160
Hypothesis POSSIBLE STIMULATION OF THERMOGENESIS IN BROWN ADIPOSE TISSUE BY THYROID-STIMULATING HORMONE DEBORAH DONIACH
Department of Immunology, Middlesex Hospital Medical School, London W1P 9PG
EXPERIMENTAL EVIDENCE
suggested that in addition to stimulating the thyroid gland (i.e., the main regulator of metabolic-rate in adults) thyroidstimulating hormone (T.S.H.) stimulates the second thermoregulatory organ (i.e., the brown adipose tissue). Brown fat functions as a thermogenic organ in hibernating animals, in newborn infants, and during cold acclimatisation. However, B.F. may persist in childhood and in some adults. Its hypertrophy in response to T.S.H. could account for certain unexplained features of myxœdema in which serum-T.S.H. is raised, such as swelling of the supraclavicular fat pad and the less commonly encountered symptoms of ascites or pericardial and pleural serous effusions which can persist for years in undiagnosed cases and respond rapidly to thyroxine when serum-T.S.H. returns to normal. Lack of thyroxine is not the cause of these features since they are not found in pituitary myxœdema, where thyroid hormone levels are as low but T.S.H. It is
Sum ary
is absent. INTRODUCTION
adipose tissue has been regarded as a bloodforming tissue, as a specialised organ of hibernating animals, and as an endocrine gland. In the 1960s it was finally established as an important effector organ for thermoregulation.1 Brown fat (B.F.) is responsible for non-shivering thermogenesis in newborn infants, in cold-adapted adults, and in hibernating animals. It has been extensively studied by physiologists and its metabolism analysed by mitochondriologists.2,3 It is widely believed that heat production by B.F. is controlled entirely by noradrenaline and that hypertrophy of B.F. in cold acclimatisation is stimulated by thyroid hormones. However, clinical and experimental evidence suggests that another important factor may be involved in the regulation of B.F. I believe that this missing factor is pituitary thyroid-stimulating hormone (T.S.H.). BROWN
CHARACTERISTICS OF BROWN FAT
The functioning B.F. adipocyte consists of a central nucleus and numerous small fat globules, each surrounded by a ring of extremely active mitochondria. In white " storage " fat the cytoplasm is filled with a single fat vacuole; there are few other organelles and the nucleus is squashed as a crescent against the cell wall. In starvation, white depot fat is used up and the adipocytes become indistinguishable from other
connective-tissue cells.
Brown fat
stores
its
after birth and yields it only in advanced cachexia and after hibernation. The B.F. cell may be likened to a central-heating plant using lipid as its fuel. The heating is switched on by noradrenaline (lipolysis), the fuel is replenished by thyroid hormone with the help of cortisone (lipogenesis). I suggest that T.S.H. increases the size of the energy-producing machinery-i.e., the bulk of the mitochondria in the neonatal state, in cold stress, in hibernation, and during myxoedema.
lipid
Serum-T.s.H. level increases during cold stress.4 The most convenient way to analyse the hormone control of B.F. is to keep rats or mice at 4°C for a few weeks and treat them with either thiouracil or thyroidectomy, adrenalectomy, or hypophysectomy. The three constituents of B.F. (lipid, water, and nitrogen) can then be measured. Early work clearly showed that after thyroidectomy or thiouracil administration (when T.S.H. is very high) the interscapular brown fat pad lost its lipid globules, despite the good nutritional condition of the animals; but the protein content of the cells increased and there was no decrease in the size of the organ.5 Most workers likened it to the hibernating gland. Adrenalectomy also led to loss of lipid globules.6 After hypoor lesions in the hypothalamus which the animal of T.R.H. and indirectly of T.S.H., the deprive B.F. pad shrivelled up and lost its fat globules and its other constituents. More sophisticated studies differentiated between phospholipids which are plentiful in mitochondria3 and the neutral fats of the " fuel"" globules.5 Here again there was clear evidence that triglycerides were mainly lost after thyroidectomy when T.S.H. was high. In cold-adapted rats the increase in oxygen consumption and blood-flow in the brown fat was maintained.’ Immunosympathectomy, which leads to loss of sympathetic mediators,8 did ndt abolish the hypertrophy of B.F. mitochondria in thyroidectomised animals kept in the cold.
physectomy
CIRCUMSTANTIAL EVIDENCE IN THE NEONATE
is well
developed in many neonates, including babies, in whom it constitutes 2-6% of the body-weight. Since its role is to protect the vital organs, it is mainly situated around the large vessels where it transmits heat directly to the blood. It surrounds the carotid arteries in the neck, then spreads B.F.
human
behind the clavicles into the axillae. There is also an interscapular pad which warms the thermoregulation centre in spinal cord and thus makes it possible for sympathetic stimuli to start the heating mediated " by noradrenaline and also " shivering thermogenesis in muscles 1 There are deposits of B.F. in the mediastinum and in the abdomen around the pancreas, the kidneys, and the suprarenal glands. Serum-T.S.H. rises suddenly to about 20 times the normal adult level within half an hour of birth.9 This then leads to thyroid stimulation. The increase in T.s.H. is related to thermogenesis, since cooling babies 3-4 hours after birth leads to a rebound in the serum-T.S.H. level 9 The B.F. organ gradually atrophies after about 3 months of age, at about the time when thyroid hormones drop to adult levels, but if a child has cryo-
161 surgery (as in
open-heart operations) serum-T.S.H. again rises, presumably to help hommothermy.11 This does not happen in "warm" surgery, so it is not
thyroid-stimulating-antibody-related immunoglobulin may stimulate metabolism in B.F. on
that the rise in T.s.H. may restore function in the B.F. organ of the cooled baby.
unreasonable
possible analogues of leg.
the lateral aspect of the
to assume
EVIDENCE FROM PATHOLOGICAL STATES
Athyrotic cretinism and adult myxadema.-In 1850 Curling noted that patients with untreated congenital hypothyroidism sometimes had peculiar fat pads along the common carotids, in the supraclavicular region, and axillt." In 1908 Shattock 12 examined the brown fat in shrews and hedgehogs before, during, and after hibernation, and then looked at the swollen fat pads discovered at necropsy in young patients with cretinism. He accurately described the B.F. adipocyte and compared it with white fat cells. The abnormal fat deposits in the patients with cretinism had all the characteristics of the " hibernating gland ", and furthermore, these lumps disappeared when the patients were treated with thyroid extracts. Shattock therefore concluded that the B.F. swellings were somehow related the thyroid deficiency. Slight swelling of supraclavicular fat pads is not uncommon even in adult myxoedema, and in untreated patients it should be quite easy to demonstrate increased heat production in these swellings by thermography. In neonates the nuchal B.F. pad is
to
than other areas.13 Another rather rare complication of myxoedema is the development of ascites or, less uncommonly, of pericardial or pleural effusions 14 These resemble a transudate with high protein content. Myxoedema is not always severe in these patients. Serum-T.s.H. may reach several hundred times the normal level in some individuals before the onset of a classical myxoedematous facies, and it is conceivable that if small amounts of B.F. persisted into adult life, as they are known to do in some subjects,15 T.s.H. overstimulation would increase the bulk and activity of the mitochondria and this could lead to an increased blood-supply to B.F., and, with unrestrained activity of noradrenaline and cortisone, to changes in capillary permeability and serous exudation. A more speculative suggestion is that perhaps myxoedematous ileus might result from T.s.H. overstimulation of the B.F. cells that have been identified within the muscle layers of the intestineY Endocrine exophthalmos and pretibial myxadema.Patients with Graves’ disease have circulating thyroidstimulating antibodies,16 which mimic pituitary T.S.H., bind to the T.S.H. receptor on the thyroid cell membrane, and turn on the cyclic-A.M.P. system, thus causing continuous overproduction of thyroid hormones. IgG from patients with progressive exophthalmos, which represents antibodies related to
warmer
thyroid-stimulating antibodies, can cause exophthalmos in fish and guineapigs 17 Kohn and Winand 18 demonstrated that retro-orbital tissues have plasma membrane receptors for T.s.H. Kohn has also found that these T.s.H.-sensitive receptors were only present on brown-fat membranes and not in white fat. In addition, Alexander et al.19 demonstrated that at least in calves retro-orbital fat has the characteristics of In pretibial myxoedema it is also likely that a B.F.
FUTURE EXTENSIONS OF THE HYPOTHESIS
Study of thyroid autoimmunity led to the present hypothesis. The influence of various hormones on the B.F. organ should be re-examined with these new ideas in mind. During cold-stress corticotrophin is released from the pituitary in addition to T.s.H., and B.F. may possibly have important functions in protecting addisonian patients from steroid deprivation. Several workers have commented on the striking amount of periadrenal B.F. in Addison’s disease,20 and it has been suggested that B.F. is capable of producing steroid hormones. However, hypertrophy of B.F. by excess corticotrophin or steroid hormones in Cushing’s syndrome may possibly explain the mild proptosis sometimes seen in this disease and possibly the hump at the back of the neck. REFERENCES 1. 2.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Smith, R. E., Horwitz, B. Physiol. Rev. 1969, 49, 330. Baum, H. in The Cell in Medical Science (edited by F. Beck and J. B. Lloyd); p. 183. New York, 1974. Flatmark, T., Pedersen, J. I. Rev. Bioenergetics, 1975, 416, 53. Florsheim, W. H. in Handbook of Physiology (edited by R. O. Greep and E. B. Astwood); vol. IV, p. 449. Washington, 1974. Ikemoto, H., Hiroshige, T., Itoh, S. Jap. J. Physiol. 1967, 17, 516. Fawcett, D. W., Jones, I. C. Endocrinology, 1949, 45, 609. Kuroshima, A., Konno, N., Itoh, S. Jap. J. Physiol. 1967, 17, 523. Steiner, G., Schönbaum, E., Johnson, G. E., Sellers, E. A. Clin. J. Physiol. Pharmac. 1968, 46, 453. Fisher, D. A., Odell, W. D. J. clin. Invest. 1969, 48, 1670. Wilber, J. F., Baum, D. J. Endocr. Metab. 1970, 31, 372. Curling, T. B. Med. Chir. Trans. Lond. 1850, 33, 303. Shattock, S. G. Proc. R. Soc. Med. 1909, 2, 207. Silverman, W. A., Zamelis, A., Sinclair, J. C., Agate, F. J. Pediatrics,
Springfield, 1964, 33, 984. Sachdev, Y., Hall, R. Lancet, 1975, i, 564. Wegener, F. Beitr. path. Anat. 1951, 111, 252. Hall, R., Smith, B. R., Mukhtar, E. D. Clin. Endocr. 1975, 4, 213. Doniach, D., Florin-Christensen, A. Clins Endocr. Metab. 1975, 4, 341. 18. Kohn, L. D., Winand, R. J. in Molecular Aspects of Membrane Phenomena. Berlin, 1975. 19. Alexander, G., Bennett, J. W., Gemmell, R. T. J. Physiol. 1975, 244, 223. 20. Friedman, N. B. Endocrinology, 1948, 42, 181.
14. 15. 16. 17.
Reviews of Books Mountain Medicine A Clinical F.R.C.S.
Study of Cold and High Altitude. MICHAEL WARD, London:Crosby Lockwood Staples. 1975. Pp. 376.
E10.
WITH the increase in
popularity of mountaineering, people are finding their way onto large mountains where the problems of hypothermia, frostbite, acute mountain sickness, and high-altitude pulmonary oedema may make themselves suddenly and tragically felt. These problems can largely be avoided by knowledge and foresight, and the mountains can be properly enjoyed together with the fascinating experience of the way the human body adapts to a reduction in oxygen pressure. In this book Mr Ward provides the knowledge and a wideranging discussion on the adaptations. He has brought together the results of original work in a wide variety of disciplines, all having a bearing on man at high altitudes. After introductory chapters on history, the atmosphere, and the sociological effects of the mountain environment,
more
and
more
the book is divided between the effects of altitude on the cardiorespiratory system, the effects of cold, and the medical
Hypothesis POSSIBLE STIMULATION OF THERMOGENESIS IN BROWN ADIPOSE TISSUE BY THYROID-STIMULATING HORMONE DEBORAH DONIACH
Department of Immunology, Middlesex Hospital Medical School, London W1P 9PG
EXPERIMENTAL EVIDENCE
suggested that in addition to stimulating the thyroid gland (i.e., the main regulator of metabolic-rate in adults) thyroidstimulating hormone (T.S.H.) stimulates the second thermoregulatory organ (i.e., the brown adipose tissue). Brown fat functions as a thermogenic organ in hibernating animals, in newborn infants, and during cold acclimatisation. However, B.F. may persist in childhood and in some adults. Its hypertrophy in response to T.S.H. could account for certain unexplained features of myxœdema in which serum-T.S.H. is raised, such as swelling of the supraclavicular fat pad and the less commonly encountered symptoms of ascites or pericardial and pleural serous effusions which can persist for years in undiagnosed cases and respond rapidly to thyroxine when serum-T.S.H. returns to normal. Lack of thyroxine is not the cause of these features since they are not found in pituitary myxœdema, where thyroid hormone levels are as low but T.S.H. It is
Sum ary
is absent. INTRODUCTION
adipose tissue has been regarded as a bloodforming tissue, as a specialised organ of hibernating animals, and as an endocrine gland. In the 1960s it was finally established as an important effector organ for thermoregulation.1 Brown fat (B.F.) is responsible for non-shivering thermogenesis in newborn infants, in cold-adapted adults, and in hibernating animals. It has been extensively studied by physiologists and its metabolism analysed by mitochondriologists.2,3 It is widely believed that heat production by B.F. is controlled entirely by noradrenaline and that hypertrophy of B.F. in cold acclimatisation is stimulated by thyroid hormones. However, clinical and experimental evidence suggests that another important factor may be involved in the regulation of B.F. I believe that this missing factor is pituitary thyroid-stimulating hormone (T.S.H.). BROWN
CHARACTERISTICS OF BROWN FAT
The functioning B.F. adipocyte consists of a central nucleus and numerous small fat globules, each surrounded by a ring of extremely active mitochondria. In white " storage " fat the cytoplasm is filled with a single fat vacuole; there are few other organelles and the nucleus is squashed as a crescent against the cell wall. In starvation, white depot fat is used up and the adipocytes become indistinguishable from other
connective-tissue cells.
Brown fat
stores
its
after birth and yields it only in advanced cachexia and after hibernation. The B.F. cell may be likened to a central-heating plant using lipid as its fuel. The heating is switched on by noradrenaline (lipolysis), the fuel is replenished by thyroid hormone with the help of cortisone (lipogenesis). I suggest that T.S.H. increases the size of the energy-producing machinery-i.e., the bulk of the mitochondria in the neonatal state, in cold stress, in hibernation, and during myxoedema.
lipid
Serum-T.s.H. level increases during cold stress.4 The most convenient way to analyse the hormone control of B.F. is to keep rats or mice at 4°C for a few weeks and treat them with either thiouracil or thyroidectomy, adrenalectomy, or hypophysectomy. The three constituents of B.F. (lipid, water, and nitrogen) can then be measured. Early work clearly showed that after thyroidectomy or thiouracil administration (when T.S.H. is very high) the interscapular brown fat pad lost its lipid globules, despite the good nutritional condition of the animals; but the protein content of the cells increased and there was no decrease in the size of the organ.5 Most workers likened it to the hibernating gland. Adrenalectomy also led to loss of lipid globules.6 After hypoor lesions in the hypothalamus which the animal of T.R.H. and indirectly of T.S.H., the deprive B.F. pad shrivelled up and lost its fat globules and its other constituents. More sophisticated studies differentiated between phospholipids which are plentiful in mitochondria3 and the neutral fats of the " fuel"" globules.5 Here again there was clear evidence that triglycerides were mainly lost after thyroidectomy when T.S.H. was high. In cold-adapted rats the increase in oxygen consumption and blood-flow in the brown fat was maintained.’ Immunosympathectomy, which leads to loss of sympathetic mediators,8 did ndt abolish the hypertrophy of B.F. mitochondria in thyroidectomised animals kept in the cold.
physectomy
CIRCUMSTANTIAL EVIDENCE IN THE NEONATE
is well
developed in many neonates, including babies, in whom it constitutes 2-6% of the body-weight. Since its role is to protect the vital organs, it is mainly situated around the large vessels where it transmits heat directly to the blood. It surrounds the carotid arteries in the neck, then spreads B.F.
human
behind the clavicles into the axillae. There is also an interscapular pad which warms the thermoregulation centre in spinal cord and thus makes it possible for sympathetic stimuli to start the heating mediated " by noradrenaline and also " shivering thermogenesis in muscles 1 There are deposits of B.F. in the mediastinum and in the abdomen around the pancreas, the kidneys, and the suprarenal glands. Serum-T.S.H. rises suddenly to about 20 times the normal adult level within half an hour of birth.9 This then leads to thyroid stimulation. The increase in T.s.H. is related to thermogenesis, since cooling babies 3-4 hours after birth leads to a rebound in the serum-T.S.H. level 9 The B.F. organ gradually atrophies after about 3 months of age, at about the time when thyroid hormones drop to adult levels, but if a child has cryo-
161 surgery (as in
open-heart operations) serum-T.S.H. again rises, presumably to help hommothermy.11 This does not happen in "warm" surgery, so it is not
thyroid-stimulating-antibody-related immunoglobulin may stimulate metabolism in B.F. on
that the rise in T.s.H. may restore function in the B.F. organ of the cooled baby.
unreasonable
possible analogues of leg.
the lateral aspect of the
to assume
EVIDENCE FROM PATHOLOGICAL STATES
Athyrotic cretinism and adult myxadema.-In 1850 Curling noted that patients with untreated congenital hypothyroidism sometimes had peculiar fat pads along the common carotids, in the supraclavicular region, and axillt." In 1908 Shattock 12 examined the brown fat in shrews and hedgehogs before, during, and after hibernation, and then looked at the swollen fat pads discovered at necropsy in young patients with cretinism. He accurately described the B.F. adipocyte and compared it with white fat cells. The abnormal fat deposits in the patients with cretinism had all the characteristics of the " hibernating gland ", and furthermore, these lumps disappeared when the patients were treated with thyroid extracts. Shattock therefore concluded that the B.F. swellings were somehow related the thyroid deficiency. Slight swelling of supraclavicular fat pads is not uncommon even in adult myxoedema, and in untreated patients it should be quite easy to demonstrate increased heat production in these swellings by thermography. In neonates the nuchal B.F. pad is
to
than other areas.13 Another rather rare complication of myxoedema is the development of ascites or, less uncommonly, of pericardial or pleural effusions 14 These resemble a transudate with high protein content. Myxoedema is not always severe in these patients. Serum-T.s.H. may reach several hundred times the normal level in some individuals before the onset of a classical myxoedematous facies, and it is conceivable that if small amounts of B.F. persisted into adult life, as they are known to do in some subjects,15 T.s.H. overstimulation would increase the bulk and activity of the mitochondria and this could lead to an increased blood-supply to B.F., and, with unrestrained activity of noradrenaline and cortisone, to changes in capillary permeability and serous exudation. A more speculative suggestion is that perhaps myxoedematous ileus might result from T.s.H. overstimulation of the B.F. cells that have been identified within the muscle layers of the intestineY Endocrine exophthalmos and pretibial myxadema.Patients with Graves’ disease have circulating thyroidstimulating antibodies,16 which mimic pituitary T.S.H., bind to the T.S.H. receptor on the thyroid cell membrane, and turn on the cyclic-A.M.P. system, thus causing continuous overproduction of thyroid hormones. IgG from patients with progressive exophthalmos, which represents antibodies related to
warmer
thyroid-stimulating antibodies, can cause exophthalmos in fish and guineapigs 17 Kohn and Winand 18 demonstrated that retro-orbital tissues have plasma membrane receptors for T.s.H. Kohn has also found that these T.s.H.-sensitive receptors were only present on brown-fat membranes and not in white fat. In addition, Alexander et al.19 demonstrated that at least in calves retro-orbital fat has the characteristics of In pretibial myxoedema it is also likely that a B.F.
FUTURE EXTENSIONS OF THE HYPOTHESIS
Study of thyroid autoimmunity led to the present hypothesis. The influence of various hormones on the B.F. organ should be re-examined with these new ideas in mind. During cold-stress corticotrophin is released from the pituitary in addition to T.s.H., and B.F. may possibly have important functions in protecting addisonian patients from steroid deprivation. Several workers have commented on the striking amount of periadrenal B.F. in Addison’s disease,20 and it has been suggested that B.F. is capable of producing steroid hormones. However, hypertrophy of B.F. by excess corticotrophin or steroid hormones in Cushing’s syndrome may possibly explain the mild proptosis sometimes seen in this disease and possibly the hump at the back of the neck. REFERENCES 1. 2.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Smith, R. E., Horwitz, B. Physiol. Rev. 1969, 49, 330. Baum, H. in The Cell in Medical Science (edited by F. Beck and J. B. Lloyd); p. 183. New York, 1974. Flatmark, T., Pedersen, J. I. Rev. Bioenergetics, 1975, 416, 53. Florsheim, W. H. in Handbook of Physiology (edited by R. O. Greep and E. B. Astwood); vol. IV, p. 449. Washington, 1974. Ikemoto, H., Hiroshige, T., Itoh, S. Jap. J. Physiol. 1967, 17, 516. Fawcett, D. W., Jones, I. C. Endocrinology, 1949, 45, 609. Kuroshima, A., Konno, N., Itoh, S. Jap. J. Physiol. 1967, 17, 523. Steiner, G., Schönbaum, E., Johnson, G. E., Sellers, E. A. Clin. J. Physiol. Pharmac. 1968, 46, 453. Fisher, D. A., Odell, W. D. J. clin. Invest. 1969, 48, 1670. Wilber, J. F., Baum, D. J. Endocr. Metab. 1970, 31, 372. Curling, T. B. Med. Chir. Trans. Lond. 1850, 33, 303. Shattock, S. G. Proc. R. Soc. Med. 1909, 2, 207. Silverman, W. A., Zamelis, A., Sinclair, J. C., Agate, F. J. Pediatrics,
Springfield, 1964, 33, 984. Sachdev, Y., Hall, R. Lancet, 1975, i, 564. Wegener, F. Beitr. path. Anat. 1951, 111, 252. Hall, R., Smith, B. R., Mukhtar, E. D. Clin. Endocr. 1975, 4, 213. Doniach, D., Florin-Christensen, A. Clins Endocr. Metab. 1975, 4, 341. 18. Kohn, L. D., Winand, R. J. in Molecular Aspects of Membrane Phenomena. Berlin, 1975. 19. Alexander, G., Bennett, J. W., Gemmell, R. T. J. Physiol. 1975, 244, 223. 20. Friedman, N. B. Endocrinology, 1948, 42, 181.
14. 15. 16. 17.
Reviews of Books Mountain Medicine A Clinical F.R.C.S.
Study of Cold and High Altitude. MICHAEL WARD, London:Crosby Lockwood Staples. 1975. Pp. 376.
E10.
WITH the increase in
popularity of mountaineering, people are finding their way onto large mountains where the problems of hypothermia, frostbite, acute mountain sickness, and high-altitude pulmonary oedema may make themselves suddenly and tragically felt. These problems can largely be avoided by knowledge and foresight, and the mountains can be properly enjoyed together with the fascinating experience of the way the human body adapts to a reduction in oxygen pressure. In this book Mr Ward provides the knowledge and a wideranging discussion on the adaptations. He has brought together the results of original work in a wide variety of disciplines, all having a bearing on man at high altitudes. After introductory chapters on history, the atmosphere, and the sociological effects of the mountain environment,
more
and
more
the book is divided between the effects of altitude on the cardiorespiratory system, the effects of cold, and the medical
