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Biomedical subjects

N J Rothwell

Publications and source records attributed to N J Rothwell.

At least 145 records · Page 8Linked to original sources
PubMed1989

Muscle wasting associated with endotoxemia in the rat: modification by the beta 2-adrenoceptor agonist clenbuterol.

A single injection of endotoxin (1 mg/kg, sc) in rats caused significant fever, body weight loss and reduction in gastrocnemius muscle mass, none of which was mimicked by pair-feeding. Infusion of endotoxin via osmotic minipump over five days caused transient fever and suppression of growth. Recovery of body weight was significantly enhanced by the administration of the beta 2-adrenoceptor agonist clenbuterol (added to the diet at 4 mg/kg). In a separate experiment, injections of endotoxin (day 0 and day 2) caused significant reductions in body weight gain (42%), mass (9%) and protein content (13%) of gastrocnemius muscle over 3 days. Addition of clenbuterol to the diet reversed all of these effects but did not alter food intake or the febrile response to endotoxin. Clenbuterol caused large (20%) increases in the ratio of RNA to protein in muscle indicating that it may have stimulated protein synthesis. beta 2-adrenoceptor agonists may therefore be of value in preventing or inhibiting muscle atrophy associated with infection or injury.

Animals↗
PubMed1989

Bacterial infection (Legionella pneumophila) stimulates fever, metabolic rate and brown adipose tissue activity in the guinea pig.

The objective of this study was to assess whether bacterial infection stimulates oxygen consumption and brown adipose tissue (BAT) activity. Guinea pigs infected with Legionella pneumophila showed marked fever and a significant (33%) increase in resting oxygen consumption (VO2), 24h after infection. At this time, food intake and body weight were normal and the in vitro thermogenic activity of BAT taken from infected animals was elevated by 64% above that of control guinea pigs. VO2 and BAT activity fell to control values by 48h as infected animals became moribund and over this period food intake was markedly reduced.

Adipose Tissue↗
PubMed1989

Comparison of the effects of several endotoxin preparations on body temperature and metabolic rate in the rat.

The effects of several bacterial endotoxins on body temperature and resting oxygen consumption (VO2) were compared in normal rats. Low doses (0.05 mg/kg, i.m.) of 0127:B8 phenol-extracted endotoxin caused significant increases in both parameters. Maximal febrile responses (+1.6 degrees C) occurred at a dose of 0.05 mg/kg, but higher doses produced smaller effects. The maximal increase in VO2 (17%) occurred at doses of 0.5-1.0 mg/kg. A TCA extract of the same strain of endotoxin elicited a similar pattern of responses but was less potent than the phenol extract, whereas another endotoxin 026:B6 (TCA extract) was much less potent. The data illustrate the importance of constructing dose-response curves when comparing different endotoxins and indicate that in the rat, oxygen consumption provides a useful index of the response to pyrogens.

Animals↗
PubMed1989

Effects of an analogue of thyrotrophin-releasing hormone, RX77368, on infarct size and cerebral blood flow in focal cerebral ischaemia in the rat.

Effects of a stable analogue of thyrotrophin-releasing hormone, RX77368, on cerebral blood flow and infarct size have been studied in an acute model of cerebral ischaemia in the rat. Two hours after electrocoagulation of the left middle cerebral artery (MCA), the mean area of ischaemia (+/- SEM), determined histochemically, was 11.5 +/- 2.2% of a single hemisphere and blood flow, determined using radiolabelled microspheres, was reduced by 40% in the left forebrain (p less than 0.001 compared with sham-operated animals). Administration of RX77368 (50 micrograms/kg, intracerebroventricularly) within 10 min of arterial occlusion caused a significant (p less than 0.01) reduction in mean lesion size to 3.7 +/- 1.8% and stimulation of blood flow to the left ischaemic forebrain (60% above saline treated). Peripheral administration of RX77368 (1 mg/kg intraperitoneally) also significantly stimulated blood flow to the ischaemic forebrain and caused an apparent decrease in frequency of large infarcted areas of brain tissue, although mean lesion size was not significantly affected. These findings indicate that RX77368 ameliorates tissue damage in acute focal cerebral ischaemia. Such effects may be related to stimulation of cerebral blood flow.

Adipose Tissue↗
PubMed1989

CRF is involved in the pyrogenic and thermogenic effects of interleukin 1 beta in the rat.

Interleukin 1 beta (IL-1 beta) is an endogenous peptide that induces fever, largely by central stimulation of sympathetically mediated thermogenesis. Microinjection (icv) of human recombinant IL-1 beta (50 ng) caused acute (response within 60 min) increases in colonic temperature (1.8 degrees C), oxygen consumption (Vo2; 36%), white blood cell count (96%), and brown adipose tissue (BAT) activity (mitochondrial GDP binding, 129%) in conscious rats. All of these effects were prevented or markedly inhibited by prior injection (icv) of an antagonist to corticotropin-releasing factor (CRF) [alpha-helical CRF-(9-41), 25 micrograms] and reduced by pretreatment with purified antibody to CRF. Injection of endotoxin (2 mg/kg ip), human recombinant tumor necrosis factor-alpha (TNF alpha; 5 micrograms icv) or prostaglandin E2 (PGE2; 100 ng icv) all stimulated body temperature (0.9-1.6 degrees C) and Vo2 (18-25%); TNF alpha did not affect white blood cell count but increased BAT activity by 38%. Prior injection of the CRF antagonist did not modify the actions of endotoxin, TNF alpha, or PGE2. Central injection of CRF (4 micrograms) produced a 23% increase in metabolic rate, which was unaffected by injection of the cycloxygenase inhibitor ibuprofen (5 mg/kg ip). These data indicate that the central effects of interleukin 1 beta on metabolic rate, body temperature, BAT activity, and white blood cell count are all mediated by release of CRF. The thermogenic effects of endotoxin, TNF alpha, and PGE2 are not dependent on CRF.

Adipose Tissue↗
PubMed1989

Pyrogenic and thermogenic effects of interleukin 1 beta in the rat.

Single injections of recombinant human interleukin 1 beta (IL-1 beta) caused large (up to 2 degrees C) and sustained (3 h) increases in body temperature in conscious rats. Intracerebroventricular injections (10-100 ng) were much more effective and elicited greater responses than intravenous injections (0.1-1 microgram). IL-1 beta increased resting oxygen consumption by 25-49% in a dose-dependent manner. The activity of the thermogenic proton conductance pathway in brown adipose tissue (BAT) mitochondria was assessed from purine nucleotide (GDP) binding and was elevated by 40 and 86% 1 h after intravenous (1 microgram) or intracerebroventricular (100 ng) injection of IL-1 beta, respectively. Regional tissue blood flow was determined in anesthetized rats from the distribution of radiolabeled microspheres. Blood flow to liver (hepatic arterial), testes, skin, and white adipose tissue was unaffected by IL-1 beta injection. Blood flow to brain and kidney was increased (142 and 50%) but reduced (58%) to skeletal muscle after intravenous but not intracerebroventricular injection of interleukin. In contrast, blood flow to BAT was markedly elevated after intravenous (288%) or intracerebroventricular (382%) injection of IL-1 beta. Severing the sympathetic nerves supplying the interscapular BAT depot prevented the increase in blood flow. These data indicate that the potent pyrogenic effects of IL-1 beta in the rat are due largely to a central action. Fever is associated with increases in metabolic rate and BAT activity, and these results provide support for the involvement of brown fat in thermogenesis associated with fever.

Adipose Tissue, Brown↗
PubMed1989

Surgical removal of brown fat results in rapid and complete compensation by other depots.

Interscapular, scapular, and cervical brown adipose tissue (BAT) depots were removed from young male rats (BATX). These depots represented 40% of both the total dissectible mass and cytochrome oxidase content of BAT in these animals. Sham-operated and BATX rats were fed a low (8%) protein diet for periods of 9 or 16 days. Over both periods, body weight gain and energy intake, gain, expenditure, and efficiency were almost identical in sham and BATX groups. Four days after lipectomy the maximal thermogenic response (increase in O2 consumption) to norepinephrine (400 micrograms/kg sc) was 30% lower for BATX rats than for controls, but by day 13 this difference had disappeared. Nine days after lipectomy the total mass and cytochrome oxidase activity of the remaining dissectible BAT was comparable to that of the sham-operated controls, although the protein content was slightly reduced. The specific mitochondrial GDP binding (an index of thermogenic activity) was increased significantly in BATX rats, and total BAT mitochondrial GDP binding was no different from control values. At the end of the experiment (day 16), no regeneration of excised tissue had occurred, but the remaining BAT depots had shown almost complete compensation; the mass and the oxidative and thermogenic capacity of the total dissectible brown fat were virtually identical in both groups.

Adipose Tissue, Brown↗
PubMed1989

Energy balance and brown adipose tissue thermogenesis during chronic endotoxemia in rats.

The effects of continuously administered endotoxin on 7-day energy balance were investigated in male rats. Three groups of rats were implanted with osmotic pumps; two groups received saline-filled pumps, whereas the third received endotoxin. One of the saline groups was pair fed to match the food intake of the endotoxemic rats. After 7 days, body energy and protein and fat contents of rats were determined together with the energy content of food and feces. Endotoxin infusion not only induced fever, but it also suppressed appetite and significantly decreased body weight gain. Metabolizable energy intake was reduced by approximately 20% in infected rats. Although protein and fat gains were lowest in the endotoxin group, there appeared to be a selective loss of protein when considered as percent of body weight. Percent body fat was unaltered between the groups. Energy expenditure considered in absolute (kJ) or body weight-independent (kJ/kg0.67) terms yielded similar patterns of results; expenditure (kJ) was 10 and 20% (P less than 0.05, P less than 0.01) lower in the endotoxemic and pair-fed rats, respectively, compared with controls. Hence, compared with pair-fed rats, endotoxin-infused animals had a 10% rise in their expenditure. Brown adipose tissue thermogenesis was assessed by mitochondrial binding of guanosine 5'-diphosphate, and results showed that binding was greatest in endotoxemic rats and lowest in the pair-fed animals. The present results suggest that in this endotoxemic model appetite suppression exacerbates changes in energy balance. However, the reduction in body weight gain is also dependent on a decrease in metabolic efficiency and an increase in total energy expenditure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1989

Effects of malaria on O2 consumption and brown adipose tissue activity in mice.

Increased energy expenditure often occurs during illness or after injection of endotoxin and can contribute to the generation of fever. In laboratory rats and mice the thermogenic response has been attributed to the sympathetic activation of brown adipose tissue (BAT), although mice often fail to show pyrexia. In this study the effects of malaria on O2 consumption and BAT were studied in mice inoculated with Plasmodium berghei. Parasitemia was maximal (greater than 50% of erythrocytes showing positive Leishman staining) 72 h after inoculation. Up to this time body weight and food intake were similar to values for control mice, although colonic temperatures were slightly depressed in infected mice. Thereafter, infected mice showed marked hypophagia, loss of body weight, and severe hypothermia; colonic temperature was less than 31 degrees C at 96 h when the experiment was terminated. Resting O2 consumption (VO2) measured at 24 degrees C was slightly elevated in infected mice 12 h after inoculation and reached a peak value (31% above controls) at 48 h. VO2 returned to the same value as controls at 96 h. In vitro thermogenic activity of BAT (assessed from binding of guanosine diphosphate to isolated mitochondria) was not significantly altered in infected mice. These data demonstrate a marked thermogenic response to malarial infection, but this is not accompanied by fever in mice and is dissociated from stimulation of BAT activity.

Adipose Tissue, Brown↗
PubMed1989

Thermogenic effects of the antiglucocorticoid RU-486 in the rat: involvement of corticotropin-releasing factor and sympathetic activation of brown adipose tissue.

Acute injection (sc) of the antiglucocorticoid RU-486 (5-10 mg/kg) stimulated oxygen consumption (VO2) and brown adipose tissue (BAT) activity (mitochondrial GDP binding) in the rat. A peak effect was seen 60-80 min after injection. The rise in VO2 was prevented by prior injection of the beta-adrenergic antagonist propranolol, and the effect on BAT was abolished by surgical denervation of the sympathetic supply to the tissue. Central injection (cerebroventricular) of a much lower dose (3-8 micrograms/kg) of RU-486 also stimulated VO2, and this effect was inhibited by a CRF receptor antagonist [alpha-helical CRF-(9-41)]. Peripheral injection of RU-486 also elicited acute thermogenic responses in older (greater than 12 months) rats and in genetically obese (Zucker) rats. In lean animals, daily injection of RU-486 inhibited weight gain and stimulated BAT without affecting food intake. The thermogenic effects of RU-486 appear to be due to central stimulation of sympathetic outflow and may involve CRF release. The data support previous studies on the effects of adrenalectomy and CRF on thermogenesis in the rat.

Adipose Tissue↗
PubMed1989

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

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

Adipose Tissue↗
PubMed1988

Thermogenic effects of thyrotrophin-releasing hormone and its analogues in the rat.

Acute or chronic injection of RX 77,368 (a TRH analogue; 1 mg/kg s.c.) stimulated oxygen consumption (VO2) and brown adipose tissue activity in the rat, and decreased weight gain. Other TRH analogues (CG 3509, RGH 2202) and TRH itself also stimulated VO2. These thermogenic actions are probably mediated centrally by stimulation of sympathetic outflow to brown fat.

Adipose Tissue, Brown↗
PubMed1988

Central effects of TNF alpha on thermogenesis and fever in the rat.

Intracerebroventricular (icv) injection of purified recombinant human tumour necrosis factor alpha (TNF alpha, 4-8 micrograms) in conscious rats, produced increases in colonic temperature (1.0 degrees C) and resting oxygen consumption (VO2, 14%) which were maximal after 80-90 minutes. Pretreatment with propranolol (10 mg/kg s.c.) significantly inhibited the rise in VO2, and prevented the increase in body temperature. Icv injection of an antagonist to corticotropin releasing factor (alpha-helical CRF 9-41, 25 micrograms), which prevents the pyrogenic and thermogenic actions of interleukin-1 beta, did not influence the effects of TNF alpha on temperature or VO2. Injection of a fragment of TNF alpha (113-130 amino acid sequence) did not affect body temperature or VO2. TNF alpha injection (icv) significantly increased brown adipose tissue (BAT) in vitro mitochondrial GDP binding, and this effect was slightly inhibited, but not prevented, by surgical denervation of the tissue, and was unaffected by pretreatment with alpha-helical CRF 9-41. These data indicate that TNF alpha can stimulate thermogenesis by a direct central action. The effects are largely, but not totally, dependent on the sympathetic nervous system but, unlike the thermogenic actions of interleukin they do not require release of CRF.

Animals↗