prior intravenous injection of propranolol. There was also a significant increase in the mitochondrial proton conductance pathway of brown adipose tissue, assessed from the binding of guanosine diphosphate (GDP) to mitochondria isolated from the interscapular (89% above control) and perirenal and para-aortic depots (130%). Acute surgical sympathectomy of interscapular brown adipose tissue immediately prior to injection of CRF significantly attenuated the increase in mitochondrial GDP-binding. Hypophysectomized (HYPX) rats showed a large (180%) increase in GDP-binding of brown adipose tissue 7 days after surgery and this was almost completely prevented by denervation of the interscapular depot prior to hypophysectomy. Acute injection of morphine also reduced the GDP-binding in hypophysectomized, but not in control rats. These data demonstrate that central injection of CRF stimulates thermogenesis in brown adipose tissue, probably by modifying sympathetic outflow. The activation of brown adipose tissue following hypophysectomy was also dependent on the sympathetic innervation and could be due to an increase in release of CRF.

Adipose Tissue, Brown↗

PubMed1987

Effects of ciglitazone on energy balance, thermogenesis and brown fat activity in the rat.

Young male rats were treated with vehicle or ciglitazone (150 mg/kg/day, intragastric) for 8 or 14 days. Drug treatment did not affect food intake but reduced body weight and energy gains over 14 days, and significantly depressed energetic efficiency. Energy expenditure and resting oxygen consumption (VO2), when corrected for body size, were elevated in ciglitazone-treated rats, but the difference in VO2 was abolished by treatment of the animals with a beta-adrenergic antagonist (propranolol). The acute thermic response (postprandial rise in VO2) to a fat meal was similar for both groups, but the response to carbohydrate ingestion was greater in ciglitazone-treated rats (18%) than controls (11.5%). The mass of interscapular brown adipose tissue was not affected by drug treatment, but its protein content was increased and its thermogenic activity (mitochondrial purine nucleotide binding) was elevated by 25% after chronic treatment with ciglitazone. These results indicate that ciglitazone enhances thermogenesis via sympathetic activation of brown adipose tissue, probably as a result of improved insulin sensitivity.

Adipose Tissue, Brown↗

PubMed1987

Influence of carbohydrate and fat intake on diet-induced thermogenesis and brown fat activity in rats fed low protein diets.

Voluntary intake of protein, fat and carbohydrate (CHO) was modified by feeding young rats either a control purified diet [% metabolizable energy (ME): protein 21, fat 7, CHO 72], a control diet plus sucrose solution (20%) to drink (final intakes 17, 6 and 77% ME as protein, fat and CHO, respectively) or a low protein diet substituted with either CHO (8, 7 and 85% ME as protein, fat and CHO, respectively) or fat (8, 20 and 72% ME as protein, fat and CHO, respectively). Total ME intakes corrected for body size were similar for all rats, but body weight, energy gain and net energetic efficiency were lower in both low protein-fed groups than in the control group. The acute thermogenic response (% rise in oxygen consumption) to a standard balanced-nutrient meal was higher (12%) in sucrose-supplemented and in low protein groups (15-16%) than in control rats (8%). Brown adipose tissue protein content and thermogenic capacity (assessed from purine nucleotide binding to isolated mitochondria) were greater than control values in sucrose-fed and protein-deficient animals, and the greatest levels of activity were seen in low protein-fed rats with a high fat intake. The results demonstrate that the changes in energy balance, thermogenesis and brown adipose tissue activity that result from protein deficiency cannot be ascribed to changes in the level of energy intake or to a specific increase in the amount or proportion of either CHO or fat. They suggest that the protein-to-energy ratio must be the primary influence on thermogenesis and brown fat activity in these animals.

Adipose Tissue, Brown↗

PubMed1987

Effect of environmental temperature on energy balance and thermogenesis in rats fed normal or low protein diets.

Rats fed a low protein (9% metabolizable energy) diet and housed at 24 degrees C gained less weight and body energy then controls fed a normal (25%) protein diet. Energy intake and expenditure corrected for body size [kJ/(kg0.75 X d)] were similar in rats fed the two diets, but energetic efficiency was suppressed in low protein-fed rats, and the thermogenic response to norepinephrine and the activity of brown adipose tissue (mitochondrial GDP binding) were both significantly elevated. Housing at a higher temperature (29 degrees C) suppressed energy expenditure and brown fat activity in animals fed either diet, and gross efficiency was greater in control animals at 29 degrees C than at 24 degrees C but unaffected in the protein-deficient group. The differences in brown fat activity between dietary groups were still apparent at 29 degrees C. The results suggest that thermogenesis induced by feeding low protein diets is not markedly inhibited by a higher environmental temperature.

Adipose Tissue↗

PubMed1987

Changes in tissue blood flow and beta-receptor density of skeletal muscle in rats treated with the beta2-adrenoceptor agonist clenbuterol.

Rats injected with the beta2-adrenoceptor agonist clenbuterol (2 mg kg-1 per day) for 18 days gained significantly more weight than controls. Tissue blood flow assessed 24 h after the last injection from the distribution of radiolabelled microspheres was increased in white (5 fold) and brown (3 fold) adipose tissue of clenbuterol-treated rats but was unaffected in kidney, brain and diaphragm, and was reduced by about 80% in skeletal muscle. Acute injection of clenbuterol one hour before measuring blood flow, increased blood flow to brown fat (20 fold) in both treated and control groups. Blood flow to skeletal muscle increased more in the rats treated chronically with clenbuterol (6 fold increase) than in control rats (2 fold increase), but absolute flow rates were still significantly lower in the rats treated chronically with clenbuterol. Skeletal muscle beta-adrenoceptor density and subtype were assessed from ligand binding and displacement studies using [3H]-dihydroalprenolol. Rats treated with clenbuterol for 18 days showed a 50% reduction in beta-receptor density, but the ratio of beta 1/beta 2-receptors was unaffected (15% beta 1/85% beta 2). The results indicate that, although clenbuterol produces acute increases in muscle blood flow, chronic treatment results in lower flow rates immediately (1 h) and 24 h after the previous injection. The attenuated response following chronic treatment is associated with a marked reduction in skeletal muscle beta-adrenoceptor density. The data suggest that any anabolic effects of clenbuterol on muscle which may require, or may be mediated by increases in blood supply, cannot be sustained by chronic treatment. Conversely, blood flow to white and brown adipose tissue would appear to be potentiated by chronic treatment, possibly reflecting increases in lipolytic and/or thermogenic activity.

Animals↗

PubMed1987

Regional blood flow and skeletal muscle energy status in endotoxemic rats.

Endotoxins induce muscle wasting in part as a result of depressed protein synthesis. To investigate whether these changes reflect impaired energy transduction, blood flow, O2 extraction, and high-energy phosphates in muscle and whole-body O2 consumption (VO2) have been measured. VO2 was measured for 6h after an initial sublethal dose of endotoxin (Escherichia coli lipopolysaccharide 0.3 mg/100 g body wt sc) or saline and during 6h after a second dose 24 h later. In fed or fasted rats, VO2 was either increased or better maintained after endotoxin. In anesthetized fed rats 3-4 after the second dose of endotoxin VO2 was increased, and this was accompanied by increased blood flow to liver (hepatic arterial supply), kidney, and perirenal brown adipose tissue and a 57 and 64% decrease in flow to back and hindlimb muscle, respectively, with no change in any other organ. Hindlimb arteriovenous O2 was unchanged, indicating markedly decreased aerobic metabolism in muscle, and the contribution of the hindlimb to whole-body VO2 decreased by 46%. Adenosine 5'-triphosphate levels in muscle were unchanged in endotoxin-treated rats, and this was confirmed by topical nuclear magnetic resonance spectroscopy, which also showed muscle pH to be unchanged. These results show that although there is decreased blood flow and aerobic oxidation in muscle, adenosine 5'-triphosphate availability does not appear to be compromised so that the endotoxin-induced muscle catabolism and decreased protein synthesis must reflex some other mechanism.

Animals↗

PubMed1987

Influence of clenbuterol on energy balance, thermogenesis and body composition in lean and genetically obese Zucker rats.

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.

Adipose Tissue, Brown↗

PubMed1987

Effect of diet and fenfluramine on thermogenesis in the rat: possible involvement of serotonergic mechanisms.

A single injection of 5-hydroxytryptamine (5HT, 1 mg/kg, s.c.) in rats stimulated resting oxygen consumption (Vo2) by 21 percent; this was reduced (to 8 percent) by pretreatment with hexamethonium (5 mg/kg, s.c.). DL-fenfluramine injection (20 mg/kg, s.c.) stimulated metabolic rate (Vo2) by about 40 percent, but caused only 11 and 15 per cent increases in animals pretreated with hexamethonium or metergoline (5 mg/kg, s.c.), respectively. Interscapular brown adipose tissue (BAT) activity, assessed from mitochondrial GDP-binding, was increased by 96 per cent in intact tissue 1 h after fenfluramine injection; this response was completely prevented by surgical sympathectomy of interscapular BAT. Metergoline significantly inhibited (by 46 percent) the acute thermic response (postprandial rise in Vo2) to a 40-kJ meal in normal rats, and depressed resting Vo2 in protein-deficient rats by 18 percent, but did not affect resting Vo2 in control animals. BAT activity (mitochondrial GDP-binding) was elevated by 56 per cent in rats fed the low-protein diet, but this difference was almost completely abolished by prior treatment with metergoline. These data demonstrate a potent thermogenic effect of fenfluramine which apparently involves serotonergic pathways and activation of sympathetic outflow to BAT, and indicate that acute thermic responses to food and chronic thermogenic responses to low-protein diets may also involve serotonergic mechanisms.

Adipose Tissue, Brown↗

PubMed1986

Thermogenic responses to adrenoceptor agonists and brown fat adrenoceptors in overfed rats.

Rats fed a cafeteria diet to produce hyperphagia showed increases in the maximal thermogenic responses (rise in oxygen consumption) to isoprenaline (mixed beta-agonist), prenalterol (beta 1-selective agonist) and clenbuterol (beta 2-agonist), and left-shifts in the dose-response curves to the latter two. The maximal response to phenylephrine (alpha-agonist) was similar for control and cafeteria rats. Ligand binding studies revealed increases in beta-adrenoceptor density of 33-38% in brown fat cells and isolated membranes from cafeteria-fed rats, but a 30% reduction in beta-receptors in heart membranes. Cold-adaptation caused a 22% reduction in beta-receptor density in brown fat membranes, but no change in heart. The ratio of beta 1/beta 2-receptors in brown fat was reduced from 59/45 in control to 47/54 in cafeteria-fed rats, but was not significantly altered in heart (58/44) or in brown fat from cold-adapted animals (64/30). alpha-Adrenoceptor density was increased above control values by 69 and 25% in brown adipose tissue from cafeteria and cold-adapted rats, respectively.

Adipose Tissue, Brown↗

PubMed1986

Whither brown fat?

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Adipose Tissue, Brown↗

PubMed1986

Energy balance and brown fat activity in adrenalectomized male, female, and castrated male rats.

Adrenalectomy (ADX) attenuated body weight and energy gains in male and female rats by inhibiting food intake and reducing energetic efficiency, and these changes were associated with marked increases in the thermogenic activity of brown adipose tissue (BAT). Feeding a palatable cafeteria diet to intact female rats stimulated energy intake, expenditure, and BAT activity and caused only small increases in body energy gain. Heat production in cafeteria-fed female rats was further enhanced by ADX. Castration in male rats had similar effects on energy balance and BAT to adrenalectomy, causing decreases in energy intake, expenditure, body energy gain, and energetic efficiency, but elevated BAT activity. Combined castration and ADX had synergistic effects resulting in marked increases in brown fat activity. These data indicate that male steroids may inhibit thermogenesis in a similar manner to the glucocorticoids, but the effects of adrenalectomy on energy balance are comparable in male and female rats.

Adipose Tissue, Brown↗