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Sudden infant death syndrome (SIDS): Disordered brown fat metabolism and thermogenesis
r
1
Medical Hypotheses
Sudden Infant Death Syndrome (SIDS): Disordered Brown Fat Metabolism and Thermogenesis G. REID’ and H. TERVlTt *25 Gilchrist St, Te Aroha, New Zealand,
t 7 McCracken Avenue, Hamilton, New Zealand.
Abstract - Foster found areas with the highest incidence of SIDS in USA in 1983-1984 coincided with the highest areas recorded with the highest incidence of goitre in First World War troops (1). Reid compared the two populations described as having the highest incidence of SIDS worldwide. Both were selenium deficient areas (King County WA, USA and Canterbury, New Zealand). Besides being a selenium livestock responsive area, Canterbury school children, prior to 1925, had a 56% incidence of goitre (2-6). Brown adipose tissue (BAT) synthesises fatty acids from glucose. BAT is a major tissue in fatty acid metabolism for the generation of heat (7). BAT has the specific property of converting thyroxine (T4) to triodothyronine (T3) via Type IY deiodinase enzyme. There is a many fold increase in the activity of this deiodinase in BAT after exposure of rats to sudden cold, which is greatly impaired in selenium deficient animals (7). The accepted picture of SIDS worldwide is that there is an increased incidence in infants of young smoking mothers. The incidence peaks in the second and third month of life, in winter and as latitude increases.
Introduction In prenatal and early postnatal life the energy source is mainly glucose. In a restricted oxygen environment, cells lack the capacity to oxidise long chain fatty acids. As mitochondrial development increases with aerobic metabolism, cytochromes increase and carnitine fatty acid oxidation pathways increase (8,9). Brown adipose tissue (BAT) tissue is highly specialised for fatty acid synthesis and oxidation. The total carnitine content of BAT in the rat is highest in the suckling period and after cold exposure (IO). Dale received Da1.eaccepted
After cold acclimation the levels of mitochondrial inner membrane components in BAT normally revert to the same values as were maximal during early postnatal development (10). It appears that BAT normally increases in metabolic activity in the early postnatal period and declines during later development at normal ambient temperatures. Cold acclimation normally reverses the trend in BAT and electron transport chain enzymes attain the same maximum levels observed in early postnatal life (10). We consider that the failure to convert glucose to fatty acids and the failure of fatty acid oxidation in
13 October 1993 8 November 1993
245
246 BAT is related to the delay in peak incidence of SIDS until the second or third month of life. A news media report describes the problems of low birth weight babies with poor growth in utero (11). These babies in intensive care units (incubators) are reported to have high blood sugar, poor circulation and breathing problems. Warm ambient temperatures reduce the high capacity of BAT to synthesise fatty acids from glucose and fatty acids are both the fuel and the signal for activation of thermogenesis (7). All the disorders of fatty acid metabolism, carnitine metabolism, haem synthesis (12,13) and cytochrome disorders, as well as hypoxia and ischemia affect the metabolism of BAT in mammals other than the pig. Disorders of the thyroid and selenium deficiency also affect BAT. The thyroid utilises phosphotidylinositol when stimulated with thyroid-stimulating hormone and BAT also utilises triacylglycerides during lipogenesis. Triacylglyceride is produced during stimulated breakdown of phosphotidylinositol (14). Discussion High free fatty acids in the blood diminish glucose uptake by the tissues, a state found in zinc deficient rats, in the prediabetic state and in hydrocortisone induced insulin resistance. Nicotinic acid reduced ketosis in dairy cows (15-17). Fat pads from zinc deficient rats took up glucose more slowly than did fat pads from control animals. The role of zinc was additive to insulin (18). The effect of zinc and insulin in siphoning off glucose into the adipocyte is important to BAT development. Plasma zinc levels decline when insulin resistance and hydrocortisone levels rise (16,17,19). Fasting and obesity lead to functional atrophy of BAT BAT has a high rate of glucose uptake, glucose being the primary substrate for lipogenesis in this tissue (7). Glucose uptake is stimulated by insulin and noradrenalin. BAT is particularly sensitive to insulin. A fatty acid binding protein has recently been isolated from BAT. Fatty acids in BAT play a dual role as both the primary fuel and signal for activation of thermogenesis. In BAT the primary product is heat (7). Increased blood flow and oxygen provide the fuel and oxygen supply for BAT thermogenesis and for heat dissipation (7). In BAT intracellular triiodothyronine (T3) activates the gene in mitochondrial DNA for transcription of mitochondrial inner membrane uncoupling protein (UCP) for control of oxidative phosphorylation (7). In tissues other than BAT and the anterior pituitary (liver, muscle) T4 is converted to TJ by a Type I deiodinase containing an atom of selenium (7). In muscle
MEDIcALHYPOTHESES and liver T3 boosts active sodium transport across cell membranes via the cell membrane sodium pump. This system controls the sodium-potassium ration in the cell, utilises oxygen and stimulates thermogenesis during cold acclimation (non-shivering thermogenesis (NST)) (20). The increased diaphragm and pectora1 muscle tissue respiration of cold acclimated rats is largely due to increased sodium dependent respiration (21). Tissue respiration of liver and kidney significantly increased in animals exposed to coldfor periods greater than 7 days (21).
In the rat NST began during the first week of cold exposure, increased during the second week and peaked in the third week (21). The increased thermogenesis in tissue other than BAT is a gradual process with a Time Lage Factor. BAT-increased thermogenesis is a response to sudden cold. Type I deiodinase is the muscle and liver tissue enzyme and Type II deiodinase is the BAT enzyme removing an atom of I from T4 for T3 synthesis. BAT tissue contains a Type II deiodinase which catalyses T4 conversion to T3 within the tissue. This enzyme is initially stimulated up to 20-fold by sudden exposure to cold and by the release of noradrenaline in the rat. The Type II deiodinase is not a selenium enzyme but its activity is greatly impaired in selenium (Se) and iodine (I) deficient animals (7). The recorded areas in New Zealand with known soil deficiencies of Se and I coincide with recorded information of the areas with the highest incidence of SIDS (2). A Time Lag Factor of about 5 days after a cold day has been identified with an increased incidence of SIDS (22-24). Young housed calves may die suddenly with post mortem lesions of myocardial degeneration (25). Modest amounts of exercise improve meat colour of piglets. Exercise has been shown to improve meat colour by increasing myoglobin content (2). Myoglobin, cytochrome C and certain muscle enzymes contain selenium (26). When vitamin E and selenium deficient housed calves were turned out to pasture in wet and windy weather there was an increased demand for heat production. The type of White Muscle Disease under these conditions occurs almost exclusively in the 2 weeks following turnout (25) (Time Lag). Deticienties of vitamin E and selenium are important factors in the aetiology of this disease, but these deficiencies merely render muscle liable to degeneration when environmental stresses are superimposed
(25).
We suggest that the initial stress on muscle was a failure of BAT thermogenesis.
SIDS: DISORDERED BROWN FAT METABOLISM AND THERMOGENESIS
We suggest that the calves raised in warm housed conditions were unable to prime fatty acid synthesis and mitochrondrial activity in BAT. When challenged with sudden cold BAT was unable to initiate fast track thermogenesis which precedes a gradual thermogenic response in muscle and liver, without adequate dietary selenium. The calves (housed) lacked the ability in BAT to supply both the fuel and the signal for activation of thermogenesis (7). The increased incidence of SIDS a few days after the onset of cold has a similar time frame and is likely to stem from the same BAT disorder, before the onset of the gradually increased thermogenesis in muscle and organs. We have previously expressed the view that the Time Lag Factor in SIDS resembles the Time Lag Factor in selenium deficient housed (warm) unexercised livestock after exposure to sudden cold on turnout (24). We now suggest that the Time Lag Factor in these two situations may originate in BAT when victims are unable to revert rapidly to the early postnatal elevated thermogenesis of BAT (10). BAT thermogenesis is the sudden response to cold which precedes sodium pump thermogenesis, the gradual response to cold acclimation with a Time Lag Factor. Conclusion Non-shivering thermogenesis (NST) is the body response to cold. (Babies do not shiver.) There are two responses to exposure to cold: 1. The increased thermogenesis in BAT is a response to exposure to sudden cold, involving the transformation of fatty acids to heat in BAT mitochondria. 2. The increased thermogenesis in tissue such as muscle and liver upon exposure to cold, is a gradual process reaching a peak in the third week of cold acclimation in the rat (21). There is a Time Lag Factor to cold acclimation in the pig and the housed calf. BAT requires insulin for fatty acid synthesis from glucose, a pathway which declines in warm ambient temperature. BAT atrophies during fasting, in warm ambient temperatures and in obesity. T3 in BAT mitochondria activates transcription of the UCP gene which is boosted by insulin (7). Fatty acids in BAT are both the fuel and an intracellular signal in thermogenesis. Type II deiodinase activity in BAT greatly increases upon exposure to sudden cold. Type II deiodinase converts T4 to T3 in this tissue.
241
Factors limiting increased thermogenesis in BAT are the fatty acid and carnitine disorders, hypoxia, thyroid insufficiency and selenium deficiency. Factors which impair BAT synthesis of glucose into fatty acids are insulin deficiency fasting, obesity and a warm ambient environment. The human infant synthesises and utilises fatty acids in BAT for the generation of heat. The piglet does not. Housed calves, deficient in selenium, would also be deprived of the fast track thermogenic response in BAT to sudden cold. Muscle tissue responds to exercise. Besides increased blood flow and oxygen levels, muscle colour increases, particularly the Type I red muscle fibres which contain cytochrome and myoglobin and are rich in pectoral and diaphragm muscles (25). The second thermogenic response to cold in liver and muscle is a gradual response of increased metabolism by the cell membrane sodium pump (21). The utilization of adenosine triphosphate by the sodium pump is boosted by T3 to increase transmembrane oxidative metabolism and generation of heat (20,21). In tissue such as liver and muscle Type I deiodinase converts T4 to T3. This Type I deiodinase is an enzyme containing one atom of selenium. Increased diaphragm and pectoral muscle tissue respiration of cold acclimated rats is largely due to this increased sodium-dependent respiration (21). Tissue respiration reaches its maximum in the third week of acclimation after exposure to cold (21). The greatest response is in red diaphragm and pectoral muscle, followed by liver. When baby pigs, which lack BAT, were raised in cold and draughty conditions, especially during the cooler months of the year, they began to die after about 3 weeks. The first problem was impaired circulation (27). Many of the deaths took place at night. There were two modes of death. In the first, animals suddenly developed spasmodic breathing (diaphragm?) and cardiac over action. In the second, pigs became increasingly listless, the skin was cold and clammy and the respiration became shallow. The picture closely resembled a death from oligenic shock (27). The grossly deranged liver structure was considered a result of deranged circulation after prolonged exposure to excessive cooling (27). Such conditions have been observed in SIDS victims. The human infant raised in warmth and comfort may lack normal fast track increased thermogenesis when exposed to sudden cold. BAT metabolism may be sluggish when Type II deiodinase response to sudden cold is grossly impaired. A disordered thermo-
248 genie response in muscle disorders and in liver disorders is likely to interfere with cold acclimation in the longer term, when Type I deiodinase stimulates muscle and liver T3 synthesis. An inappropriate thermogenic response would be exacerbated in iodine and selenium deficient subjects. The failure to increase the thermogenic response appropriately when exposed to cold may explain the increased incidence of SIDS in selenium and iodine deficient areas in New Zealand particularly in winter and in infants of young smoking mothers with closely spaced pregnancies and low birth weight babies needing special care. There is a Time Lag Factor in diaphragm and pectoral muscle response to cold acclimation (21). SIDS incidence in Finland was seasonally related to rapid and great temperature changes (NovemberDecember and May-June). Low birth weight victims found in the prone position, were more prevalent at about 12 weeks of age. The combined value of glucose and lactate in vitreous humor was always elevated, with lactate usually higher than glucose. During the coldest winter months the incidence of SIDS deaths was average (28). The shock of rapid and great temperature changes appears a likely problem. Some premature infants in Christchurch (Canterbury) neonatal unit registered some of the lowest plasma selenium levels recorded in humans (29). Vitamin E levels in piglets, heat stressed 18 days after a previous heat stressing, were only half prestressed levels 24 h later (29). Exercise training (daily bath!) and thyroxine reduce lactate formation in muscle (30). Carnitine and fatty acid transport (to BAT!) increases with physical training and increased respiratory capacity of muscle (31). Infants with low levels of selenium and vitamin E subjected to thermogenic shock would have an impaired response in BAT and to overheating. Circulatory shock is both a response to cold and to dehydration of overheating. Daily exercise and thyroxine reduce the effects of circulatory shock on muscle. Circulatory shock damages the electron transport chain in mitochondria (32,33). Trained muscles appear to compensate for decreased blood flow by increased extraction of oxygen from blood and thereby decrease lactate production (30). References
MEDICAL HYPOTHESES
3
4
9 IO
II. 12.
13
14. 1.5 16. 17. 18.
19.
20.
21.
22.
23. 24. 25. 26. 27.
Foster H. D. Health Disease and Environment. London: Belhaven Press, 1992. 2. Reid G M. Sudden Infant Death Syndrome: A Study of Two
High Incidence Populations. Abstracts: Sudden Infant Death Conference, Graz. Austria, 1988: 142. Bergman A B, Ray C, Pomeroy M, Wahl P, Beckwith J B. Studies of SIDS in King County WA III. Epidemiology Paed 1972; 49: 860-870. Hartley W J, Grant A B. A review of selenium responsive diseases of New Zealand livestock. Fed Proc 1961; 20: 679688. Hercus C H, Purves H D. Studies of the Thyroid. New Zealand Department of Health Annual Report 1937; 103-109. USDA. Technical Bulletin 758, 1967. Trayhum P. Brown Adipose Tissue: from thermal physiology to bioenergetics. J Biosci 1993; 18: 161-173. Warshaw J B. Cellular energy metabolism during fetal development. IV Fatty Acid Activation Acyl transfer and fatty acid oxidation during development of the chick and the rat. Development Biology 1972; 28: 537-544. Flatmark T, Peterson J I. Brown adipose tissue mitochondria. Biochem et Biophys Acta 1975; 416: 53-103. Sk&la J. Barnard T, Lindberg 0. Changes in interscapular brown adipose tissue of the rat during perinatal and early postnatal development after cold acclimation II Mitochondrial Changes. Comp Biochem Biophys 1970; 33: 509-528. Charlton V. Neonatal Specialist Un of Cal. San Francisco. Quoted in New Zealand’Herald, Aug I, 1988. Pascoe G A. Sakai-Wong J, Soliven E, Correia M A. Regulation of intestinal cytochrome P450 and heme by dietary nutrients. Chem Pharmacol 1983; 32: (20) 3027-3035. Jones M S, Jones 0 T G. The structural organization of haem Synthesis in Rat Liver mitochondria. Biochem J 1969; 113: 507-5 14. Michell R H. lnositol phospholipids and cell surface receptor function. Biochem et Biophys Acta 1975; 415: 81-147. Roth H P, Kirshgessner M. Review of zinc and insulin metabolism. Biol Trace Element Review 1981; 13-32. Littledyke E T, Whipp S C. Schroeder L. Studies of parturient paresis. J A V MA 1969; 155(12): 19.55-1962. Reid G. Metabolic disorders of cattle. Med Hypoth 1993; 40: 296-300. Quarterman J. The metabolic role of zinc with special reference to carbohydrate and lipid metabolism. Rowett Res lnst Annual Report 1968; 24: 100-108. Wegner T N, Ray D E, Cox C D, Stott G H. Effects of stress on serum zinc and plasma corticoids in dairy cattle. J Dairy Sci 1973; 56(6): 748-752. Endelman I S, Ismail-Beigi F. Thyroid thermogenesis and active sodium transport. Recent Progress in Hormone Research 1974; 30: 235-257. Guernsey D L, Stevens E D. The cell membrane sodium pump as a mechanism for increasing thermogenesis during cold acclimation in rats. Science 1977; 196: 908-910. Campbell M J. Sudden Infant Death Syndrome and environmental temperature: further evidence for a time-lagged relationship. Med J Aust 1989; 151: 365-367. Hassall I B. Sudden Infant Death Syndrome - the ANZ factor. Med J Aust 1989; 151: 365-367. Reid G M. Sudden Infant Death Syndrome (SIDS): A time lag factor. Med Hypoth 1991; 34: 186-189. Bradley R. Skeletal muscle in health and disease. In Practice, March 1981; 5-13. Underwood E J. Trace Elements in Human and Animal Nutrition, 4th ed. New York Academic Press, 1977: 312. Naftalin J M, Howie J W. Hepatic changes in young pigs reared in a cold and damp environment. J Path Bact 1969; 61: 319-328. Tiainen E. Sudden Infant Death Syndrome Conference Abst. Syndrome
I
28.
SIDS. DISORDERED BROWN FAT METABOLISM AND THERMOGENESIS
29
30. 3 I.
Graz Austria June 1988: P.64. Dolamore B A, Sluis K B, McGrouther J C, Grant S, Darlow B A, Winterboum C C. Low selenium and infant health in Christchurch. Proc Nutr Sot NZ 1990; 15: 181-186. Holloszy J 0. Biochemical adaptations of muscle. .I Biol Chem 1967; 252:(g) 2278-2282. Froberg S 0. Ostman I S. Effect of training on esterfied fatty
249
acids and camitine in muscle and in Iipolysis in adipose tissue in vitro. Acta Physiol Stand 1972; 86: 166-174. 32. Corbucci G. Gaspareto G, Candiani A el al. Shock induced damage to mitochondrial function and some cellular antioxidants in humans. Circulatory Shock 1985; IS: 15-26. 33. Reid G M, Tervit H. Sudden Infant Death Syndrome (SIDS) and disordered blood flow. Med Hypoth 1991; 36: 295-299.
1
Medical Hypotheses
Sudden Infant Death Syndrome (SIDS): Disordered Brown Fat Metabolism and Thermogenesis G. REID’ and H. TERVlTt *25 Gilchrist St, Te Aroha, New Zealand,
t 7 McCracken Avenue, Hamilton, New Zealand.
Abstract - Foster found areas with the highest incidence of SIDS in USA in 1983-1984 coincided with the highest areas recorded with the highest incidence of goitre in First World War troops (1). Reid compared the two populations described as having the highest incidence of SIDS worldwide. Both were selenium deficient areas (King County WA, USA and Canterbury, New Zealand). Besides being a selenium livestock responsive area, Canterbury school children, prior to 1925, had a 56% incidence of goitre (2-6). Brown adipose tissue (BAT) synthesises fatty acids from glucose. BAT is a major tissue in fatty acid metabolism for the generation of heat (7). BAT has the specific property of converting thyroxine (T4) to triodothyronine (T3) via Type IY deiodinase enzyme. There is a many fold increase in the activity of this deiodinase in BAT after exposure of rats to sudden cold, which is greatly impaired in selenium deficient animals (7). The accepted picture of SIDS worldwide is that there is an increased incidence in infants of young smoking mothers. The incidence peaks in the second and third month of life, in winter and as latitude increases.
Introduction In prenatal and early postnatal life the energy source is mainly glucose. In a restricted oxygen environment, cells lack the capacity to oxidise long chain fatty acids. As mitochondrial development increases with aerobic metabolism, cytochromes increase and carnitine fatty acid oxidation pathways increase (8,9). Brown adipose tissue (BAT) tissue is highly specialised for fatty acid synthesis and oxidation. The total carnitine content of BAT in the rat is highest in the suckling period and after cold exposure (IO). Dale received Da1.eaccepted
After cold acclimation the levels of mitochondrial inner membrane components in BAT normally revert to the same values as were maximal during early postnatal development (10). It appears that BAT normally increases in metabolic activity in the early postnatal period and declines during later development at normal ambient temperatures. Cold acclimation normally reverses the trend in BAT and electron transport chain enzymes attain the same maximum levels observed in early postnatal life (10). We consider that the failure to convert glucose to fatty acids and the failure of fatty acid oxidation in
13 October 1993 8 November 1993
245
246 BAT is related to the delay in peak incidence of SIDS until the second or third month of life. A news media report describes the problems of low birth weight babies with poor growth in utero (11). These babies in intensive care units (incubators) are reported to have high blood sugar, poor circulation and breathing problems. Warm ambient temperatures reduce the high capacity of BAT to synthesise fatty acids from glucose and fatty acids are both the fuel and the signal for activation of thermogenesis (7). All the disorders of fatty acid metabolism, carnitine metabolism, haem synthesis (12,13) and cytochrome disorders, as well as hypoxia and ischemia affect the metabolism of BAT in mammals other than the pig. Disorders of the thyroid and selenium deficiency also affect BAT. The thyroid utilises phosphotidylinositol when stimulated with thyroid-stimulating hormone and BAT also utilises triacylglycerides during lipogenesis. Triacylglyceride is produced during stimulated breakdown of phosphotidylinositol (14). Discussion High free fatty acids in the blood diminish glucose uptake by the tissues, a state found in zinc deficient rats, in the prediabetic state and in hydrocortisone induced insulin resistance. Nicotinic acid reduced ketosis in dairy cows (15-17). Fat pads from zinc deficient rats took up glucose more slowly than did fat pads from control animals. The role of zinc was additive to insulin (18). The effect of zinc and insulin in siphoning off glucose into the adipocyte is important to BAT development. Plasma zinc levels decline when insulin resistance and hydrocortisone levels rise (16,17,19). Fasting and obesity lead to functional atrophy of BAT BAT has a high rate of glucose uptake, glucose being the primary substrate for lipogenesis in this tissue (7). Glucose uptake is stimulated by insulin and noradrenalin. BAT is particularly sensitive to insulin. A fatty acid binding protein has recently been isolated from BAT. Fatty acids in BAT play a dual role as both the primary fuel and signal for activation of thermogenesis. In BAT the primary product is heat (7). Increased blood flow and oxygen provide the fuel and oxygen supply for BAT thermogenesis and for heat dissipation (7). In BAT intracellular triiodothyronine (T3) activates the gene in mitochondrial DNA for transcription of mitochondrial inner membrane uncoupling protein (UCP) for control of oxidative phosphorylation (7). In tissues other than BAT and the anterior pituitary (liver, muscle) T4 is converted to TJ by a Type I deiodinase containing an atom of selenium (7). In muscle
MEDIcALHYPOTHESES and liver T3 boosts active sodium transport across cell membranes via the cell membrane sodium pump. This system controls the sodium-potassium ration in the cell, utilises oxygen and stimulates thermogenesis during cold acclimation (non-shivering thermogenesis (NST)) (20). The increased diaphragm and pectora1 muscle tissue respiration of cold acclimated rats is largely due to increased sodium dependent respiration (21). Tissue respiration of liver and kidney significantly increased in animals exposed to coldfor periods greater than 7 days (21).
In the rat NST began during the first week of cold exposure, increased during the second week and peaked in the third week (21). The increased thermogenesis in tissue other than BAT is a gradual process with a Time Lage Factor. BAT-increased thermogenesis is a response to sudden cold. Type I deiodinase is the muscle and liver tissue enzyme and Type II deiodinase is the BAT enzyme removing an atom of I from T4 for T3 synthesis. BAT tissue contains a Type II deiodinase which catalyses T4 conversion to T3 within the tissue. This enzyme is initially stimulated up to 20-fold by sudden exposure to cold and by the release of noradrenaline in the rat. The Type II deiodinase is not a selenium enzyme but its activity is greatly impaired in selenium (Se) and iodine (I) deficient animals (7). The recorded areas in New Zealand with known soil deficiencies of Se and I coincide with recorded information of the areas with the highest incidence of SIDS (2). A Time Lag Factor of about 5 days after a cold day has been identified with an increased incidence of SIDS (22-24). Young housed calves may die suddenly with post mortem lesions of myocardial degeneration (25). Modest amounts of exercise improve meat colour of piglets. Exercise has been shown to improve meat colour by increasing myoglobin content (2). Myoglobin, cytochrome C and certain muscle enzymes contain selenium (26). When vitamin E and selenium deficient housed calves were turned out to pasture in wet and windy weather there was an increased demand for heat production. The type of White Muscle Disease under these conditions occurs almost exclusively in the 2 weeks following turnout (25) (Time Lag). Deticienties of vitamin E and selenium are important factors in the aetiology of this disease, but these deficiencies merely render muscle liable to degeneration when environmental stresses are superimposed
(25).
We suggest that the initial stress on muscle was a failure of BAT thermogenesis.
SIDS: DISORDERED BROWN FAT METABOLISM AND THERMOGENESIS
We suggest that the calves raised in warm housed conditions were unable to prime fatty acid synthesis and mitochrondrial activity in BAT. When challenged with sudden cold BAT was unable to initiate fast track thermogenesis which precedes a gradual thermogenic response in muscle and liver, without adequate dietary selenium. The calves (housed) lacked the ability in BAT to supply both the fuel and the signal for activation of thermogenesis (7). The increased incidence of SIDS a few days after the onset of cold has a similar time frame and is likely to stem from the same BAT disorder, before the onset of the gradually increased thermogenesis in muscle and organs. We have previously expressed the view that the Time Lag Factor in SIDS resembles the Time Lag Factor in selenium deficient housed (warm) unexercised livestock after exposure to sudden cold on turnout (24). We now suggest that the Time Lag Factor in these two situations may originate in BAT when victims are unable to revert rapidly to the early postnatal elevated thermogenesis of BAT (10). BAT thermogenesis is the sudden response to cold which precedes sodium pump thermogenesis, the gradual response to cold acclimation with a Time Lag Factor. Conclusion Non-shivering thermogenesis (NST) is the body response to cold. (Babies do not shiver.) There are two responses to exposure to cold: 1. The increased thermogenesis in BAT is a response to exposure to sudden cold, involving the transformation of fatty acids to heat in BAT mitochondria. 2. The increased thermogenesis in tissue such as muscle and liver upon exposure to cold, is a gradual process reaching a peak in the third week of cold acclimation in the rat (21). There is a Time Lag Factor to cold acclimation in the pig and the housed calf. BAT requires insulin for fatty acid synthesis from glucose, a pathway which declines in warm ambient temperature. BAT atrophies during fasting, in warm ambient temperatures and in obesity. T3 in BAT mitochondria activates transcription of the UCP gene which is boosted by insulin (7). Fatty acids in BAT are both the fuel and an intracellular signal in thermogenesis. Type II deiodinase activity in BAT greatly increases upon exposure to sudden cold. Type II deiodinase converts T4 to T3 in this tissue.
241
Factors limiting increased thermogenesis in BAT are the fatty acid and carnitine disorders, hypoxia, thyroid insufficiency and selenium deficiency. Factors which impair BAT synthesis of glucose into fatty acids are insulin deficiency fasting, obesity and a warm ambient environment. The human infant synthesises and utilises fatty acids in BAT for the generation of heat. The piglet does not. Housed calves, deficient in selenium, would also be deprived of the fast track thermogenic response in BAT to sudden cold. Muscle tissue responds to exercise. Besides increased blood flow and oxygen levels, muscle colour increases, particularly the Type I red muscle fibres which contain cytochrome and myoglobin and are rich in pectoral and diaphragm muscles (25). The second thermogenic response to cold in liver and muscle is a gradual response of increased metabolism by the cell membrane sodium pump (21). The utilization of adenosine triphosphate by the sodium pump is boosted by T3 to increase transmembrane oxidative metabolism and generation of heat (20,21). In tissue such as liver and muscle Type I deiodinase converts T4 to T3. This Type I deiodinase is an enzyme containing one atom of selenium. Increased diaphragm and pectoral muscle tissue respiration of cold acclimated rats is largely due to this increased sodium-dependent respiration (21). Tissue respiration reaches its maximum in the third week of acclimation after exposure to cold (21). The greatest response is in red diaphragm and pectoral muscle, followed by liver. When baby pigs, which lack BAT, were raised in cold and draughty conditions, especially during the cooler months of the year, they began to die after about 3 weeks. The first problem was impaired circulation (27). Many of the deaths took place at night. There were two modes of death. In the first, animals suddenly developed spasmodic breathing (diaphragm?) and cardiac over action. In the second, pigs became increasingly listless, the skin was cold and clammy and the respiration became shallow. The picture closely resembled a death from oligenic shock (27). The grossly deranged liver structure was considered a result of deranged circulation after prolonged exposure to excessive cooling (27). Such conditions have been observed in SIDS victims. The human infant raised in warmth and comfort may lack normal fast track increased thermogenesis when exposed to sudden cold. BAT metabolism may be sluggish when Type II deiodinase response to sudden cold is grossly impaired. A disordered thermo-
248 genie response in muscle disorders and in liver disorders is likely to interfere with cold acclimation in the longer term, when Type I deiodinase stimulates muscle and liver T3 synthesis. An inappropriate thermogenic response would be exacerbated in iodine and selenium deficient subjects. The failure to increase the thermogenic response appropriately when exposed to cold may explain the increased incidence of SIDS in selenium and iodine deficient areas in New Zealand particularly in winter and in infants of young smoking mothers with closely spaced pregnancies and low birth weight babies needing special care. There is a Time Lag Factor in diaphragm and pectoral muscle response to cold acclimation (21). SIDS incidence in Finland was seasonally related to rapid and great temperature changes (NovemberDecember and May-June). Low birth weight victims found in the prone position, were more prevalent at about 12 weeks of age. The combined value of glucose and lactate in vitreous humor was always elevated, with lactate usually higher than glucose. During the coldest winter months the incidence of SIDS deaths was average (28). The shock of rapid and great temperature changes appears a likely problem. Some premature infants in Christchurch (Canterbury) neonatal unit registered some of the lowest plasma selenium levels recorded in humans (29). Vitamin E levels in piglets, heat stressed 18 days after a previous heat stressing, were only half prestressed levels 24 h later (29). Exercise training (daily bath!) and thyroxine reduce lactate formation in muscle (30). Carnitine and fatty acid transport (to BAT!) increases with physical training and increased respiratory capacity of muscle (31). Infants with low levels of selenium and vitamin E subjected to thermogenic shock would have an impaired response in BAT and to overheating. Circulatory shock is both a response to cold and to dehydration of overheating. Daily exercise and thyroxine reduce the effects of circulatory shock on muscle. Circulatory shock damages the electron transport chain in mitochondria (32,33). Trained muscles appear to compensate for decreased blood flow by increased extraction of oxygen from blood and thereby decrease lactate production (30). References
MEDICAL HYPOTHESES
3
4
9 IO
II. 12.
13
14. 1.5 16. 17. 18.
19.
20.
21.
22.
23. 24. 25. 26. 27.
Foster H. D. Health Disease and Environment. London: Belhaven Press, 1992. 2. Reid G M. Sudden Infant Death Syndrome: A Study of Two
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