The evolution of endothermy

J. theor. Bid. (1973) 38, 597-611

The Evolution

of Endothermy

E. D. STEVENS

University

Department of Zoology, of Hawaii, Honolulu, Hawaii

96822

(Received 16 June 1972) A theory to account for the evolution of heat production for endothermy in the vertebrates is presented. It is argued that thermoregulatory responses to cold, thyroxine, and the Na+ pump are related functionally and phylogenetically. Fish regulate their body temperature behaviorally. For example, if the ambient temperature is too cold, they exhibit appetitive behavior and swim to an area where it is warmer. The incidental heat produced by the increased activity is lost through the gills due to the pattern of circulation. In fish the increased requirement for oxygen during increased activity demands an increased transfer of oxygen and of ions and water across the gill membranes. Thus, any increase in oxygen demand causes an obligatory stimulation of the Na+ pump. The evolution of endothermy (that is, of non-shivering thermogenesis) from behavioral thermoregulation of fish can be envisioned as a bypassing of the behavoiral response of fish and a direct stimulation of the Na+ pump to produce heat. The attraction of this argument is the ubiquity of Na+ transport across membranes. It is also argued that thyroxine was selected for as one type of control. Thyroxine could be selected as a control mechanism because its main function in fish is ion regulation. In addition, thyroxine effects the general level of spontaneous activity, increases chill resistance, alters the ability to sense salinity, and also alters the behavioral response of fish to changes in temperature. The argument is further supported by recent observations which indicate that a major fraction of the thyroxine induced elevated metabolic rate in mammals is due to stimulation of the Na+ pump. The above suppositions may also explain why the internal temperature sense of mammals is so sensitive to Na+, and may in fact suggest one possible feedback signal in homeotherms.

1. Introduction Recent papers concerning metabolism of homeotherms have clarified those mechanisms involved in heat production that operate to ensure a constant body temperature. In this paper I relate these papers with others in comparative vertebrate physiology to consider some aspects of the evolution of homeothermy, especially adaptive responses to cold. The comparative 597

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physiology of thermoregulation in the various vertebrate groups has been considered in detail by Whittow (1970,197l). In the present paper I shall consider the regulation of body temperature and responses to lowered ambient temperature within the vertebrates and show how these responses may have developed phylogenetically. Following a brief summary of the argument, supporting evidence will be presented in detail. The hypothesis is that thermoregulatory responses to cold, thyroxine, and the Na’ pump are all related functionally and phylogenetically. Ismail-Beigi & Edelman (1970) suggested that an important source of metabolic heat during cold acclimation may be due to increased usage of ATP by the Na+ pump. They showed that the thyroxine-stimulated increase in oxygen uptake by mammalian tissues was due to stimulation of the Na+ pump. Thyroxine has many other effects on all of the systems involved in adaptive responses of mammals to cold, and it is for these reasons that I argue that thermoregulatory responses to cold, thyroxine, and the Na+ pump are related in a functional sense. Thyroxine also has many effects on fish which implicate its involvement in thermoregulation. For example, thyroxine increases chill resistance in fish. Thyroxine also causes an increase in the amount of spontaneous

Exit = change belwvior

FIG. 1. A schematic model to explain behavioral thermoregulation in fish. Appetitive, behavior continues until the fish finds its preferred temperature. The incidental heat produced by the activity is lost through the gills. The increased activity causes an obligatory stimulation of the Na+ pump, and it is suggested that in the evolution of endothermy that this feature became important as a source of heat in itself.

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activity in fish and thus increases oxygen demand. Any increase in oxygen uptake causes an obligatory stimulation of the Na+ pump in fish, and it is argued that this mechanism was selected for as the main effector in the evolution of heat production. Thus, some biochemical and physiological responses by mammals to cold evolved from certain aspects of the behavioral thermoregulatory mechanisms exhibited by fish. Figure 1 outlines the main ideas. Thyroxine affects many levels of the system and is thus a good choice for one type of control. Evolution of endothermy was accomplished by deleting the muscular activity associated with behavioral thermoregulation, so that heat was produced by direct stimulation of the Na+ pump. 2. Adaptive Responses of Ectotherms to Cold Animals can respond behaviorally, physiologically, or biochemically to acute decreases in ambient temperature. The evolution of homeothermy involved selection for physiological and biochemical solutions to problems created by temperature. We generally consider that fish, amphibians, and reptiles regulate temperature behaviorally. Birds and mammals, on the other hand, employ physiological and biochemical tricks in addition to the behavioral ones. I argue that some physiological mechanisms evolved from behavioral mechanisms, and that biochemical mechanisms evolved from physiological ones. The body temperature of fishes, with the exception of tunas, is at most 2°C above ambient (Stevens & Fry, 1970) because metabolic heat is efficiently transferred from the blood to ambient water at the gills. (Tunas are exceptional in that they circulate the blood through a counter-current heat exchanger before pasing it through the gills. Thus, they reduce heat loss and consequently achieve higher body temperatures.) All fish can, however, achieve some independence from environmental temperature by selecting a particular temperature if given the opportunity to do so. Thus, low ambient temperature can stimulate a fish to increased activity and body temperature will be increased if the fish swims into warmer water--even though the metabolic heat generated by the excess activity is rapidly lost through the gills. Absolute preferred temperature varies from fish to fish and will depend on a number of factors, especially the thermal history of the animal. But what is important in so far as we are concerned is that low temperature can cause increased activity which eventually may result in an increased body temperature. Peterson & Anderson (1969) subjected fish to acute changes in temperature. They found that a temperature change in either direction resulted in a period of increased spontaneous activity, and that the magnitude of the response was related to the rate of temperature change. Similar results were T.B. 40

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obtained by Olla & Studholme (1971). Rozin & Mayer (1961) demonstrated that fish can be trained to regulate the water temperature of their holding tank (34°C in the case of goldfish) by activating a valve which admitted cold water as the temperature increased. Neill, Magnuson & Chipman (1972) also have a convincingdemonstration of behavioralthermoregulationinfish. Clearly,then, fish can detect ambient temperature changes and regulate body temperature by selecting a specific ambient temperature. (For details see extensive reviews by Fry, 1967, 1971.) A schematic model showing how temperature selection may operate in fish is illustrated in Fig. 1. This figure also shows that appetitive behavior results in an elevated metabolic rate, but that the heat so produced is lost through the gills and does not influence body temperature to a significant degree. Similarly, behavioral mechanisms permit a certain amount of temperature independence in amphibians and reptiles. There are few studies on temperature preference in amphibians, but these show that frogs and salamanders chose a specific temperature when given the opportunity to do so (Brattstrom, 1963 ; Lucas & Reynolds, 1967; Lillywhite, 1971). Many studies demonstrate the ability of reptiles to thermoregulate behaviorally and maintain a relatively stable body temperature in nature (Brattstrom, 1965). Thus, fishes, amphibians, and reptiles all achieve some indpendence of temperatute by actively moving when the temperature is too low. The incidental heat produced by muscular activity is important only to the very large reptiles, but even they usually are considered to be ectothermic except during bouts of strenuous activity when metabolic rate is increased to a level similar to that of a resting mammal of equivalent weight (Bartholomew, 1972). That is, large reptiles can produce enough heat to be endotherms during periods of strenuous activity. Two important features were required to become an endothermic homeotherm: first, there had to be a large increase in heat production (that is, the metabolic rate), and second, the rate of heat loss had to be regulated. The present essay is concerned with heat production rather than heat loss. The fact that water holds less oxygen but more heat than air presented a major obstacle to the evolution of endothermy in water breathers. The specific heat of water is four times that of air, and the specific gravity of water is 770 times that of air, so that water can hold about 3000 times as much heat as an equal volume of air. Even though some fish have the capacity for a high metabolic rate almost all of the heat is lost to the water at the gills. Although amphibians solved the problem of breathing water, they could not solve the problem of heat loss because breathing air created problems that were solved by having a well-vascularized naked skin (Rahn, 1966). The well-vascular&d naked skin precludes the insulation necessary for an endothermic way of life.

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There are a number of obvious differences between reptiles and amphibians when considered from a thermoregulatory point of view. Reptiles have a thick, well-protected skin in comparison with the naked skin of amphibians. Rahn (1966) has argued that this is because reptiles have had time to evolve alternate solutions to the use of the skin for regulation of acid-base balance. There are two consequences of the thicker skin. Thicker skin provides some insulation, but since reptiles are ectothermic (that is, they rely on incoming radiant energy for heat) this feature is rarely taken advantage of. However, the decreased thermal conductivity does permit better regulation of body temperature and lizards and turtles have evolved physioIogica1 mechanisms to regulate heat loss by changing patterns of circulation to the skin. A disadvantage of thicker skin is that they can no longer cool evaporatively therefore behavioral mechanisms must be adequate. Reptiles tend to be diurnal and generally inhabit warmer and drier climes than amphibians. As a consequence of living in the sunshine at higher ambient temperatures, their body temperature tends to be higher than amphibians. For example some lizards maintain their body temperature at 33 +4”C (Bogart, 1949). In contrast, the body temperature of amphibians in nature tends to be less than 20°C (Bartholomew, 1972). Lizards are extremely good at behavioral thermoregulation and so it has been speculated that this feature was subject to strong selection pressure (Bogart, 1949). The extraordinary ability to regulate temperature behaviorally then opened the way for the evolution of an increased metabolic rate and homeothermy. Although the range of body temperatures of reptiles vary widely the same species tend to have similar body temperatures even in dissimilar environments (Bartholomew, 1972). A most impressive ability to thermoregulate physiologically is demonstrated by brooding python snakes (Vinegar, Hutchinson & Dowling, 1970). During brooding periods they produce sufficient additional heat by muscular contractions to maintain body temperature as much as 5°C above ambient. The muscular contractions begin when ambient temperature is below 33°C and increase in frequency with decreasing temperature. This type of thermoregulation is analogous (not homologous) to shivering in mammals. In both cases heat is produced by muscular contraction but the muscular contraction does not result in the animal moving from one place to another. Homeothermy implies the presence of temperature detectors, a reference temperature and effecters. Receptors that respond to temperature change have been demonstrated in all classes of vertebrates. Whether or not all of those systems are actually used to detect temperature by these animals in nature is an open question. The participation of the forebrain in thermoregulatory behavior has been demonstrated in fish (Hammel, Stromme & Myhre,

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1969), amphibians (Lillywhite, 1971), reptiles (Hammel, Caldwell & Abrams, 1967) and in mammals (see Corbit, 1969). Temperature sensitive cells in or near the hypothalamic region have been demonstrated neurophysiologically in fish (Greer & Gardner, 1970) in reptiles (Cabanac, Hammel & Hardy, 1967), and in mammals (Cabanac, Stolwijk & Hardy, 1968). Bligh (1966) has argued that homeotherms have a fine temperature control in addition to a separate broad-band control; both located in the hypothalamus, but that ectotherms have only the broad-band control. He also suggested that the fine control may have no common origin but rather may have evolved independently in different mammalian orders. 3. The Potential for Heat Production in Fishes Tunas are able to maintain muscle temperature greatly in excess of water temperature. Bluefin tuna can maintain muscle more than 20°C warmer than

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2. Metabolic rate of some fishes at various swimming speeds. All fish are about the same size (15-20 cm body length). (a) Gold&h at 30% (Smit, Amelink-Koutstaal, Vijverberg & von Vanpel-Llein, 1971). (b) Sockeye salmon at 10°C (Brett, 1964). (c) Aholehole at 23°C (Muir & Niimi, 1972). (d) Goldfish at 20°C (Kutty, 1968). FIG.

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their environment, and can regulate muscle temperature over a wide range of ambient temperatures (Carey, Teal, Kanwisher, Lawson & Beckett, 1971). Tunas demonstrate that some fish have the potential to produce the heat necessary for endothermy; but that in order to realize this potential it is necessary to invest in elaborate anatomical structures (counter-current heat exchangers) to reduce heat loss. Other fish also possess the capacity to produce much metabolic heat: excitement metabolism. Excitement metabolism is usually defined as metabolism over and above any that can be interpreted as being brought about by physical activity (Fry, 197 1). Figure 2 illustrates the magnitude of the variability of metabolic rates at specific activity levels. The magnitude of the variability is also indicated by the following remark by Fry (1971, p. 5): “more than half the extrapolated maximum rate of oxygen consumption associated with the most vigorous sustained activity can be displayed by the goldfish with no overt movement at all.” Thus the potential to elevate temperature is present in fish, but the potential is not realized because of the pattern of the circulation through the gills. In air-breathing animals however, such a mechanism would indeed increase heat production. Thus, excitement metabolism in fishes may be homologous to some types of non-shivering thermogenesis in mammals. 4. Evolution of Endothermy If the above contentions are correct, then it is ofinterest to askwhether there are features of adaptive responses to cold common to all the vertebrates that may shed some light on its evolution. It is my thesis that the thyroid hormones played an important role in the evolution of homeothermy and that the Na+ pump produces much heat required for homeothermy. I shall first discuss the relationships of thyroid hormone and thermoregulation in mammals and then show how these are related to studies of other vertebrates. (A) MAMMALS

The prime requisite for endothermy in mammals and birds was a dramatic increase in heat production. The increase in heat production required an investment in metabolic machinery but freed the animals from direct dependence on the thermal environment. Complex structures were concommitantly evolved for the physiological regulation of heat loss. The most important features in the evolution of adaptive responses to cold in endotherms are shivering and non-shivering thermogenesis. The evolution of structures to increase thermal insulation are not considered here since they are of importance only subsequent to the evolution of endothermy. Neither are behavioral mechanisms discussed since they had already evolved in and are used by ectotherms.

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Non-shivering thermogenesis is an important factor in heat production in hibernators, newborn, and cold adapted mammals. There are a variety of tissues responsible for producing the heat. Moreover, “it has not been determined with any real certainty which organ or organs are primarily responsible for the maintenance of body temperature or what mechanisms are involved that permit an organism to acclimate or a strain or species to adapt to his environment” (Simon, Eybel, Galster 8~ Morrison, 1971). Simon et al. argue convincingly that musde produces a significant amount of heat for nonshivering thermogenesis. Many studies stress the role of brown fat in non-shivering thermogenesis in mammals. I believe that homeothermy evolved prior to the evolution of brown fat. Mammals larger than 10 kg have very little brown fat and do not respond to an infusion of noradrenaline with an elevated oxygen uptake (Heldmaier, 1971); yet there are many endotherms larger than 10 kg. Moreover, it is in tissues other than brown fat that heat production is related to thyroxine. There is a very large literature concerning thyroxine and thermoregulation in cold environments, especially in hibernating mammals. Most of the work concerns the effect of thyroxine on tissues other than brown fat; much of it deals with the general calorigenic effect of throxine. There is even a relationship between throxine and thermal insulation. Thyroxine is involved in fur molt; it also stimulates the rate of hair growth in rodents and increases the rate of wool growth in sheep (Ebling & Hale, 1970). More importantly, thyroxine is involved in heat production in endotherms. Thyroidectomy causes a slight decrease in body temperature (about 1 ‘C), but markedly reduces the ability to tolerate acute decreases in temperature. For example, the time for body temperature to drop to 30°C when guinea pigs are exposed to - 1 *SC is 122 min in intact animals but only 49 min in thyroidectomized animals (Pichotka, von Kugelen 8c Damann, 1953; cited by Laites & Weiss, 1959). That is, thyroidectomy causes a gradual reduction of cold induced non-shivering thermogenesis (Carlson, 1960). The thyroid has also been implicated in the ontogeny of thermoregulatory responses to cold, for example in the neonate pig (Kaciuba-Uscilko, Legge & Mount, 1970). Neonate chicks treated with thiouracil have a normal body temperature, but when exposed to cold (20°C) their body temperature falls much faster than that of controls (Freeman, 1971). An intact thyroid appears to be required for the acute phase of cold adaptation since thyroidectomized rats, or rats given propylthiouracil to block thyroid function, survive only a few days at low temperature. If thyroidectomy is performed after acclimation animals will survive much longer (Sellers & You, 1960). Exposure to acute cold causes an increase in TSH within 30 min and thyroxine stores are depleted 45 % in 12 hours in the rat, rabbit, and hamster (Knigge, 1960). In addition, stimulation

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of the temperature regulating center in the brain causes a release of thyroxine (Anderson, Ekman, Gale & Sundsten, 1963; Gale, Jobin, Proppe, Notter & Fox, 1970). From the above discussion it seems clear that thyroxine is involved in adaptive responses of mammals to cold. It is still not known exactly how it is involved, but some recent experiments point to the possible mechanism. These experiments will be discussed in some detail since they are also important to the discussion of the evolution of endothermy. Ismail-Beigi & Edelman (1970) have demonstrated that the mechanism of thyroid calorigenesis in rats is oubain-sensitive in both muscle and liver. Thus, a possible mechanism of thyroid calorigenesis is direct stimulation of the sodium pump by thyroxine. The Naf pump increases ATP utilization rather than altering the coupling between ATP production and metabolic rate. Ismail-Beigi & Edelman (1970) summarized the arguments against hormonal augmentation of heat production by uncoupling of mitochondrial phosphorlyation. Beyer (1963) has summarized the arguments for uncoupling. In any event ATP production cannot be sustained unless it is utilized since its production will depend on the concentration of ADP. Even if it is fully coupled only about 25 % of the enthalpy of substrate oxidation is conserved in ATP (Prusiner & Poe, 1970). Therefore if the coupling is not markedly reduced, it follows that thyroxine must stimulate some energy-using process. In normal mammalian tissues, the transmembrane sodium pump accounts for 20-45 % of resting oxygen uptake (Whitman, 1964). Furthermore, the hypothesis has a distinct advantage because of the ubiquitousness of the sodium pump. Ismail-Beigi & Edelman parenthetically suggested that a similar mechanism may operate in cold adaptation?. This hypothesis is attractive for several reasons and may also be useful in understanding the evolution of thermoregulatory responses to cold. The relationships between thyroxine and the adaptive response to cold in mammals have been alluded to previously. Also of interest are recent studies showing that the “set point” of body temperature in mammals depends on the ratio [Na+]/[Ca++] in the spinal fluid near the hypothalamus (Myers & Veale, 1971). An increase in [Na+] causes an increase in body temperature. Thus, as illustrated in Fig. 1, the control may respond to [Na’j in addition to temperature, or perhaps the feedback signal is the [Na+]. t Note added in proof: We (Kido & Stevens, unpub. ms.) have subsequently shown that the major fraction of elevated oxygen uptake of liver and skeletal muscle tissue slices that occurs during cold adaptation in mice is ouabain sensitive. In cold-adapted mice ouabainsensitive oxygen uptake accounts for 38 ‘A of the total oxygen uptake of liver, and 20% of the total in muscle. In warm-adapted mice only 23 ‘A of the total is ouabain-sensitive in liver, and only 147; in skeletal muscle.

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So far I have described relationships between thyroxine, adaptive responses to cold, and the sodium pump in mammals. The following sections will examine these relationships in the other classes of vertebrates to show a possible evolutionary scheme. (B) AMPHIBIANS

Most experience concerning thyroxine and amphibians pertain to metamorphosis (Cohen, 1970). However, it does have other interesting actions. The addition of either thyroxine or propylthiouracil to tank water containing tadpoles reversibly decreases the ability of the tadpoles to select a particular temperature (Lucas & Reynolds, 1967). Thyroxine or homotransplants of thyroid tissue elevate metabolic rate in amphibians, but the effect is temperature dependent. For example, thyroxine elevated oxygen uptake in frogs acclimated to 20°C but not in those acclimated to lYC, when both were tested at 20°C (Mayer, 1967). In another study thyroxine increased oxygen uptake by 10 y0 in frogs acclimated to 18°C and by 33 % in those acclimated to 30°C (McNabb, 1969). Thyroxine elevates the oxygen uptake of isolated amphibian tissue, but the response is obvious only if alanine is present in adequate amounts (Thornbutn & Matty, 1966). Thyroxine also increases the resistance of isolated skeIeta1 muscle to high temperature (Brattstrom, 1970). Thyroxine, in physiological concentrations, increases oxygen uptake and increases the rate of sodium transport across isolated toad skin or toad bladder (Green & Matty, 1963). In summary, thyroxine in amphibian larvae elevates metabolic rate and alters the ability to select a particular temperature. During metamorphosis its major role appears to be enzyme induction (Cohen. 1970). In the adult, thyroxine elevates metabolic rate but the effect is very temperature dependent, and it stimulates the sodium pump in toad skin and toad bladder preparations. (C)

REPTILES

Bogart (1949) suggested that thyroxine may be involved in thermoregulation of reptiles, primarily because of its calorigenic action. Thyroidectomy initiates sloughing and skin renewal so that the level of thyroxine determines the length of the intermoult phase (Chiu & Lynn, 1971). Thyroxine increases metabolic rate and thyroidectomy decreases it; but the effect is evident at 30°C and absent at 20°C. Since these lizards normally maintain body temperature 28-3X then thyroxine elevates metabolic rate (Mayer, 1965). Similarly, thyroxine elevates oxygen uptake of liver slices of snakes held at 32°C but not of those held at 23°C (Turner & Tipton, 1972a). Lastly, thyroid activity increases with an increase in acclimation temperature (Lynn, McCormick & Gregorek, 1965; Turner 8z Tipton, 19726).

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FISHES

Injections of thyroxine increase spontaneous activity in all classes of vertebrates and inhibition of thyroxine has the opposite effect. It has been adequately demonstrated in fish that injections of thyroxine (Woodhead, 1970; Hoar, Keenleyside & Goodall, 1955; Hoar, Mackinnon & Redlich, 1952; Sage, 1968) or in solution in aquaria (Woodhead, 1966) results in an increase in the level of spontaneous activity and an increase in the relative amount of time swimming. This being the case, one might expect that more active fish would thermoregulate (behaviorally) more quickly, and perhaps more precisely. In some recent experiments we have demonstrated that the presence of thyroxine in aquarium water does alter the activity response of fish to rapid temperature change (0.3 deg/min). However, we have not yet demonstrated that it alters the ability to thermoregulate behaviorally. This effect is not necessarily a metabolic effect of thyroxine because Emlen, Segal & Mandell (1972) have recently suggested that a similar response in mammals was due to thyroxine increasing the sensitivity of synapses which utilize norepinephrine as a transmitter substance. Thyroxine injections sometimes increase the metabolic rate of fish, but the effect seems to depend on season and size of fish (Gorbman, 1969). Since thyroxine increases spontaneous activity, an increase in oxygen uptake would be predicted. In so far as I know the effect of thyroxine on metabolic rate during controlled activity has not been measured. There are many experiments relating thyroid activity to temperature tolerance (see McErlean & Brinkley, 1971). Most concern resistance to high temperature and they suggest varying effects of thyroxine or thiourea treatment depending on season and acclimation temperature. In any event in the present discussion I am concerned with adaptive responses to cold and not upper lethal temperature. Hoar (1959) showed that thyroxine can increase chill resistance in fish, but only during summer or after acclimation to long photoperiods. The olfactory epithelium of fish is sensitive to salinity and to temperature. Thyroxine treatment alters the sensing of Na+ and also alters the adaptive responses to changes in the salinity of the environment. In a variety of electrophysiological experiments Gorbman and his colleagues have shown that the olfactory epithelium of fish can detect the salinity of the environment. More importantly, Oshima and Gorbman (1966u,b) have shown that thyroxine increases the sensitivity of the olfactory epithelium to detection of salinity. We have demonstrated that the olfactory epithelium of fish is not only sensitive to salinity but is also a very temperature sensitive sense organ in fish. Thus the olfactory epithelium is temperature sensitive and its sensitivity to salinity is enhanced by thyroxine. (The olfactory bulb of all terrestrial vertebrates

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(Graystone, Low, Rogers & McLennen, 1970) and of lungfish (Dupt & Godet, 1969) is characterized by very regular potentials. The frequency of the potentials increases with increasing body temperature with a Q!,, between 1a4 to 1.7.) The other relationship between the sodium pump and thyroxine concerns acclimation to a new salinity. When fresh water adapted fish are put in sea water there is a decrease in thyroxine secretion (Hickman, 1959). Moreover, thyroxine inhibition reduces the ability of fish to adapt to increased salinity (Fontaine, 1956). Lastly, thyroxine injections cause a preference for an increased salinity and thiourea treatment favours freshwater preference (Baggerman, 1963). Morphogenic effects of thyroxine have been ignored for the purposes of this discussion. The aspect of selective regulation of protein synthesis by thyroxine has been reviewed by Tata (1969). In this regard, Yaron (1969) noted that, in fish, thyroid cell height was positively correlated with ambient temperature. However cell height was also very high when water temperature was lowest, but this was the period when the fish were spawning. Apparently there are at least two factors which must be considered, ambient temperature and reproductive stage. The anomolous “excitement” metabolism has been previously mentioned (Fig. 2). An elevated metabolic rate produces heat in mammals, but this excess heat is lost through the gills of fishes due to the pattern of circulation. However, what should be noted is than an elevated metabolic rate is associated with an increased transfer factor of the gills (Randall, Holeton & Stevens, 1967). The increased transfer factor means that the effective exchange area of the gills is increased to transfer more oxygen. However, since the gills are also permeable to salt and water, then excitement also results in an increased movement of salt and water across the gills (Stevens, 1972). The cost of osmoregulation is by no means negligible in fish. Farmer & Beamish (1969) have estimated that osmoregulation accounts for about 30% of total oxygen uptake in marine forms and about 20 % in freshwater forms. The fraction remains about the same during sustained activity so that the metabolic cost of osmoregulation increases in proportion to total oxygen uptake. The increased metabolic cost of osmoregulation during activity must be due to a stimulation of the kidney and/or the salt glands. That is. any increase in oxygen demand causes an obligatory stimulation of the Na+ pump in fishes. It is not hard to imagine that this mechanism could evolve to a system in which any hear demand causes a stimultion of the sodium pump; especially since oxygen uptake and heat production are so intimately related in endotherms. In conclusion, I suggest that adaptive responses to cold, thyroxine, and the sodium pump are related functionally and also phylogenetically. The mech-

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anism for production of heat by stimulation of the Na+ pump seems an easy evolutionary step because it is automatically stimulated by any increase in oxygen demand in fish. Thyroxine could be selected for as a control mechanism because its function involves Na+ regulation in fish.The above suppositions may also explain why the internal temperature sense is so sensitive to sodium concentration, and may in fact suggest the posible feedback signal in homeotherms. Figure 1 summarizes the argument. Thyroxine affects many levels of the system and is thus the choice for one type of control. Evolution of endothermy was accomplished by deleting the increased muscular activity associated with appetitive behavior and stimulating the Na+ pump directly to increase heat production. This work was supported by PHS Research Grant No. HL 12608 from the National Institutes of Health. It is a pleasure to acknowledge Drs E. F. J. Fry, G. C. Whittow, A, Dizon and W. H. Neil1 who, in many discussions, helped me to formulate these ideas. In addition, Drs Dizon and Neil1 provided many useful criticisms which were incorporated into the manuscript. REFERENCES ANDERSON,

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