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The Hypothalamus and the Regulation of Food Intake
The Hypothalamus and the Regulation of Food Intake C.J. V.SMITH Department of Biology, The University of Toledo, Toledo, Ohio 43606 (Received for publication January 22, 1979) 1979 Poultry Science 58:1619-1624
report by Feldman et al. (1957) indicated that mid-hypothalamic lesions resulted in the development of an aphagic condition in chickens. Since that earlier report, a number of investigators have published on the involvement of various hypothalamic regions in the food intake control mechanism of birds (Table 1). Lepkovsky and Yasuda (1966) demonstrated that electrolytic lesions of the medial-basal hypothalamus resulted in hyperphagia and a significant accumulation of body lipids. Four types of responses to the lesions were noted: a) normophagic animals with only a small increase in body lipid content, b) normophagic animals with a significant increase in abdominal and carcass lipid, c) hyperphagic animals with significantly elevated body lipids, and d) hyperphagic animals, that in addition to an increase in body lipids, also had enlarged fatty livers. The latter group also displayed signs of being functionally castrated. Subsequent work by Snapir et al. (1969) showed that effective medial-basal hypothalamic lesions also increased plasma lipids, and that the administration of testosterone propionate was effective in restoring plasma lipid levels to normal. Snapir et al. (1973) also demonstrated that lesions just superior to the pituitary stalk produced an increase in body weight, increased fat deposition, and reduced testes weight. However, lesions placed more anteriorly resulted in an increase in body weight and carcass lipid composition, but caused only a small reduction in testes weight. In another experiment, Snapir et al. (1974) found that the administration of crude pituitary extracts to lesioned obese cockerels reduced body weight, abdominal adipose tissues, and liver lipid content. While the reductions were significant, all parameters were still above control levels. White-throated sparrows lesioned in the ventral portion of the anterior hypothalamus at the
1619
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There is a long history of interest in the brain, especially the hypothalamus, as the site controlling food intake in animals. The first research reports date from the late 1840's. Since that time hypothalamic mechanism(s) for the control of food intake have been extensively studied, but there are still considerable differences of opinion among researchers regarding the role of the hypothalamus and the exact nature of the control mechanism(s). Not until the late 1930's was it conclusively demonstrated that destruction of the ventromedial region of the hypothalamus of rats resulted in the development of obesity and an increased food intake (Hetherington and Ranson, 1940). Subsequently, Anand and Brobeck (1951) lesioned an area lateral to the ventromedial area and produced an aphagic condition in rats. This led to a hypothesis linking the ventromedial area being designated the "satiety center" and the lateral hypothalamic area the "feeding center". The twenty year interval from the early 1950's to the early 1970's was a period during which considerable effort was expended attempting to delineate the exact role of the ventromedial and lateral areas in controlling food intake in mammals. A significant amount of supporting as well as contradictory data were marshalled for each of the centers. During the last few years the scope of the work regarding the control of food intake has broadened, with extra-hypothalamic control sites receiving considerable attention. In addition, other areas such as the liver are coming under closer scrutiny as possible sites involved in a much more comprehensive control system. Attention is called to a number of excellent reviews on research in the area of food intake control in mammals that have appeared in recent years (i.e., Novin et al., 1976). Interest in the possible mechanism controlling food intake in birds was given an initial impetus by the work on mammals. An early
1620
SMITH TABLE 1. Studies involving electrolytic lesioning of the avian brain which resulted in hyperphagia and/or the development of obesity Brain area lesioned
Species Domestic chicken (Gallus domesticus)
Ventromedial hypothalamus Mammillary bodies Basal hypothalamus
Obesity
References
Yes (d) a
Yes (d)
Yes (s) Yes (d)
Yes (s) Yes (d)
(n) (n) Yes (s)
Yes (s) Yes (d) Yes (s)
Lepkovsky and Yasuda (1966) Snapireia/. (1969) Snapirgf al. (1973) Snapirera/. (1974) Lepkovsky et al. (1968) Kuenzel and Helms (1970) Kuenzel (1972) Kuenzel (1974) Kuenzel and Helms (1967) Hawkes and George (1975)
(n), not reported; (s), statement of results; (d), data presented.
level of the anterior commissure showed significant weight and body lipid increases (Kuenzel and Helms, 1967). The weight gain and lipid deposition in these birds appeared to be quite similar to that found in White-throated sparrows during the normal premigratory fattening period. Additional work with this same species of bird indicated that migratory restlessness ("Zugenruhe") and testes weight were both reduced as a result of effective lesions. Hawkes and George (1975) reported that ventromedial hypothalamic lesions in Mallard ducks increased food intake, fat deposition, and plasma free fatty acid levels. Feeding deficits have been reported to occur when the lateral basal area of the brain is lesioned at sites ranging from the posterior hypothalamic area forward to the nucleus basalis (Feldman et al., 1957; Lepkovsky et al., 1968; Smith, 1969; Zeigler et al, 1969; Kuenzel, 1972; and Hawkes and George, 1975) (Table
2). The work of Zeigler et al. (1969) has implicated cranial nerve number V (trigeminal) and its associated central structures — the quintofrontal tract, nucleus basalis, tr. fronto-archistriaticus, and the archistriatum — in the control of feeding behavior. They have shown that manipulation of the trigeminal system does affect feeding behavior, but whether or not the trigeminal system has any involvement in the physiological control of food intake remains to be determined. An examination of all the anatomical data presented in the papers cited above indicates that the various feeding deficits observed may have been the result of damage to some portion of the trigeminal sysem. Electrical stimulation of the avian hypothalamus generally has little effect on food intake. Of the more than six hundred hypothalamic sites investigated, only nine have given a positive response (Akerman et al., I960; Tweeton et al., 1973) (Table 3). Historically, most of the elec-
TABLE 2. Summary of studies demonstrating aphagia in birds as a result of electrolytic lesioning of the brain Species
Brain area lesioned
Hypophagia
Weight loss
Domestic chicken (Gallus domesticus)
Anterior hypothalamus
Yes (s)a
Yes (s)
Lateral hypothalamus Lateral hypothalamus
Yes (d) Yes (d)
(n) Yes (d)
Feldman et al. (1957) Lepkovsky et al. (1968) Smith (1969) Kuenzel (1972)
Anterior hypothalamus
Yes (s)
Yes (s)
Hawkes and George (1975)
Main-sensory trigeminal Yes (d) Nucleus, quinto-frontal tract
Yes(s)
Zeigler et al. (1969)
White-throated sparrow (Zonotrichia albicollis) Mallard duck (Anas platyrhynchos) Pigeon (Columba livia) a
(n), not reported; (s), statement of results; (d), data presented.
Reference
Downloaded from http://ps.oxfordjournals.org/ at North Dakota State University on May 28, 2015
Anterior hypothalamus White-throated sparrow Ventromedial hypothalamus (Zonotrichia albicollis) Ventromedial hypothalamus Ventromedial hypothalamus Mallard duck Ventromedial hypothalamus (Anas platyrhynchos)
Hyperphagia
THE HYPOTHALAMUS AND FOOD INTAKE
1621
TABLE 3. The influence of electrical stimulation at various sites in the avian brain on feeding behavior and food intake No. of Observed sites feeding studied behavior
Species
Brain area stimulated
Domestic chicken (Gallus domesticus) Pigeon (Columba livia)
Anterior hypothalamus, 625 Para- and supraoptic nuclei Lateral hypothalamus, 19 Preoptic area
Yes
only 5 sites
Tweeton etal. (1973)
Yes
only 4 sites
Akerman etal. (1960)
explained by a multitude of reasons, none of which have been proven. These reasons might include the fact that there may be no glucoreceptor cells in the avian brain, or if there are, they may not be involved in the control of feed intake. Perhaps there is a problem in methodology in that the route of administration or the dose administrated did not result in a positive response. Since the original finding of GTGinduced obesity in mice was a serendipitous observation, the ultimate answer to the question of why GTG has no effect in birds may occur in the same way. Olney (1969) reported that the administration of monosodium glutamate (MSG) to neonatal mice induced ventromedial hypothalamic damage and a subsequent obesity. This observation led to a series of investigations with birds, all of which resulted in negative data (Robinzon et al, 1975; Carew and Foss, 1971) (Table 5). Again, one can only hypothesize why MSG has no effect in birds. Thus, the basic question of why birds do not respond to either GTG or MSG in a manner similar to that seen in certain mammals remains unanswered. In recent years a great amount of work has been reported on the neuropharmacology of brain structures identified as being involved in the food intake control mechanism of mammals (Hoebel, 1976). Snapir et al. (1976) reported that the injection of 6-hydroxydopamine (6OHDA), a neurotoxin thought to selectively destroy neurons containing dopamine, resulted in an increased food consumption, obesity, and testicular atrophy in male geese. Although several hypothalamic areas were injected, bilateral injections into the ventromedial hypothalamus gave the best response. Injections in the septal area and unilateral ventromedial injections resulted in an increased food intake, but no change in body weight (Table 5). The injection or implantation of 6-OHDA into the ventre-
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trical stimulation studies have been concerned with feeding behavior rather than any hypothalamic physiological regulatory mechanism. In rats, for example, stimulation of various hypothalamic sites can cause either an increase in food consumption by satiated rats, or cause a suppression of food intake in hungry animals, depending on the site stimulated. Similar experiments have not been reported for birds. Brecher and Waxier (1949) demonstrated that the injection of high levels of gold thioglucose (GTG) into mice produced destruction of the ventromedial area of the hypothalamus and thereby induced obesity. It was hypothesized that the glucose portion of the molecule was being taken up by glucose-sensitive cells which in turn were being destroyed by the presence of the heavy metal, gold. This observation was used, in part, as the basis for the glucostatic theory of food intake regulation as proposed by Mayer (1953). Basically, the glucostatic theory proposed that the hypothalamic glucose-sensitive cells (glucoreceptors) are sensitive to glucose utilization by the body and regulate food intake accordingly. Later work indicated that the uptake of GTG in the ventromedial area and the resulting damage was insulin dependent; that is, insulin was required for the response (Debons et al, 1968; Smith, 1972). A number of investigators have attempted to induce obesity in different species of birds by injecting GTG (Svacha and Reid, 1973; Simkins and Pensack, 1970; Gentle, 1976; Carpenter et al, 1969). All results to date have been negative. Negative results were also obtained when small quantities of the compound were implanted directly into various brain areas shown previously to have some influence on food consumption (Smith and Szper, 1976) (Table 4). Failure to obtain a response in birds after GTG injection or implantation can possibly be
Observed actual food consumption Reference
1622
SMITH TABLE 4. Increased feeding and/or weight gain in response to an acute administration of gold thioglucose to chemically lesion areas of the brain Increased a
Species Domestic chicken (Gallus domesticus)
Age at treatment
Length of study
Food consumption
Weight gain Reference
.01-.4, IV b .25, .38,1V .01-1.0, IV .17-.5,im .15, 1.0, im
1 wk 1 wk 10 mo 1,2,or 4 days 5 days
15 wk 14 wk 8 wk 15 wk 12 wk
no moderate no no no
no no no slight no
.1-1.0, im Hypothalamic implant sites .2, im
2 or 21 days 20 or 25 wk
33 wk 6 wk
(n) no
no no
1, 7,or 14days 7 wk
no
no
Svacha and Reid (1973) Simkins and Pensack (1970) Gentle (1976) Smith and Szper (1976) Carpenter et al. (1969)
mg/g body weight. (n), not reported: IV, intravenous; im, intramuscular.
medial hypothalamus of rats also induced an increased food intake and the development of obesity (Hoebel, 1976; and others). When all the data concerning the role of the hypothalamus in regulating food intake in birds are examined, several tentative conclusions may be drawn. First, lesioning of certain areas in the medial basal region of the anterior half of the hypothalamus may result in the development of an increased food consumption, an increased lipid deposition, and a testicular regression. It
should be noted that all three responses, while characteristic, may not be present simultaneously and that additional responses may or may not be observed depending on the nature of the lesion and the species being studied. While such data may help to locate the site of a possible control mechanism, it provides little information on the nature of any possible control system within the hypothalamus. Second, existing data on hypothalamic electrical stimulation suffers from a lack of concrete information re-
TABLE 5. Increased feeding and/or weight gain in response to the administration of chemical compounds employed to lesion areas of the brain Increased 3
Species
Compound
Domestic chicken (Gallus domesticus)
Monosodium glutamate (MSG)
Domestic goose (Anser anser)
6-hydroxydopamine
Age at treatment
Food Weight Length of study consumption gain Reference
1,4, Sc b
5 days
33 wk
(n)
yes
1-5,Sc
1 day
16 wk
no
no
4 wk 38 wk
no
no
Dosage and route of administration
.5-10% in diet 1 day 200 jug 3—4 mo hypothalamic injections ventromedial area septal area
mg/g body weight. (n), not reported, Sc, subcutaneous.
Robinzon etal. (1975) Carew and Foss(1971) Snapir et al. (1976)
yes no
yes yes
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Japanese quail (Coturnix coturnix japonica)
Dosage and route of administration
THE HYPOTHALAMUS AND FOOD INTAKE
Currently, there are t w o general mechanisms t h a t have been p r o p o s e d for t h e regulation of food intake in birds, and these b o t h appear t o have some validity. One involves t h e a m o u n t of energy stored as lipid in t h e b o d y of t h e bird (Lepkovsky, 1 9 7 3 ) . This is q u i t e similar t o t h e lipostatic c o n t r o l hypothesis p r o p o s e d for m a m m a l s ( K e n n e d y , 1 9 5 3 ; Hervey, 1 9 6 9 ) . In essence, it is t h o u g h t t h a t food intake is inversely related t o a base line level of stored lipid. T h e second p r o p o s e d m e c h a n i s m involves t h e rate of filling and e m p t y i n g of t h e u p p e r digestive tract, including t h e c r o p (Polin a n d Wolford, 1 9 7 3 ) . Both of t h e proposed mechanisms need considerable additional d a t a before their validity can be considered established. At t h e present t i m e t h e r e is little evidence directly linking either of t h e proposed mechanisms with the hypothalamus. While t h e r e is a fair a m o u n t of d a t a regarding t h e h y p o t h a l a m i c influence on food intake in birds, we are far from being able t o outline a possible control mechanism. U n d o u b t e d l y w i t h t h e e x p e n d i t u r e of additional t i m e and energy t h e role of t h e h y p o t h a l a m u s in t h e c o n t r o l of food intake will b e c o m e clearer.
REFERENCES Akerman, B., B. Andersson, E. Fabricius, and L. Swensson, 1960. Observations on central regulation of body temperature and of food and water intake in the pigeon (Columba livia). Acta Physiol. Scand. 50:328-336. Anand, B. K., and J. R. Brobeck, 1951. Hypothalamic control of food intake. Yale J. Biol. Med. 24:
123-140. Brecher, G., and S. H. Waxier, 1949. Obesity in albino mice due to single injections of gold thioglucose. Proc. Soc. Exp. Biol. Med. 7 0 : 4 9 8 - 5 0 1 . Carew, Jr., L. B., and D. C. Foss, 1971. Monosodium glutamate in chicks. Poultry Sci. 50:1501 — 1502. Carpenter, J. W., C. M. Stein, A. Silverstein, and A. van Tienhoven, 1969. The effect of gold thioglucose on food consumption and reproduction of the Japanese quail (Cotumix coturnix japonica). Poultry Sci. 4 8 : 5 7 4 - 5 7 8 . Debons, A. F., J. Krimsky, H. J. Likuski, A. From, and R. J. Cloutier, 1968. Gold thioglucose damage to the satiety center: inhibition in diabetes. Amer. J. Physiol. 214:652-658. Feldman, S. E., S. Larsson, M. K. Dimick, and S. Lepkovsky, 1957. Aphagia in chickens. Amer. J. Physiol. 191:259-261. Gentle, M. J.,1976. The effect of gold thioglucose on the central nervous system of chicks (Gallus domesticus). Toxicol. Appl. Pharmacol. 35:223— 228. Hawkes, M. P. G., and J. C. George, 1975. Effect of hypothalamic lesions on levels of plasma free fatty acids in the Mallard duck. Arch. Int. Physiol. Biochim. 83:763-770. Hervey, G. R., 1969. Regulation of energy balance. Nature 2 2 3 : 6 2 9 - 6 3 1 . Hetherington, A. W., and S. W. Ranson, 1940. Hypothalamic lesions and adiposity in the rat. Anat. Rec. 78:149-172. Hoebel, B. G., 1976. Satiety: Hypothalamic stimulation, anorectic drugs and neurochemical substrates. Page 33—50 JM Hunger: Basic mechanisms and clinical implications. D. Novin, W. Wyrwicka, and G. Bray, ed., Raven Press, New York. Kennedy, G. C , 1953. The role of depot fat in the hypothalamic control of food intake in the rat. Proc. Roy. Soc. (London) B140:578-592. Kuenzel, W. J., 1972. Dual hypothalamic feeding system in a migratory bird, Zonotricbia albicollis. Amer. J. Physiol. 223:1138-1142. Kuenzel, W. J., 1974. Multiple effects of ventromedial hypothalamic lesions in the White-throated sparrow, Zonotricbia albicollis. J. Comp. Physiol. 90: 169-182. Kuenzel, W. J., and C. W. Helms, 1967. Obesity produced in a migratory bird by hypothalamic lesions. Bioscience 17:395—396. Kuenzel, W. J., and C. W. Helms, 1970. Hyperphagia, polydipsia and other effects of hypothalamic lesions in the White-throated sparrow, Zonotricbia albicollis. Condor 72:66-75. Lepkovsky, S., 1973. Hypothalamic-adipose tissue interrelationships. Fed. Proc. 32:1705-1708. Lepkovsky, S., N. Snapir, and F. Furuta, 1968. Temperature regulation and appetitive behavior in chickens with hypothalamic lesions. Physiol. Behav. 3:911-915. Lepkovsky, S., and M. Yasuda, 1966. Hypothalamic lesions, growth and body composition of male chickens. Poultry Sci. 45:582-588. Mayer, J., 1953. Glucostatic mechanisms of regulation of food intake. New England J. Med: 249: 13-16. Novin, D., W. Wyrwicka, and G. A. Bray, 1976.
Downloaded from http://ps.oxfordjournals.org/ at North Dakota State University on May 28, 2015
garding any control mechanism(s). This t e c h nique m a y be helpful, nevertheless, in tracing certain nerve tracts involved in feeding. Only t h e w o r k of Zeigler ( 1 9 7 4 ) has provided any significant clues regarding t h e location of a specific anatomical area involved in t h e c o n t r o l of feeding. This w o r k on t h e trigeminal nerve and its associated central nervous s y t e m structures, at least, m a y direct investigators in t h e p r o p e r direction. Third, a t t e m p t s t o alter f o o d intake by injecting either gold thioglucose or m o n o s o d i u m g l u t a m a t e have failed t o p r o d u c e any positive results. These findings have led t o t h e speculation t h a t p e r h a p s t h e r e is an absence of glucose-sensitive cells as a part of a food i n t a k e c o n t r o l system in t h e avian brain. This might possibly suggest t h a t circulating carb o h y d r a t e levels i.e., b l o o d glucose, are n o t directly involved in any h y p o t h a l a m i c mechanism regulating f o o d i n t a k e in t h e bird.
1623
1624
SMITH lesions. Endocrinology 84:611—618. Snapir, N., I. Nir, F. Furuta, and S. Lepkovsky, 1974. Effects of functional and surgical castration of White Leghorn cockerels and replacment therapy on food intake, obesity, reproductive traits, and certain components of blood, liver, muscle, and bone. Gen. Comp. Endocrinol. 24:53—64. Snapir, N., H. Ravona, and M. Perek, 1973. Effect of electrolytic lesions in various regions of the basal hypothalamus in White Leghorn cockerels upon food intake, obesity, blood plasma, triglycerides, and proteins. Poultry Sci. 52:629-639. Snapir, N., M. Yaakobi, B. Robinzon, H. Ravona, and M. Perek, 1976. Involvement of the medial hypothalamus and the septal area in the control of food intake and body weight in geese. Pharm. Biochem. Behav. 5:609-615. Svacha, A. J., and B. L. Reid, 1973. Effect of gold thioglucose in the domestic fowl. Poultry Sci. 52=926-930. Tweeton, J. R., R. E. Phillips, and F. W. Peek, 1973. Feeding behavior elicited by electrical stimulation of the brain of chickens, Gallus gallus. Poultry Sci. 52:167-172. Zeigler, H. P., 1974. Feeding behavior in the pigeon: A neurobehavioral analysis. Page 101—132 in Birds: Brain and behavior. I. J. Goldman and M. W. Schein, ed. Academic Press, New York. Zeigler, H. P., H. L. Green, and H. J. Karten, 1969. Neural control of feeding behavior in the pigeon. Psychoneural Sci. 15:156-157.
Downloaded from http://ps.oxfordjournals.org/ at North Dakota State University on May 28, 2015
Hunger: Basic mechanisms and clinical implications. Raven Press, New York. Olney, J. W., 1969. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164:719-721. Polin, D., and J. H. Wolford, 1973. Factors influencing food intake and caloric balance in chickens. Fed. Proc. 32:1720-1726. Robinzon, B., N. Snapir, and M. Perek, 1975. The relation between monosodium glutamate induced brain damage, and body weight, food intake, semen production and endocrine criteria in the fowl. Poultry Sci. 54:234-241. Simkins, K. L., and J. M. Pensack, 1970. Effect of gold thioglucose on survival, feed consumption, and body weight of broilers. Poultry Sci. 49: 1341-1345. Smith, C. J. V., 1969. Alterations in the food intake of chickens as a result of hypothalamic lesions. Poultry Sci. 48:475-477. Smith, C. J. V., 1972. Hypothalamic glucoreceptors — The influence of gold thioglucose implants in the ventromedial and lateral hypothalamic areas of normal and diabetic rats. Physiol. Behav. 9:39— 396. Smith, C. J. V., and I. Szper, 1976. The influence of direct implantation of gold thioglucose into the brain of chickens on food consumption and weight gain. Poultry Sci. 55:2421-2423. Snapir, N., I. Nir, F. Furuta, and S. Lepkovsky, 1969. Effect of administered testosterone propionate on cocks functionally castrated by hypothalamic
report by Feldman et al. (1957) indicated that mid-hypothalamic lesions resulted in the development of an aphagic condition in chickens. Since that earlier report, a number of investigators have published on the involvement of various hypothalamic regions in the food intake control mechanism of birds (Table 1). Lepkovsky and Yasuda (1966) demonstrated that electrolytic lesions of the medial-basal hypothalamus resulted in hyperphagia and a significant accumulation of body lipids. Four types of responses to the lesions were noted: a) normophagic animals with only a small increase in body lipid content, b) normophagic animals with a significant increase in abdominal and carcass lipid, c) hyperphagic animals with significantly elevated body lipids, and d) hyperphagic animals, that in addition to an increase in body lipids, also had enlarged fatty livers. The latter group also displayed signs of being functionally castrated. Subsequent work by Snapir et al. (1969) showed that effective medial-basal hypothalamic lesions also increased plasma lipids, and that the administration of testosterone propionate was effective in restoring plasma lipid levels to normal. Snapir et al. (1973) also demonstrated that lesions just superior to the pituitary stalk produced an increase in body weight, increased fat deposition, and reduced testes weight. However, lesions placed more anteriorly resulted in an increase in body weight and carcass lipid composition, but caused only a small reduction in testes weight. In another experiment, Snapir et al. (1974) found that the administration of crude pituitary extracts to lesioned obese cockerels reduced body weight, abdominal adipose tissues, and liver lipid content. While the reductions were significant, all parameters were still above control levels. White-throated sparrows lesioned in the ventral portion of the anterior hypothalamus at the
1619
Downloaded from http://ps.oxfordjournals.org/ at North Dakota State University on May 28, 2015
There is a long history of interest in the brain, especially the hypothalamus, as the site controlling food intake in animals. The first research reports date from the late 1840's. Since that time hypothalamic mechanism(s) for the control of food intake have been extensively studied, but there are still considerable differences of opinion among researchers regarding the role of the hypothalamus and the exact nature of the control mechanism(s). Not until the late 1930's was it conclusively demonstrated that destruction of the ventromedial region of the hypothalamus of rats resulted in the development of obesity and an increased food intake (Hetherington and Ranson, 1940). Subsequently, Anand and Brobeck (1951) lesioned an area lateral to the ventromedial area and produced an aphagic condition in rats. This led to a hypothesis linking the ventromedial area being designated the "satiety center" and the lateral hypothalamic area the "feeding center". The twenty year interval from the early 1950's to the early 1970's was a period during which considerable effort was expended attempting to delineate the exact role of the ventromedial and lateral areas in controlling food intake in mammals. A significant amount of supporting as well as contradictory data were marshalled for each of the centers. During the last few years the scope of the work regarding the control of food intake has broadened, with extra-hypothalamic control sites receiving considerable attention. In addition, other areas such as the liver are coming under closer scrutiny as possible sites involved in a much more comprehensive control system. Attention is called to a number of excellent reviews on research in the area of food intake control in mammals that have appeared in recent years (i.e., Novin et al., 1976). Interest in the possible mechanism controlling food intake in birds was given an initial impetus by the work on mammals. An early
1620
SMITH TABLE 1. Studies involving electrolytic lesioning of the avian brain which resulted in hyperphagia and/or the development of obesity Brain area lesioned
Species Domestic chicken (Gallus domesticus)
Ventromedial hypothalamus Mammillary bodies Basal hypothalamus
Obesity
References
Yes (d) a
Yes (d)
Yes (s) Yes (d)
Yes (s) Yes (d)
(n) (n) Yes (s)
Yes (s) Yes (d) Yes (s)
Lepkovsky and Yasuda (1966) Snapireia/. (1969) Snapirgf al. (1973) Snapirera/. (1974) Lepkovsky et al. (1968) Kuenzel and Helms (1970) Kuenzel (1972) Kuenzel (1974) Kuenzel and Helms (1967) Hawkes and George (1975)
(n), not reported; (s), statement of results; (d), data presented.
level of the anterior commissure showed significant weight and body lipid increases (Kuenzel and Helms, 1967). The weight gain and lipid deposition in these birds appeared to be quite similar to that found in White-throated sparrows during the normal premigratory fattening period. Additional work with this same species of bird indicated that migratory restlessness ("Zugenruhe") and testes weight were both reduced as a result of effective lesions. Hawkes and George (1975) reported that ventromedial hypothalamic lesions in Mallard ducks increased food intake, fat deposition, and plasma free fatty acid levels. Feeding deficits have been reported to occur when the lateral basal area of the brain is lesioned at sites ranging from the posterior hypothalamic area forward to the nucleus basalis (Feldman et al., 1957; Lepkovsky et al., 1968; Smith, 1969; Zeigler et al, 1969; Kuenzel, 1972; and Hawkes and George, 1975) (Table
2). The work of Zeigler et al. (1969) has implicated cranial nerve number V (trigeminal) and its associated central structures — the quintofrontal tract, nucleus basalis, tr. fronto-archistriaticus, and the archistriatum — in the control of feeding behavior. They have shown that manipulation of the trigeminal system does affect feeding behavior, but whether or not the trigeminal system has any involvement in the physiological control of food intake remains to be determined. An examination of all the anatomical data presented in the papers cited above indicates that the various feeding deficits observed may have been the result of damage to some portion of the trigeminal sysem. Electrical stimulation of the avian hypothalamus generally has little effect on food intake. Of the more than six hundred hypothalamic sites investigated, only nine have given a positive response (Akerman et al., I960; Tweeton et al., 1973) (Table 3). Historically, most of the elec-
TABLE 2. Summary of studies demonstrating aphagia in birds as a result of electrolytic lesioning of the brain Species
Brain area lesioned
Hypophagia
Weight loss
Domestic chicken (Gallus domesticus)
Anterior hypothalamus
Yes (s)a
Yes (s)
Lateral hypothalamus Lateral hypothalamus
Yes (d) Yes (d)
(n) Yes (d)
Feldman et al. (1957) Lepkovsky et al. (1968) Smith (1969) Kuenzel (1972)
Anterior hypothalamus
Yes (s)
Yes (s)
Hawkes and George (1975)
Main-sensory trigeminal Yes (d) Nucleus, quinto-frontal tract
Yes(s)
Zeigler et al. (1969)
White-throated sparrow (Zonotrichia albicollis) Mallard duck (Anas platyrhynchos) Pigeon (Columba livia) a
(n), not reported; (s), statement of results; (d), data presented.
Reference
Downloaded from http://ps.oxfordjournals.org/ at North Dakota State University on May 28, 2015
Anterior hypothalamus White-throated sparrow Ventromedial hypothalamus (Zonotrichia albicollis) Ventromedial hypothalamus Ventromedial hypothalamus Mallard duck Ventromedial hypothalamus (Anas platyrhynchos)
Hyperphagia
THE HYPOTHALAMUS AND FOOD INTAKE
1621
TABLE 3. The influence of electrical stimulation at various sites in the avian brain on feeding behavior and food intake No. of Observed sites feeding studied behavior
Species
Brain area stimulated
Domestic chicken (Gallus domesticus) Pigeon (Columba livia)
Anterior hypothalamus, 625 Para- and supraoptic nuclei Lateral hypothalamus, 19 Preoptic area
Yes
only 5 sites
Tweeton etal. (1973)
Yes
only 4 sites
Akerman etal. (1960)
explained by a multitude of reasons, none of which have been proven. These reasons might include the fact that there may be no glucoreceptor cells in the avian brain, or if there are, they may not be involved in the control of feed intake. Perhaps there is a problem in methodology in that the route of administration or the dose administrated did not result in a positive response. Since the original finding of GTGinduced obesity in mice was a serendipitous observation, the ultimate answer to the question of why GTG has no effect in birds may occur in the same way. Olney (1969) reported that the administration of monosodium glutamate (MSG) to neonatal mice induced ventromedial hypothalamic damage and a subsequent obesity. This observation led to a series of investigations with birds, all of which resulted in negative data (Robinzon et al, 1975; Carew and Foss, 1971) (Table 5). Again, one can only hypothesize why MSG has no effect in birds. Thus, the basic question of why birds do not respond to either GTG or MSG in a manner similar to that seen in certain mammals remains unanswered. In recent years a great amount of work has been reported on the neuropharmacology of brain structures identified as being involved in the food intake control mechanism of mammals (Hoebel, 1976). Snapir et al. (1976) reported that the injection of 6-hydroxydopamine (6OHDA), a neurotoxin thought to selectively destroy neurons containing dopamine, resulted in an increased food consumption, obesity, and testicular atrophy in male geese. Although several hypothalamic areas were injected, bilateral injections into the ventromedial hypothalamus gave the best response. Injections in the septal area and unilateral ventromedial injections resulted in an increased food intake, but no change in body weight (Table 5). The injection or implantation of 6-OHDA into the ventre-
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trical stimulation studies have been concerned with feeding behavior rather than any hypothalamic physiological regulatory mechanism. In rats, for example, stimulation of various hypothalamic sites can cause either an increase in food consumption by satiated rats, or cause a suppression of food intake in hungry animals, depending on the site stimulated. Similar experiments have not been reported for birds. Brecher and Waxier (1949) demonstrated that the injection of high levels of gold thioglucose (GTG) into mice produced destruction of the ventromedial area of the hypothalamus and thereby induced obesity. It was hypothesized that the glucose portion of the molecule was being taken up by glucose-sensitive cells which in turn were being destroyed by the presence of the heavy metal, gold. This observation was used, in part, as the basis for the glucostatic theory of food intake regulation as proposed by Mayer (1953). Basically, the glucostatic theory proposed that the hypothalamic glucose-sensitive cells (glucoreceptors) are sensitive to glucose utilization by the body and regulate food intake accordingly. Later work indicated that the uptake of GTG in the ventromedial area and the resulting damage was insulin dependent; that is, insulin was required for the response (Debons et al, 1968; Smith, 1972). A number of investigators have attempted to induce obesity in different species of birds by injecting GTG (Svacha and Reid, 1973; Simkins and Pensack, 1970; Gentle, 1976; Carpenter et al, 1969). All results to date have been negative. Negative results were also obtained when small quantities of the compound were implanted directly into various brain areas shown previously to have some influence on food consumption (Smith and Szper, 1976) (Table 4). Failure to obtain a response in birds after GTG injection or implantation can possibly be
Observed actual food consumption Reference
1622
SMITH TABLE 4. Increased feeding and/or weight gain in response to an acute administration of gold thioglucose to chemically lesion areas of the brain Increased a
Species Domestic chicken (Gallus domesticus)
Age at treatment
Length of study
Food consumption
Weight gain Reference
.01-.4, IV b .25, .38,1V .01-1.0, IV .17-.5,im .15, 1.0, im
1 wk 1 wk 10 mo 1,2,or 4 days 5 days
15 wk 14 wk 8 wk 15 wk 12 wk
no moderate no no no
no no no slight no
.1-1.0, im Hypothalamic implant sites .2, im
2 or 21 days 20 or 25 wk
33 wk 6 wk
(n) no
no no
1, 7,or 14days 7 wk
no
no
Svacha and Reid (1973) Simkins and Pensack (1970) Gentle (1976) Smith and Szper (1976) Carpenter et al. (1969)
mg/g body weight. (n), not reported: IV, intravenous; im, intramuscular.
medial hypothalamus of rats also induced an increased food intake and the development of obesity (Hoebel, 1976; and others). When all the data concerning the role of the hypothalamus in regulating food intake in birds are examined, several tentative conclusions may be drawn. First, lesioning of certain areas in the medial basal region of the anterior half of the hypothalamus may result in the development of an increased food consumption, an increased lipid deposition, and a testicular regression. It
should be noted that all three responses, while characteristic, may not be present simultaneously and that additional responses may or may not be observed depending on the nature of the lesion and the species being studied. While such data may help to locate the site of a possible control mechanism, it provides little information on the nature of any possible control system within the hypothalamus. Second, existing data on hypothalamic electrical stimulation suffers from a lack of concrete information re-
TABLE 5. Increased feeding and/or weight gain in response to the administration of chemical compounds employed to lesion areas of the brain Increased 3
Species
Compound
Domestic chicken (Gallus domesticus)
Monosodium glutamate (MSG)
Domestic goose (Anser anser)
6-hydroxydopamine
Age at treatment
Food Weight Length of study consumption gain Reference
1,4, Sc b
5 days
33 wk
(n)
yes
1-5,Sc
1 day
16 wk
no
no
4 wk 38 wk
no
no
Dosage and route of administration
.5-10% in diet 1 day 200 jug 3—4 mo hypothalamic injections ventromedial area septal area
mg/g body weight. (n), not reported, Sc, subcutaneous.
Robinzon etal. (1975) Carew and Foss(1971) Snapir et al. (1976)
yes no
yes yes
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Japanese quail (Coturnix coturnix japonica)
Dosage and route of administration
THE HYPOTHALAMUS AND FOOD INTAKE
Currently, there are t w o general mechanisms t h a t have been p r o p o s e d for t h e regulation of food intake in birds, and these b o t h appear t o have some validity. One involves t h e a m o u n t of energy stored as lipid in t h e b o d y of t h e bird (Lepkovsky, 1 9 7 3 ) . This is q u i t e similar t o t h e lipostatic c o n t r o l hypothesis p r o p o s e d for m a m m a l s ( K e n n e d y , 1 9 5 3 ; Hervey, 1 9 6 9 ) . In essence, it is t h o u g h t t h a t food intake is inversely related t o a base line level of stored lipid. T h e second p r o p o s e d m e c h a n i s m involves t h e rate of filling and e m p t y i n g of t h e u p p e r digestive tract, including t h e c r o p (Polin a n d Wolford, 1 9 7 3 ) . Both of t h e proposed mechanisms need considerable additional d a t a before their validity can be considered established. At t h e present t i m e t h e r e is little evidence directly linking either of t h e proposed mechanisms with the hypothalamus. While t h e r e is a fair a m o u n t of d a t a regarding t h e h y p o t h a l a m i c influence on food intake in birds, we are far from being able t o outline a possible control mechanism. U n d o u b t e d l y w i t h t h e e x p e n d i t u r e of additional t i m e and energy t h e role of t h e h y p o t h a l a m u s in t h e c o n t r o l of food intake will b e c o m e clearer.
REFERENCES Akerman, B., B. Andersson, E. Fabricius, and L. Swensson, 1960. Observations on central regulation of body temperature and of food and water intake in the pigeon (Columba livia). Acta Physiol. Scand. 50:328-336. Anand, B. K., and J. R. Brobeck, 1951. Hypothalamic control of food intake. Yale J. Biol. Med. 24:
123-140. Brecher, G., and S. H. Waxier, 1949. Obesity in albino mice due to single injections of gold thioglucose. Proc. Soc. Exp. Biol. Med. 7 0 : 4 9 8 - 5 0 1 . Carew, Jr., L. B., and D. C. Foss, 1971. Monosodium glutamate in chicks. Poultry Sci. 50:1501 — 1502. Carpenter, J. W., C. M. Stein, A. Silverstein, and A. van Tienhoven, 1969. The effect of gold thioglucose on food consumption and reproduction of the Japanese quail (Cotumix coturnix japonica). Poultry Sci. 4 8 : 5 7 4 - 5 7 8 . Debons, A. F., J. Krimsky, H. J. Likuski, A. From, and R. J. Cloutier, 1968. Gold thioglucose damage to the satiety center: inhibition in diabetes. Amer. J. Physiol. 214:652-658. Feldman, S. E., S. Larsson, M. K. Dimick, and S. Lepkovsky, 1957. Aphagia in chickens. Amer. J. Physiol. 191:259-261. Gentle, M. J.,1976. The effect of gold thioglucose on the central nervous system of chicks (Gallus domesticus). Toxicol. Appl. Pharmacol. 35:223— 228. Hawkes, M. P. G., and J. C. George, 1975. Effect of hypothalamic lesions on levels of plasma free fatty acids in the Mallard duck. Arch. Int. Physiol. Biochim. 83:763-770. Hervey, G. R., 1969. Regulation of energy balance. Nature 2 2 3 : 6 2 9 - 6 3 1 . Hetherington, A. W., and S. W. Ranson, 1940. Hypothalamic lesions and adiposity in the rat. Anat. Rec. 78:149-172. Hoebel, B. G., 1976. Satiety: Hypothalamic stimulation, anorectic drugs and neurochemical substrates. Page 33—50 JM Hunger: Basic mechanisms and clinical implications. D. Novin, W. Wyrwicka, and G. Bray, ed., Raven Press, New York. Kennedy, G. C , 1953. The role of depot fat in the hypothalamic control of food intake in the rat. Proc. Roy. Soc. (London) B140:578-592. Kuenzel, W. J., 1972. Dual hypothalamic feeding system in a migratory bird, Zonotricbia albicollis. Amer. J. Physiol. 223:1138-1142. Kuenzel, W. J., 1974. Multiple effects of ventromedial hypothalamic lesions in the White-throated sparrow, Zonotricbia albicollis. J. Comp. Physiol. 90: 169-182. Kuenzel, W. J., and C. W. Helms, 1967. Obesity produced in a migratory bird by hypothalamic lesions. Bioscience 17:395—396. Kuenzel, W. J., and C. W. Helms, 1970. Hyperphagia, polydipsia and other effects of hypothalamic lesions in the White-throated sparrow, Zonotricbia albicollis. Condor 72:66-75. Lepkovsky, S., 1973. Hypothalamic-adipose tissue interrelationships. Fed. Proc. 32:1705-1708. Lepkovsky, S., N. Snapir, and F. Furuta, 1968. Temperature regulation and appetitive behavior in chickens with hypothalamic lesions. Physiol. Behav. 3:911-915. Lepkovsky, S., and M. Yasuda, 1966. Hypothalamic lesions, growth and body composition of male chickens. Poultry Sci. 45:582-588. Mayer, J., 1953. Glucostatic mechanisms of regulation of food intake. New England J. Med: 249: 13-16. Novin, D., W. Wyrwicka, and G. A. Bray, 1976.
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garding any control mechanism(s). This t e c h nique m a y be helpful, nevertheless, in tracing certain nerve tracts involved in feeding. Only t h e w o r k of Zeigler ( 1 9 7 4 ) has provided any significant clues regarding t h e location of a specific anatomical area involved in t h e c o n t r o l of feeding. This w o r k on t h e trigeminal nerve and its associated central nervous s y t e m structures, at least, m a y direct investigators in t h e p r o p e r direction. Third, a t t e m p t s t o alter f o o d intake by injecting either gold thioglucose or m o n o s o d i u m g l u t a m a t e have failed t o p r o d u c e any positive results. These findings have led t o t h e speculation t h a t p e r h a p s t h e r e is an absence of glucose-sensitive cells as a part of a food i n t a k e c o n t r o l system in t h e avian brain. This might possibly suggest t h a t circulating carb o h y d r a t e levels i.e., b l o o d glucose, are n o t directly involved in any h y p o t h a l a m i c mechanism regulating f o o d i n t a k e in t h e bird.
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SMITH lesions. Endocrinology 84:611—618. Snapir, N., I. Nir, F. Furuta, and S. Lepkovsky, 1974. Effects of functional and surgical castration of White Leghorn cockerels and replacment therapy on food intake, obesity, reproductive traits, and certain components of blood, liver, muscle, and bone. Gen. Comp. Endocrinol. 24:53—64. Snapir, N., H. Ravona, and M. Perek, 1973. Effect of electrolytic lesions in various regions of the basal hypothalamus in White Leghorn cockerels upon food intake, obesity, blood plasma, triglycerides, and proteins. Poultry Sci. 52:629-639. Snapir, N., M. Yaakobi, B. Robinzon, H. Ravona, and M. Perek, 1976. Involvement of the medial hypothalamus and the septal area in the control of food intake and body weight in geese. Pharm. Biochem. Behav. 5:609-615. Svacha, A. J., and B. L. Reid, 1973. Effect of gold thioglucose in the domestic fowl. Poultry Sci. 52=926-930. Tweeton, J. R., R. E. Phillips, and F. W. Peek, 1973. Feeding behavior elicited by electrical stimulation of the brain of chickens, Gallus gallus. Poultry Sci. 52:167-172. Zeigler, H. P., 1974. Feeding behavior in the pigeon: A neurobehavioral analysis. Page 101—132 in Birds: Brain and behavior. I. J. Goldman and M. W. Schein, ed. Academic Press, New York. Zeigler, H. P., H. L. Green, and H. J. Karten, 1969. Neural control of feeding behavior in the pigeon. Psychoneural Sci. 15:156-157.
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Hunger: Basic mechanisms and clinical implications. Raven Press, New York. Olney, J. W., 1969. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164:719-721. Polin, D., and J. H. Wolford, 1973. Factors influencing food intake and caloric balance in chickens. Fed. Proc. 32:1720-1726. Robinzon, B., N. Snapir, and M. Perek, 1975. The relation between monosodium glutamate induced brain damage, and body weight, food intake, semen production and endocrine criteria in the fowl. Poultry Sci. 54:234-241. Simkins, K. L., and J. M. Pensack, 1970. Effect of gold thioglucose on survival, feed consumption, and body weight of broilers. Poultry Sci. 49: 1341-1345. Smith, C. J. V., 1969. Alterations in the food intake of chickens as a result of hypothalamic lesions. Poultry Sci. 48:475-477. Smith, C. J. V., 1972. Hypothalamic glucoreceptors — The influence of gold thioglucose implants in the ventromedial and lateral hypothalamic areas of normal and diabetic rats. Physiol. Behav. 9:39— 396. Smith, C. J. V., and I. Szper, 1976. The influence of direct implantation of gold thioglucose into the brain of chickens on food consumption and weight gain. Poultry Sci. 55:2421-2423. Snapir, N., I. Nir, F. Furuta, and S. Lepkovsky, 1969. Effect of administered testosterone propionate on cocks functionally castrated by hypothalamic