F’rostsglandins Leukotrienes and Essential 0 Longman Group UK Ltd 1992
Fatty Acids
(1992) 46, 1-7
Review
Eicosanoids, Thermogenesis and Thermoregulation N. J. Rothwell Department of Physiological Sciences, 9PT, UK (Reprint requests to NJR)
University of Manchester,
INTRODUCTION The involvement of prostaglandins in fever is well established, and it is now apparent that they act as important mediators of the thermogenic responses to infection, inflammation and disease. Several cytokines (particularly interleukins 1 and 6) have been identified as endogenous pyrogens and activators of thermogenesis. Their effects appear to depend on synthesis of prostanoids and corticotrophin releasing factor, within the brain. Endogenous inhibitors of fever and thermogenesis have been identified which attenuate responses to these cytokines. Dietary modification of fatty acid intake also markedly alters pyrogenic and thermogenic responses, probably by effects on prostanoid synthesis. Eicosanoids have been assumed to play a small role in thermoregulation and thermogenesis under normal conditions, but recent data indicate their involvement in responses to hypherphagia and a possible role in normal body weight regulation. The history of eicosanoid involvement in fever dates back to 1763, when it was first demonstrated that the bark of the willow tree inhibits fevers; the active ingredient was subsequently identified as salicylic acid. Since then, and particularly over the last 30 years, substantial evidence has accumulated to confirm the.importance and to extend our understanding of the role of eicosanoids in pyrogenesis. Indeed cyclooxygenase inhibitors remain the most common and effective antipyretic agents. The discovery and basic mechanisms of the involvement of eicosanoids in fever has been elegantly and extensively reviewed in a number of articles (l-4)) and will therefore not be discussed in detail here. This review will focus on recent observations on the mechanisms of induction, action and modulation of
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Mechanisms of thermoregulation, thermogenesis and fever The obligatory maintenance of body temperature within narrow limits in homeotherms is under direct control by the central nervous system (CNS), which modifies peripheral effector mechanisms of heat production and heat loss. Variations in heat loss can be achieved by both autonomic (changes in local blood flow, piloerection, sweating) and behavioural (e.g. huddling, licking) processes. In contrast, variations in heat production are largely under autonomic control and dependent on either shivering or non-shivering thermogenesis (NST). NST is a more effective means of raising body temperature, and predominates in small mammals, neonates and during chronic exposure to cold. Studies on laboratory rodents have indicated that NST results from activation of the sympathetic nervous system and local release of noradrenaline to stimulate heat production in brown adipose tissue (BAT) (6). This process involves a novel 8s adrenoceptor located on brown adipocytes and subsequent uncoupling of oxidative phosphorylation of a mitochondrial proton conductance pathway, which is unique to BAT (7). Under conditions of maximal stimulation in rodents, BAT (which usually represents less than 1% of total body mass) can receive up to 60% of the cardiac output and cause at least a 100% increase in total heat production (6). The physiological importance of BAT in humans is unknown, and undoubtedly of much smaller magnitude. However, BAT is quantitatively important in human neonates (6), is present in an active form throughout active life (8)
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Prostaalandins Leukotrienes and Essential Fattv Acids
and can be activated in certain disease states associated with fever and hypermetabolism (9). Common mechanisms of thermogenesis (i.e. sympathetic activation of BAT) are responsible for increases in metabolic rate during development of fever (6, 10, 11) NST during cold exposure or arousal from hibernation and the heat production resulting from hyperphagia or consumption of nutritionally unbalanced diets (6, 7). This latter form of thermogenesis (diet-induced thermogenesis, DIT) is involved in the regulation of energy balance and body weight (6). Genetically obese rodents (e.g. fatty Zucker rat, obese ob/ob mouse) exhibit impaired DIT as well as hyperphagia which results in excess fat deposition and in some cases defective thermoregulation (12). Fever, usually defined as a regulated increase in the set point for body temperature regulation, is one of the most common clinical features of infection and can also accompany injury, inflammation and malignant disease (1, 2, 10). Development of fever is achieved by reductions in heat loss and increased heat production via both shivering and NST. Thus, during fever normal thermoregulatory processes are utilised to achieve a higher body temperature. The induction of fever has been ascribed to the actions of endogenous pyrogens released in response to exogenous pyrogenic stimuli, injured or inflammed tissue or the presence of malignant cells. The cytokines are now considered to be the primary endogenous mediators of fever and thermogenesis in response to infection, injury or inflammation. Several cytokines have been shown to elicit fever in laboratory rodents and are released or synthesised in numerous tissues, including the brain, during pyrogenesis. Kluger (2) has reviewed in detail the evidence currently available to support a physiological role of each of these. Interleukin-1 (IL-l) and interleukin-6 (IL-6) appear to be the most prominent endogenous pyrogens which act centrally to modify body temperature. However, the means by which these large molecules enter the CNS, their sites and mechanisms of action remain poorly understood. Mechanisms
of fever
The pyrogenic
and thermogenic actions of most of the cytokines (IL-& IL-l& IL-6, TNF-ar, IF6) are prevented by prior administration of cyclooxygenase inhibitors such as flurbiprofen of ibuprofen (1, 11, 13) indicating that they are directly mediated by release of prostanoids. Notable exceptions to this are interleukin-8 and macrophage inflammatory protein-l both of which induce fevers which are insensitive to cyclooxygenase inhibitors (14, 15). In addition, prostanoids can feed back to inhibit the synthesis of cytokines such as IL-l.
Peripheral injection of cytokines causes release of prostaglandins both locally and within the CNS, at sites specifically associated with the development of fever (16). There is debate over the ability of peripherally synthesised or administered cytokines and prostaglandins to enter the CNS (4, 5, 17). It has been proposed that circulating cytokines such as IL1 act at site(s) which lack a substantial blood brain barrier such as the organum vasculosum of the lamina terminalis (OVLT) and cause the synthesis of prostaglandins, particularly PGE2 which can directly modify activity of thermosensitive neurones in the preoptic anterior hypothalamus (POAH) (18, 19). However push-pull and microdialysis studies have demonstrated local synthesis of PGE2 in the POAH during development of fever, and several cytokines (e.g. IL-ll3, IL-6) are present within the CNS, and may be synthesised in response to peripheral pyrogenic stimuli or local damage (1, 12, 19). Morimoto et al (20) have reported that local injections of prostaglandins into the brain of rabbits induces monophasic fevers, in contrast to endogenous pyrogen (partially purified IL-l) which induced biphasic fever. They proposed that prostaglandins synthesised outside the blood brain barrier act on multiple sites in the CNS to induce the first phase of fever, while prostaglandin synthesis in regions near the OVLT in response to endogenous pyrogens is responsible for the second fever peak. PGE2 is generally considered to be the major prostanoid involved in pyrogenesis, although several other eicosanoids can also induce fever and thermogenesis in experimental animals and PGE, is equipotent with PGE;!. PGF2, was originally reported not to cause fever in the rabbit (21), but subsequent studies have revealed that in the rabbit and the rat, central injection of PGF*, elicits increases in body temperature and metabolic rate of similar magnitude to PGE2 (22, 23). At present it seems unlikely that other eicosanoids (e.g. thromboxanes, leukotrienes) play a major, direct role in fever, but could indirectly influence body temperature (5). In the absence of selective antagonists for specific eicosanoids, it is difficult to answer this question. Furthermore, PGE2 and PGFzU may act via different mechanisms, since their maximal effects on fever and thermogenesis in the .rat are additive, and only PGF2, appears to depend on corticotrophin releasing factor (CRF) for its actions (23 and below). Sites of action of prostaglandins
in the CNS
Morimoto et al (20) compared the febrile responses of rabbits to local injections of PGE;? and PGF2, into 68 specific regions of the rabbit brain. The results revealed that regions of the nucleus broca
Eicosanoids, Thermogenesis
ventralis, preoptic, anterior and ventromedial hypothalamus (VMH) were most sensitive. The POAH has generally been considered the major hypothlamic area responsive to prostaglandins (1, 19). However, the fact that fever can still develop after destruction of the POAH suggests that it is not fundamental for pyrogenesis (19). In contrast, destruction of the VMH reportedly attenuates the development of fever (19) and is highly sensitive to the pyrogenic actions of prostaglandins (20). The VMH has not been specifically implicated in the control of body temperature or development of fever, but is an important site for control of autonomic function and of thermogenesis (24). Destruction of the VMH results in hyperphagia, impaired diet-induced thermogenesis, reduced brown fat activity and subsequent obesity (24). Conversely, electrical stimulation of the VMH in the rat causes marked increases in thermogenesis in BAT, which are due to activation of the sympathetic nerves supplying the tissue (25). Fyda et al (26) concluded that BAT is an important effector organ responsible for the hyperthermic and thermogenic response to central injection of PGEi in the rat. Amir and Schiavetto (27) reported that increased BAT thermogenesis by injection of PGE;? into the POAH of the rat could be prevented by administration of local anaesthetic or the GABA* receptor agonist, muscimol, into the VMH. These data suggest that pyrogenic and thermogenic effects of PGE;? are mediated by activation of sympathetic outflow via the VMH. A high density of IL-lp immunoreactivity has been reported in the VMH (28) and this also appears to be a major site of synthesis of IL-lb (assessed from mRNA) in the brain (29). Studies on fever and thermogenesis have focused mainly on the hypothalamus, but several extra hypothlamic regions are likely to mediate or modulate actions of eicosanoids. Blatteis (19) has reviewed evidence for thermosensitive regions in the cortex, pons and medulla which could participate in fever, and pyrogens such as interleukin-1 are identified and can act at sites within the cortex, hippocampus and lower brain stem. However, prostanoid receptors are also present on glial cells (particularly astrocytes) which also synthesise eicosanoids. The relative importance of neurones and glial cells as sources and sites of action of eicosanoids on fever and thermogenesis is at present uncertain. Mechanisms of action of eicosanoids on fever/thermogenesis
Several reports have now provided evidence that the effects of prostaglandins on body temperature and thermogenesis are dependent on sympathetic activation of heat production in BAT probably by central stimulation of sympathetic outflow (26, 30).
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The increased thermogenesis induced by prostaglandins can be prevented by systemic administration of sympathetic ganglionic blockers or fi-adrenoceptor antagonists (27, 30). Prostaglandins have been postulated as the final mediations of fever, acting directly on thermosensitive neurones (5, 19, 31). Thus, changes in thermogenesis are presumably secondary to the increase in set point, acting to facilitate a raised body temperature. However, several experimental interventions can modify the pyrogenic and thermogenic actions of eicosanoids. These manipulations probably inhibit fever as a result of reductions in thermogenesis, (for example in the case of p blockade). When thermogenic effector mechanisms are inhibited, pyrogenic animals should show compensatory reductions in heat loss in an attempt to raise body temperature to the higher preferred or ‘set’ point. In studies in which measurements of heat loss and metabolic rate have not been made it is difficult to distinguish the effects of pharmacological interventions on the development of fever per se, from those on thermogenesis activation of thermogenic effector mechanisms or peripheral vasomotor control .
Corticotrophin releasing factor (CRF), first identified for its effects on pituitary ACTH release, also has numerous actions within the CNS, including stimulation of thermogenesis and BAT activity (32). Inhibition of CRF action by central injection of a receptor antagonist (a helical CRF 9-41) or neutralising antibody to CRF, markedly attenuates the pyrogenic and thermogenic actions of several cytokines including IL-lg, IL-6 and IL-8 (11, 33), although the effects on metabolic rate are often greater than on body temperature. These observations have lead to the suggestion that CRF mediates effects of these cytokines on fever/ thermogenesis (11) and may also be involved in actions of IL-l on food intake and behaviour (13). In contrast, increases in body temperature and metabolic rate in rats injected with IL-la (33) or TNF-a (34) are not inhibited by CRF antagonists indicating that two separate pathways exist within the CNS. The thermogenic responses to CRF in the rat are not modified by cyclooxygenase inhibitors (33), but in vitro studies have revealed that CRF release from isolated hypothlami is stimulated by PGF*, and thromboxane AZ, but not by PGE2 (35). Central injection of low doses of PGEz or PGF*, in the rat elicits increases in body temperature and metabolic rate in conscious rats (23). The responses to are almost completely abolished by PGF2, pretreatment with the CRF receptor antagonist, while the actions of PGE2 are unaffected (23). It has therefore been postulated that CRF mediates the actions of IL-l@, IL-6 and IL-8 and PGF2, whereas TNF-a, IL-la act independently of CRF (11). The physiological importance, interrelation-
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ships and brain locations of these two mechanisms of fever and thermogenesis are not as yet known. An additional putative step in this process is 5hydroxytryptamine (5HT) which has been thought for some time to be involved in fever (36). 5HT stimulates thermogenesis in a CRF dependent manner in the rat (37), and release of CRF from isolated hypothalami by 5HT can be inhibited by thromboxane A2 antagonists (38). In vivo stimulation of BAT thermogenesis by PGE2 is prevented by injection of GABA* agonist into the VMH (27). This observation is consistent with earlier studies suggesting that GABA* receptors within the brain inhibit thermogenesis while activation of GABAa receptors stimulates metabolic rate (39). Physiological importance of eicosanoids in the control of thermogenesis and body temperature
The physiological importance of eicosanoids in the development of fever (and associated thermogenesis) in response to cytokines or bacterial infections is well-established and has been reviewed in detail (l-3). However, increases in body temperature and metabolic rate which are commonly associated with injury (40, 41) are not always sensitive to cyclooxygenase inhibitors (41), suggesting that these conditions do not represent ‘true fever’. Local, modest injury in the rat (sterile turpentine-induced abscess in the hind limb) induces rapid (within 2 h) and sustained increases in body temperature and metabolic rate which are mediated by the sympathetic nervous system (42). The early phase (O-4 h) of this response is inhibited by peripheral, but not central administration of the cyclooxygenase inhibitor, flurbiprofen, while either route of administration inhibits the later (18 h) phase of the response (42). Thus, it seems that the immediate increases in temperature and metabolic rate are due to eicosanoid synthesis at the site of this injury, while the delayed response is more characteristic of true ‘fever’ and dependent on central eicosanoid synthesis. Experimental brain injury induced in rats by focal cerebral ischaemia causes a delayed (6-8 h) increase in metabolic rate, which is not modified by lipoxygenase or cyclooxygenase inhibitors (43). The wasting syndrome (cachexia) commonly associated with many forms of malignant disease has been ascribed to both decreases in food intake and increased, or inappropriately high energy expenditure (44, 45). In experimental cancer in laboratory animals, increases in metabolic rate have been ascribed to sympathetic activation of BAT (10, 46). Gelin et al (47) have recently demonstrated that administration of the cyclooxygenase inhibitor indomethacin markedly inhibits cachexia in mice
bearing tumours and increases survival time by up to 50%. Similarly, we have observed delayed weight loss in rats with T-cell leukaemia, treated with a cyclooxygenase inhibitor, although food intake was only slightly improved (Roe, Morris & Rothwell, unpublished data). Eicosanoids are not believed to participate in the normal regulation of body temperature or in the physiological responses to cold exposure (NST), since cyclooxygenase inhibitors do not modify body temperature or metabolic rate in these conditions. However, Scales and Kluger (48) have suggested that the diurnal rhythm of body temperature may be related to prostanoid synthesis, and increased diet induced thermogenesis in hyperphagic rats is markedly attenuated by cyclooxygenase inhibitors (30). In the latter case, the enhanced thermogenic capacity (response to noradrenaline) associated with hyperphagia was also prevented by cyclooxygenase treatment. Furthermore, chronic administration of salicylic acid enhanced weight gain in these animals in spite of a slightly reduced food intake (30). Glucocorticoid
modulation
Glucocorticoids are potent inhibitors of eicosanoid synthesis, acting to inhibit the activity of phospholipase A2 which is responsible for release of arachidonic acid, the common precursor for eicosanoids. Administration of natural or synthetic glucocorticoids inhibit fever and thermogenesis, probably by central actions to suppress the synthesis or actions of prostaglandins and/or CRF (5, 12, 13, 49). Genetically obese rodents, such as the fatty (fa/fa) Zucker rat and obese (ob/ob) mouse show impaired diet-induced thermogenesis which can be normalised by adrenalectomy, or by central or peripheral administration of a glucocorticoid antagonist (RU486) (12, 50-52). Both of these obese mutants also exhibit markedly diminished pyrogenic and thermogenic responses to interleukin-lp, which are again normalised by adrenalectomy (53-56). Similarly, we have observed that the reduced effects of IL-lfi on fever and thermogenesis in ageing rats and mice are restored to normal by peripheral or central injections of a glucocorticoid antagonist (RU486) (56; Strijbos & Rothwell, unpublished data). Thus, enhanced glucocorticoid feedback in obese mutants may contribute to their impaired responses to pyrogens via suppression of eicosanoid synthesis, and could also contribute to their reduced diet induced thermogenesis. Antiinflammatory actions of glucocorticoids have been ascribed to synthesis of a secondary mediator. lipocortin-1 (57). Central or peripheral administration of recombinant lipocortin-1 or an active fragment of lipocortin-1 (N terminal 1-188) causes a
Eicosanoids, Thermogenesis
dose dependent inhibition of fever and thermogenesis induced by interleukin-lfi, in the rat (56, 49). Lipocortin-1 is present in normal rat and human brain in neurones and glia (58, 59) and immunoreactive lipocortin-1 in hippocampal neurones appears to be sensitive to glucocorticoid status (59). Defective responses to IL-18 in dexamethasone-treated animals ageing or genetically obese rats or mice are almost completely restored to normal by central injection of neutralising antilipocortin-1 antibody (56, 49; Busbridge, Strijbos & Rothwell, unpublished data). Thus, we have proposed that lipocortin-1 is an endogenous inhibitor of fever and thermogenesis, which mediates the antipyretic effects of glucocorticoids and may be responsible for diminished fever and thermogenesis seen in obese or ageing rodents. The mechanisms of these actions of glucocorticoids and lipocortin have not been fully elucidated. An obvious factor would be inhibition of eicosanoid synthesis as a result of decreased arachidonic acid release. However, lipocortin-1 apparently fails to inhibit the actions of cytokines which are independent of CRF (i.e. TNF-ar, IL-la), and can directly attenuate the thermogenic actions of exogenous CRF (62) indicating an alternative mechanism of action. Dietary fatty acid modification
Recently, there has been considerable interest in the effects of modifying fatty acid intake as a possible means of altering membrane phospholipid composition and thus inhibiting the synthesis of proinflammatory eicosanoids (60, 61). Relatively few data exist on the effects of such manipulations on fever, thermogenesis or body weight, but recent work indicates that supplementation of diets with marine fish oils or eicosapentanoic acid (EPA) may have significant effects. Bibby and Grimble (62) reported that rats fed diets high in coconut oil showed blunted responses to TNF-a, possibly due to impaired prostaglandin synthesis. Similarly, we have observed diminished thermogenic and pyrogenic effects of IL-18 in rats fed eicosapentanoic acid (EPA)-supplemented diets (63). In the latter study, the metabolic response to peripheral injury was also attenuated by EPA diets. Pomposelli et al (64) have reported attenuated febrile responses to IL-l in guinea-pigs fed fish-oil enriched diets, which were associated with an increased thromboxane B2 production. Dietary supplementation with fish oil (28% EPA) inhibited the metabolic responses to burn injury in guinea-pigs resulting in less weight and skeletal muscle loss and lower resting metabolic rates (65). Endres et al (66) observed reduced in vitro production of IL-1 in response to endotoxin in human subjects supplemented with EPA. Similarly,
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we have observed that in human volunteers, excess intake of EPA inhibited the increase in metabolic rate following intramuscular injection of typhoid vaccine, but the fever was only slightly attenuated (Cooper & Rothwell, unpublished data). Several studies have indicated that evening primrose oil (high in cis-gamma linoleic acid) promotes weight loss in normal subjects, which has been ascribed to direct thermogenic effects of increased PGEi synthesis in BAT (67). However, evidence supporting this mechanisms of action is lacking, and direct effects of PGEl on BAT as proposed by Heleniak and Aston (67) are small and occur only at high doses. Clinical implications
The evidence reviewed above indicates that eicosanoids are important mediators of fever and thermogenesis during infection, and may also be involved in diet-induced thermogenesis, normal body weight and temperature regulation and cancer cachexia. Thus, selective modifichtion of eicosanoid synthesis offers a possible therapeutic strategy for the management of obesity, weight loss, and hypermetabolism, in addition to its well established value in antipyresis. Until selective inhibitors or antagonists of specific prostanoids are clinically available, modification of dietary fatty acids could offer therapeutic benefit. References 1. Cooper K E, The neurobiology of fever: thoughts on recent developments. Annual Review of Neuroscience 10: 297-324, 1987. 2. Kluger M J, Fever: role of pyrogens and cryogens. Physiological Reviews 71: 93-127, 1991. 3. Milton A S, Prostaglandin in fever and the mode of action of antipyretics. pp 275-297 in Pyretics and antipyretics (A S Milton, ed) Springer Verlag, Heidelberg, 1982. 4. Milton A S, Thermoregulatory actions of eicosanoids in the central nervous system with particular regard to the pathogenesis of fever. Annals New York Academy of Sciences 539: 392-419, 1989. 3. c Rothwell N J. Stock M J. Whither brown fat? Bioscience Reports 6: 3-18, 1986. 6. Nicholls D G. Locke R, Thermogenic mechanisms in brown fat. Physiological Reviews 64: l-64, 1984. 7. Lean M E J, James W P T, Brown adipose tissue in man. pp 339-365 in Brown Adipose Tissue., (Trayhurn P, Nicholls D G eds) Arnold, London, 1986. 8. Bruce J, Childs C C, Cooper A L, Rothwell N J, Brown adipose tissue in children in relation to disease status. Proceedings of the Nutrition Society 49: 189A, 1990. 9. Rothwell N J, Thermogenesis in obesity and cachexia in Endocrinoloav and Metabolism hormones and nutrition %r obesity and cachexia, PD 77-85 (Muller M ed) Sorineer. Heidelbere. 1990. 10 k’othwell N J, Mechanisms of ‘ihe’ pyrogenic ictions of cytokines. European Cytokine Network 1: 211-213,199O.
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Effects of endogenous pyrogen and prostaglandin E, on hypothalamic neurons in guinea pig brain slices. Journal of Applied Physiology 63: 175-180, 1987. 31. Rothwell N J, Central effects of CRF on metabolism and energy balance. Neuroscience & Biobehavioural Reviews 14: 263-271, 1990. 32. Busbridge N J, Dascombe M J, Tilders J H, Van Oers J W A M, Linton E A, Rothwell N J, Central activation of thermogenesis and fever by interleukin-18 and interleukin-lor involves different mechanisms. Biochemistry and Biophysical Research Communications 162: 591-596, 1989. 33. Rothwell N J, Central effects of TNFar on thermogenesis and fever in the rat. Bioscience Reports 8: 345-352, 1988. 34. Bernadini R, Chiorenza A, Cologero A E, Gold P N N, Chrousos G P, Arachidonic acid metabolites modulate rat hypothalamic corticotrophin-releasing hormone secretion in vitro Neuroendocrinoloav 50: 708-715, 1989. 35. Myers R D. Neurochemistry of thermoregulation. Physiologist, 27: 41-46, 1984. 36. LeFeuvre R A, Aisenthal L, Rothwell N J. Involvement of coticotrophin releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5HT) and related compounds. Brain Research 555: 245-250, 1991. 37. Calogero A E, Bernadini R, Margioris A N. Bagdy G, Gallucci W T, Munson P J. Tamarkin C. Tomai T P, Brady L. Gold P W. Chrousos G P, Effects of serotonergic agonists and antagonists on CRH secretion by explanted hypothalami. Peptides 10: 189-200,1989. 38 Horton R W. LeFeuvre R A, Rothwell N J. Stock M J, Opposing effects of activation of central GABA, and GABAs receptors in brown fat thermogenesis in the rat. Neuropharmacology 27: 363-366.1988. 39. Little R A. Metabolic rate and thermoregulation after injury. pp 159-172, in Recent Advances in Critical Care Medicine, (Ledingham I, ed) London, Churchill, 1988. 40. Aulick L H, Wilmore D W, Hypermetabolism in trauma pp 259-304, in Mammalian Thermogenesis. (Girardier L, Stock M J eds) Chapman & Hall, London, 1983. 41. Cooper A L. Rothwell N J, Mechanisms of the early and late hypermetabolisms and fever after localised tissue injury in the rat. American Journal of Physiology, In Press, 1991. 42. McCarthy D, O’Shaugnessy C T. Rothwell N J. Endogenous mediators of cerebral ischaemia-induced hypermetabolism in the rat. British Journal of Pharmacology 99: 838P. 1989. 43. Tisdale M J. Cancer cachexia. pp 149-157. in Obesity & Cachexia. (Rothwell N J, Stock M J eds) John Wiley & Sons, London, 1991. 44. Gelin J, Hyltander A, Lundholm K, Cancer cachexia pp 209-226 in Obesity & Cachexia. (Rothweli N J, Stock M J eds) Wiley & Sons. London, 1991. 45. Rothwell N J, Automonic and central control of thermogenesis. pp 13-32, in Obesity and Cachexia. (Rothwell N J. Stock M J eds)/ Wilev_ & Sons, London. 1991. 46. Gelin J, Anderson C. Lundholm K, Effects of indomethacin, cytokines and cyclosporin A on tumour growth and the subsequent development of cancer cachexia. Cancer Research 51: 880-885, 1991 47. Scales W E, Kluger M J, Effect of antipyretic drugs on circadian rhythm of body temperature in conscious rats. American Journal of Physiology 253: R306-R313.1987. 48. Carey F, Forder R, Edge M D, Greene A R. Horan M A, Strijbos P J L M. Rothwell N J,
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Lipocortin 1 fragment modifies the pyrogenic actions of cytokines in the rat. American Journal of Physiology 259: R266R269, 1990. Marchineton D. Rothwell N J. Stock M J. York D A, E&rgy balance, diet-induced them&genesis and brown adipose tissue in lean and obes (fq/fa) Zucker rats after adrenalectomy. Journal of Nutrition 113: 1395-1402,1983. Hardwick A J, Linton E A, Rothwell N J, Thermogenic effects of the antiglucocorticoid RU 386 in the rat: involvement of corticotropin releasing factor and sympathetic activation of brown adipose tissue. Endocrinology 124: 1684-16881989 Langley S C, York D A, The effects of the antiglucocorticoid RU486 on the development of obesity in the obese fa/fa Zucker rat. American Journal of Physiology 259: R539-544, 1990. Camie J A, Johnston J A, Busbridge N J, Dascombe M J, Rothwell N J, Central effects of interleukin-18 and tumour necrosis factor cx in brown adipose tissue thermogenesis in genetically obese rats. Proceedings of the Nutrition Society 48: 148A, 1989. Dascombe M J, Hardwick A, LeFeuvre R A, Rothwell N J, Impaired effects of interleukin 18 in fever, thermogenesis and brown fat in genetically obese rats. International Journal of Obesity 13: 367-374,1989b. Busbridge N J, Camie J A, Dascombe M J, Johnston J A. Rothwell N J. Adrenalectomv reverses the impaired pyrogenic responses to interleukin 18 in obese Zucker rats. International Journal of Obesity 14: 809-819, 1990. Strijbos P J L M, The role of lipocortin-1 in the central control of fever and thermogenesis PhD thesis, University of Manchester, 1991. Flower R J, Lioocortin and the mechanisms of action of the giucocorticoids. British Journal of Pharmacology65: 987-1015, 1988. Johnson M D. Kamso-Pratt J. Whetsell W 0. Pepinsky R B; Lipocortin-1 immunoreactivity’ in the normal human central nervous system and lesions with astrocytes. American Journal of Clinical Pathology 92: 424-429, 1989. Strijbos-P J L M, Tilders F J H, Carey F, Forder R, Rothwell N J, Localisation of immunoreactive lipocortin-I in the brain and pituitary gland of the rat. Brain Research 553: 249-260, 1991.
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59. Relton J K, Carey F, Rothwell N J, The neuroprotective actions of lipocortin-1 in cerebral ischaemia in the rat. British Journal of Pharmacology In Press, 1991. 60. Terano T, Salmon J A, Higgs G A, Moncada, S, Eicosapentanoic acid as a modulator of inflammation. Effect on prostaglandin and leukotriene synthesis. Biochemical Pharmacology 35: 779-785.1986. 61. Gurr M I, The role of lipids in the regulation of the immune system. Progress in Lipid Research 22: 257-287,1983. 62. Bibby D C, Grimble R F, Dietary fat modifies some metabolic actions of human recombinant tumour necrosis factor alpha in rats. British Journal of Nutrition 63: 653-668, 1990. 63. Cooper A L, Weddell K, Saunders T, Rothwell N J, Metabolic responses to interleukin-1 (IL-l) are attenuated by dietary eicosapentaenoic 920:5n-3) and docosohexaenoic (22:6n-3) fatty acids in the rat. Proceedings of the Nutrition Society, In Press, 1992 64. Pomposelli J J, Masioli E A, Bistrian B R, Lopes S M. Blackburn G. Alteration of the febrile response in guinea pigs by fish oil enriched diets. Journal of Parenteral and Enteral Nutrition 13: 136140,1989. 65. Alexander J W, Saito H, Ogle C K, Trocki 0, The importance of lipid type in the diet after bum injury. Annals of Surgery 204: l-7, 1986. 66. Endres S, Ghorbani R, Kelley V E, Georailisk K, Lonneman G, van der Meer J W, Lennon-J G. Roeers T S. Klemoer M S. Weber P C et al. The effict of dietary supplementation with n-3 polyunsaturated fatty acids on the sunthesis of interleukin-1 and tumour necrosis factor by mononuclear cells. New England Journal of Medicine 320: 265-271, 1989. 67. Heleniak E P, Aston B, Prostaglandins, brown fat and weight loss. Medical Hvoothesis. 28: 13-33.
Editor’s Review Cross Reference Murphy S, Pearce B. Eicosanoids in the CNS: Sources and Effects. Prostaglandins, Lcukotrienes and Essential Fatty Acids: Reviews 31: 165-170, 1988.
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(1992) 46, 1-7
Review
Eicosanoids, Thermogenesis and Thermoregulation N. J. Rothwell Department of Physiological Sciences, 9PT, UK (Reprint requests to NJR)
University of Manchester,
INTRODUCTION The involvement of prostaglandins in fever is well established, and it is now apparent that they act as important mediators of the thermogenic responses to infection, inflammation and disease. Several cytokines (particularly interleukins 1 and 6) have been identified as endogenous pyrogens and activators of thermogenesis. Their effects appear to depend on synthesis of prostanoids and corticotrophin releasing factor, within the brain. Endogenous inhibitors of fever and thermogenesis have been identified which attenuate responses to these cytokines. Dietary modification of fatty acid intake also markedly alters pyrogenic and thermogenic responses, probably by effects on prostanoid synthesis. Eicosanoids have been assumed to play a small role in thermoregulation and thermogenesis under normal conditions, but recent data indicate their involvement in responses to hypherphagia and a possible role in normal body weight regulation. The history of eicosanoid involvement in fever dates back to 1763, when it was first demonstrated that the bark of the willow tree inhibits fevers; the active ingredient was subsequently identified as salicylic acid. Since then, and particularly over the last 30 years, substantial evidence has accumulated to confirm the.importance and to extend our understanding of the role of eicosanoids in pyrogenesis. Indeed cyclooxygenase inhibitors remain the most common and effective antipyretic agents. The discovery and basic mechanisms of the involvement of eicosanoids in fever has been elegantly and extensively reviewed in a number of articles (l-4)) and will therefore not be discussed in detail here. This review will focus on recent observations on the mechanisms of induction, action and modulation of
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eicosanoid action thermogenesis.
in
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Mechanisms of thermoregulation, thermogenesis and fever The obligatory maintenance of body temperature within narrow limits in homeotherms is under direct control by the central nervous system (CNS), which modifies peripheral effector mechanisms of heat production and heat loss. Variations in heat loss can be achieved by both autonomic (changes in local blood flow, piloerection, sweating) and behavioural (e.g. huddling, licking) processes. In contrast, variations in heat production are largely under autonomic control and dependent on either shivering or non-shivering thermogenesis (NST). NST is a more effective means of raising body temperature, and predominates in small mammals, neonates and during chronic exposure to cold. Studies on laboratory rodents have indicated that NST results from activation of the sympathetic nervous system and local release of noradrenaline to stimulate heat production in brown adipose tissue (BAT) (6). This process involves a novel 8s adrenoceptor located on brown adipocytes and subsequent uncoupling of oxidative phosphorylation of a mitochondrial proton conductance pathway, which is unique to BAT (7). Under conditions of maximal stimulation in rodents, BAT (which usually represents less than 1% of total body mass) can receive up to 60% of the cardiac output and cause at least a 100% increase in total heat production (6). The physiological importance of BAT in humans is unknown, and undoubtedly of much smaller magnitude. However, BAT is quantitatively important in human neonates (6), is present in an active form throughout active life (8)
2
Prostaalandins Leukotrienes and Essential Fattv Acids
and can be activated in certain disease states associated with fever and hypermetabolism (9). Common mechanisms of thermogenesis (i.e. sympathetic activation of BAT) are responsible for increases in metabolic rate during development of fever (6, 10, 11) NST during cold exposure or arousal from hibernation and the heat production resulting from hyperphagia or consumption of nutritionally unbalanced diets (6, 7). This latter form of thermogenesis (diet-induced thermogenesis, DIT) is involved in the regulation of energy balance and body weight (6). Genetically obese rodents (e.g. fatty Zucker rat, obese ob/ob mouse) exhibit impaired DIT as well as hyperphagia which results in excess fat deposition and in some cases defective thermoregulation (12). Fever, usually defined as a regulated increase in the set point for body temperature regulation, is one of the most common clinical features of infection and can also accompany injury, inflammation and malignant disease (1, 2, 10). Development of fever is achieved by reductions in heat loss and increased heat production via both shivering and NST. Thus, during fever normal thermoregulatory processes are utilised to achieve a higher body temperature. The induction of fever has been ascribed to the actions of endogenous pyrogens released in response to exogenous pyrogenic stimuli, injured or inflammed tissue or the presence of malignant cells. The cytokines are now considered to be the primary endogenous mediators of fever and thermogenesis in response to infection, injury or inflammation. Several cytokines have been shown to elicit fever in laboratory rodents and are released or synthesised in numerous tissues, including the brain, during pyrogenesis. Kluger (2) has reviewed in detail the evidence currently available to support a physiological role of each of these. Interleukin-1 (IL-l) and interleukin-6 (IL-6) appear to be the most prominent endogenous pyrogens which act centrally to modify body temperature. However, the means by which these large molecules enter the CNS, their sites and mechanisms of action remain poorly understood. Mechanisms
of fever
The pyrogenic
and thermogenic actions of most of the cytokines (IL-& IL-l& IL-6, TNF-ar, IF6) are prevented by prior administration of cyclooxygenase inhibitors such as flurbiprofen of ibuprofen (1, 11, 13) indicating that they are directly mediated by release of prostanoids. Notable exceptions to this are interleukin-8 and macrophage inflammatory protein-l both of which induce fevers which are insensitive to cyclooxygenase inhibitors (14, 15). In addition, prostanoids can feed back to inhibit the synthesis of cytokines such as IL-l.
Peripheral injection of cytokines causes release of prostaglandins both locally and within the CNS, at sites specifically associated with the development of fever (16). There is debate over the ability of peripherally synthesised or administered cytokines and prostaglandins to enter the CNS (4, 5, 17). It has been proposed that circulating cytokines such as IL1 act at site(s) which lack a substantial blood brain barrier such as the organum vasculosum of the lamina terminalis (OVLT) and cause the synthesis of prostaglandins, particularly PGE2 which can directly modify activity of thermosensitive neurones in the preoptic anterior hypothalamus (POAH) (18, 19). However push-pull and microdialysis studies have demonstrated local synthesis of PGE2 in the POAH during development of fever, and several cytokines (e.g. IL-ll3, IL-6) are present within the CNS, and may be synthesised in response to peripheral pyrogenic stimuli or local damage (1, 12, 19). Morimoto et al (20) have reported that local injections of prostaglandins into the brain of rabbits induces monophasic fevers, in contrast to endogenous pyrogen (partially purified IL-l) which induced biphasic fever. They proposed that prostaglandins synthesised outside the blood brain barrier act on multiple sites in the CNS to induce the first phase of fever, while prostaglandin synthesis in regions near the OVLT in response to endogenous pyrogens is responsible for the second fever peak. PGE2 is generally considered to be the major prostanoid involved in pyrogenesis, although several other eicosanoids can also induce fever and thermogenesis in experimental animals and PGE, is equipotent with PGE;!. PGF2, was originally reported not to cause fever in the rabbit (21), but subsequent studies have revealed that in the rabbit and the rat, central injection of PGF*, elicits increases in body temperature and metabolic rate of similar magnitude to PGE2 (22, 23). At present it seems unlikely that other eicosanoids (e.g. thromboxanes, leukotrienes) play a major, direct role in fever, but could indirectly influence body temperature (5). In the absence of selective antagonists for specific eicosanoids, it is difficult to answer this question. Furthermore, PGE2 and PGFzU may act via different mechanisms, since their maximal effects on fever and thermogenesis in the .rat are additive, and only PGF2, appears to depend on corticotrophin releasing factor (CRF) for its actions (23 and below). Sites of action of prostaglandins
in the CNS
Morimoto et al (20) compared the febrile responses of rabbits to local injections of PGE;? and PGF2, into 68 specific regions of the rabbit brain. The results revealed that regions of the nucleus broca
Eicosanoids, Thermogenesis
ventralis, preoptic, anterior and ventromedial hypothalamus (VMH) were most sensitive. The POAH has generally been considered the major hypothlamic area responsive to prostaglandins (1, 19). However, the fact that fever can still develop after destruction of the POAH suggests that it is not fundamental for pyrogenesis (19). In contrast, destruction of the VMH reportedly attenuates the development of fever (19) and is highly sensitive to the pyrogenic actions of prostaglandins (20). The VMH has not been specifically implicated in the control of body temperature or development of fever, but is an important site for control of autonomic function and of thermogenesis (24). Destruction of the VMH results in hyperphagia, impaired diet-induced thermogenesis, reduced brown fat activity and subsequent obesity (24). Conversely, electrical stimulation of the VMH in the rat causes marked increases in thermogenesis in BAT, which are due to activation of the sympathetic nerves supplying the tissue (25). Fyda et al (26) concluded that BAT is an important effector organ responsible for the hyperthermic and thermogenic response to central injection of PGEi in the rat. Amir and Schiavetto (27) reported that increased BAT thermogenesis by injection of PGE;? into the POAH of the rat could be prevented by administration of local anaesthetic or the GABA* receptor agonist, muscimol, into the VMH. These data suggest that pyrogenic and thermogenic effects of PGE;? are mediated by activation of sympathetic outflow via the VMH. A high density of IL-lp immunoreactivity has been reported in the VMH (28) and this also appears to be a major site of synthesis of IL-lb (assessed from mRNA) in the brain (29). Studies on fever and thermogenesis have focused mainly on the hypothalamus, but several extra hypothlamic regions are likely to mediate or modulate actions of eicosanoids. Blatteis (19) has reviewed evidence for thermosensitive regions in the cortex, pons and medulla which could participate in fever, and pyrogens such as interleukin-1 are identified and can act at sites within the cortex, hippocampus and lower brain stem. However, prostanoid receptors are also present on glial cells (particularly astrocytes) which also synthesise eicosanoids. The relative importance of neurones and glial cells as sources and sites of action of eicosanoids on fever and thermogenesis is at present uncertain. Mechanisms of action of eicosanoids on fever/thermogenesis
Several reports have now provided evidence that the effects of prostaglandins on body temperature and thermogenesis are dependent on sympathetic activation of heat production in BAT probably by central stimulation of sympathetic outflow (26, 30).
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The increased thermogenesis induced by prostaglandins can be prevented by systemic administration of sympathetic ganglionic blockers or fi-adrenoceptor antagonists (27, 30). Prostaglandins have been postulated as the final mediations of fever, acting directly on thermosensitive neurones (5, 19, 31). Thus, changes in thermogenesis are presumably secondary to the increase in set point, acting to facilitate a raised body temperature. However, several experimental interventions can modify the pyrogenic and thermogenic actions of eicosanoids. These manipulations probably inhibit fever as a result of reductions in thermogenesis, (for example in the case of p blockade). When thermogenic effector mechanisms are inhibited, pyrogenic animals should show compensatory reductions in heat loss in an attempt to raise body temperature to the higher preferred or ‘set’ point. In studies in which measurements of heat loss and metabolic rate have not been made it is difficult to distinguish the effects of pharmacological interventions on the development of fever per se, from those on thermogenesis activation of thermogenic effector mechanisms or peripheral vasomotor control .
Corticotrophin releasing factor (CRF), first identified for its effects on pituitary ACTH release, also has numerous actions within the CNS, including stimulation of thermogenesis and BAT activity (32). Inhibition of CRF action by central injection of a receptor antagonist (a helical CRF 9-41) or neutralising antibody to CRF, markedly attenuates the pyrogenic and thermogenic actions of several cytokines including IL-lg, IL-6 and IL-8 (11, 33), although the effects on metabolic rate are often greater than on body temperature. These observations have lead to the suggestion that CRF mediates effects of these cytokines on fever/ thermogenesis (11) and may also be involved in actions of IL-l on food intake and behaviour (13). In contrast, increases in body temperature and metabolic rate in rats injected with IL-la (33) or TNF-a (34) are not inhibited by CRF antagonists indicating that two separate pathways exist within the CNS. The thermogenic responses to CRF in the rat are not modified by cyclooxygenase inhibitors (33), but in vitro studies have revealed that CRF release from isolated hypothlami is stimulated by PGF*, and thromboxane AZ, but not by PGE2 (35). Central injection of low doses of PGEz or PGF*, in the rat elicits increases in body temperature and metabolic rate in conscious rats (23). The responses to are almost completely abolished by PGF2, pretreatment with the CRF receptor antagonist, while the actions of PGE2 are unaffected (23). It has therefore been postulated that CRF mediates the actions of IL-l@, IL-6 and IL-8 and PGF2, whereas TNF-a, IL-la act independently of CRF (11). The physiological importance, interrelation-
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ships and brain locations of these two mechanisms of fever and thermogenesis are not as yet known. An additional putative step in this process is 5hydroxytryptamine (5HT) which has been thought for some time to be involved in fever (36). 5HT stimulates thermogenesis in a CRF dependent manner in the rat (37), and release of CRF from isolated hypothalami by 5HT can be inhibited by thromboxane A2 antagonists (38). In vivo stimulation of BAT thermogenesis by PGE2 is prevented by injection of GABA* agonist into the VMH (27). This observation is consistent with earlier studies suggesting that GABA* receptors within the brain inhibit thermogenesis while activation of GABAa receptors stimulates metabolic rate (39). Physiological importance of eicosanoids in the control of thermogenesis and body temperature
The physiological importance of eicosanoids in the development of fever (and associated thermogenesis) in response to cytokines or bacterial infections is well-established and has been reviewed in detail (l-3). However, increases in body temperature and metabolic rate which are commonly associated with injury (40, 41) are not always sensitive to cyclooxygenase inhibitors (41), suggesting that these conditions do not represent ‘true fever’. Local, modest injury in the rat (sterile turpentine-induced abscess in the hind limb) induces rapid (within 2 h) and sustained increases in body temperature and metabolic rate which are mediated by the sympathetic nervous system (42). The early phase (O-4 h) of this response is inhibited by peripheral, but not central administration of the cyclooxygenase inhibitor, flurbiprofen, while either route of administration inhibits the later (18 h) phase of the response (42). Thus, it seems that the immediate increases in temperature and metabolic rate are due to eicosanoid synthesis at the site of this injury, while the delayed response is more characteristic of true ‘fever’ and dependent on central eicosanoid synthesis. Experimental brain injury induced in rats by focal cerebral ischaemia causes a delayed (6-8 h) increase in metabolic rate, which is not modified by lipoxygenase or cyclooxygenase inhibitors (43). The wasting syndrome (cachexia) commonly associated with many forms of malignant disease has been ascribed to both decreases in food intake and increased, or inappropriately high energy expenditure (44, 45). In experimental cancer in laboratory animals, increases in metabolic rate have been ascribed to sympathetic activation of BAT (10, 46). Gelin et al (47) have recently demonstrated that administration of the cyclooxygenase inhibitor indomethacin markedly inhibits cachexia in mice
bearing tumours and increases survival time by up to 50%. Similarly, we have observed delayed weight loss in rats with T-cell leukaemia, treated with a cyclooxygenase inhibitor, although food intake was only slightly improved (Roe, Morris & Rothwell, unpublished data). Eicosanoids are not believed to participate in the normal regulation of body temperature or in the physiological responses to cold exposure (NST), since cyclooxygenase inhibitors do not modify body temperature or metabolic rate in these conditions. However, Scales and Kluger (48) have suggested that the diurnal rhythm of body temperature may be related to prostanoid synthesis, and increased diet induced thermogenesis in hyperphagic rats is markedly attenuated by cyclooxygenase inhibitors (30). In the latter case, the enhanced thermogenic capacity (response to noradrenaline) associated with hyperphagia was also prevented by cyclooxygenase treatment. Furthermore, chronic administration of salicylic acid enhanced weight gain in these animals in spite of a slightly reduced food intake (30). Glucocorticoid
modulation
Glucocorticoids are potent inhibitors of eicosanoid synthesis, acting to inhibit the activity of phospholipase A2 which is responsible for release of arachidonic acid, the common precursor for eicosanoids. Administration of natural or synthetic glucocorticoids inhibit fever and thermogenesis, probably by central actions to suppress the synthesis or actions of prostaglandins and/or CRF (5, 12, 13, 49). Genetically obese rodents, such as the fatty (fa/fa) Zucker rat and obese (ob/ob) mouse show impaired diet-induced thermogenesis which can be normalised by adrenalectomy, or by central or peripheral administration of a glucocorticoid antagonist (RU486) (12, 50-52). Both of these obese mutants also exhibit markedly diminished pyrogenic and thermogenic responses to interleukin-lp, which are again normalised by adrenalectomy (53-56). Similarly, we have observed that the reduced effects of IL-lfi on fever and thermogenesis in ageing rats and mice are restored to normal by peripheral or central injections of a glucocorticoid antagonist (RU486) (56; Strijbos & Rothwell, unpublished data). Thus, enhanced glucocorticoid feedback in obese mutants may contribute to their impaired responses to pyrogens via suppression of eicosanoid synthesis, and could also contribute to their reduced diet induced thermogenesis. Antiinflammatory actions of glucocorticoids have been ascribed to synthesis of a secondary mediator. lipocortin-1 (57). Central or peripheral administration of recombinant lipocortin-1 or an active fragment of lipocortin-1 (N terminal 1-188) causes a
Eicosanoids, Thermogenesis
dose dependent inhibition of fever and thermogenesis induced by interleukin-lfi, in the rat (56, 49). Lipocortin-1 is present in normal rat and human brain in neurones and glia (58, 59) and immunoreactive lipocortin-1 in hippocampal neurones appears to be sensitive to glucocorticoid status (59). Defective responses to IL-18 in dexamethasone-treated animals ageing or genetically obese rats or mice are almost completely restored to normal by central injection of neutralising antilipocortin-1 antibody (56, 49; Busbridge, Strijbos & Rothwell, unpublished data). Thus, we have proposed that lipocortin-1 is an endogenous inhibitor of fever and thermogenesis, which mediates the antipyretic effects of glucocorticoids and may be responsible for diminished fever and thermogenesis seen in obese or ageing rodents. The mechanisms of these actions of glucocorticoids and lipocortin have not been fully elucidated. An obvious factor would be inhibition of eicosanoid synthesis as a result of decreased arachidonic acid release. However, lipocortin-1 apparently fails to inhibit the actions of cytokines which are independent of CRF (i.e. TNF-ar, IL-la), and can directly attenuate the thermogenic actions of exogenous CRF (62) indicating an alternative mechanism of action. Dietary fatty acid modification
Recently, there has been considerable interest in the effects of modifying fatty acid intake as a possible means of altering membrane phospholipid composition and thus inhibiting the synthesis of proinflammatory eicosanoids (60, 61). Relatively few data exist on the effects of such manipulations on fever, thermogenesis or body weight, but recent work indicates that supplementation of diets with marine fish oils or eicosapentanoic acid (EPA) may have significant effects. Bibby and Grimble (62) reported that rats fed diets high in coconut oil showed blunted responses to TNF-a, possibly due to impaired prostaglandin synthesis. Similarly, we have observed diminished thermogenic and pyrogenic effects of IL-18 in rats fed eicosapentanoic acid (EPA)-supplemented diets (63). In the latter study, the metabolic response to peripheral injury was also attenuated by EPA diets. Pomposelli et al (64) have reported attenuated febrile responses to IL-l in guinea-pigs fed fish-oil enriched diets, which were associated with an increased thromboxane B2 production. Dietary supplementation with fish oil (28% EPA) inhibited the metabolic responses to burn injury in guinea-pigs resulting in less weight and skeletal muscle loss and lower resting metabolic rates (65). Endres et al (66) observed reduced in vitro production of IL-1 in response to endotoxin in human subjects supplemented with EPA. Similarly,
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we have observed that in human volunteers, excess intake of EPA inhibited the increase in metabolic rate following intramuscular injection of typhoid vaccine, but the fever was only slightly attenuated (Cooper & Rothwell, unpublished data). Several studies have indicated that evening primrose oil (high in cis-gamma linoleic acid) promotes weight loss in normal subjects, which has been ascribed to direct thermogenic effects of increased PGEi synthesis in BAT (67). However, evidence supporting this mechanisms of action is lacking, and direct effects of PGEl on BAT as proposed by Heleniak and Aston (67) are small and occur only at high doses. Clinical implications
The evidence reviewed above indicates that eicosanoids are important mediators of fever and thermogenesis during infection, and may also be involved in diet-induced thermogenesis, normal body weight and temperature regulation and cancer cachexia. Thus, selective modifichtion of eicosanoid synthesis offers a possible therapeutic strategy for the management of obesity, weight loss, and hypermetabolism, in addition to its well established value in antipyresis. Until selective inhibitors or antagonists of specific prostanoids are clinically available, modification of dietary fatty acids could offer therapeutic benefit. References 1. Cooper K E, The neurobiology of fever: thoughts on recent developments. Annual Review of Neuroscience 10: 297-324, 1987. 2. Kluger M J, Fever: role of pyrogens and cryogens. Physiological Reviews 71: 93-127, 1991. 3. Milton A S, Prostaglandin in fever and the mode of action of antipyretics. pp 275-297 in Pyretics and antipyretics (A S Milton, ed) Springer Verlag, Heidelberg, 1982. 4. Milton A S, Thermoregulatory actions of eicosanoids in the central nervous system with particular regard to the pathogenesis of fever. Annals New York Academy of Sciences 539: 392-419, 1989. 3. c Rothwell N J. Stock M J. Whither brown fat? Bioscience Reports 6: 3-18, 1986. 6. Nicholls D G. Locke R, Thermogenic mechanisms in brown fat. Physiological Reviews 64: l-64, 1984. 7. Lean M E J, James W P T, Brown adipose tissue in man. pp 339-365 in Brown Adipose Tissue., (Trayhurn P, Nicholls D G eds) Arnold, London, 1986. 8. Bruce J, Childs C C, Cooper A L, Rothwell N J, Brown adipose tissue in children in relation to disease status. Proceedings of the Nutrition Society 49: 189A, 1990. 9. Rothwell N J, Thermogenesis in obesity and cachexia in Endocrinoloav and Metabolism hormones and nutrition %r obesity and cachexia, PD 77-85 (Muller M ed) Sorineer. Heidelbere. 1990. 10 k’othwell N J, Mechanisms of ‘ihe’ pyrogenic ictions of cytokines. European Cytokine Network 1: 211-213,199O.
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and Thennoregulation
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Editor’s Review Cross Reference Murphy S, Pearce B. Eicosanoids in the CNS: Sources and Effects. Prostaglandins, Lcukotrienes and Essential Fatty Acids: Reviews 31: 165-170, 1988.
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