J. theor. Biol. (1977) 66,297-306
A Biologic Radar System for the Assessment of Body Mass The Model of a Geometry Sensitive Endocrine System is Presented RUDOLPH L. LEIBEL The Cambridge Hospital, Harvard Medical School, 1493 Cambridge Street, Cambridge, Massachusetts 02139, U.S.A. (Received 21 April 1976, and in revised form 23 July 1976) Appetite control, pubarchal timing, and catch-up growth all seem to depend, to some extent, on body mass. Information regarding this variable may be supplied to the central nervous system (“ponderostat”) by a humoral radar system employing an insulin-like molecule or dependent substrate as a signal. The intensity of this signal would vary as a function of the organism’s total adipose cell surface area, which, in turn, is a product of cell size and number. The geometry of a sphere (adipose cell) is such that surface area change per unit volume change increases as the radius of the sphere is reduced. Signal shifts then are maximal when cell volume is minimal. Divergence of the adipose signal from an age-appropriate norm could influence “ponderostat” activity and, in turn, brain centers mediating appetitive and various endocrine systems. Total caloric intake and the timing of this intake with respect to somatic maturity appear to affect adipose cell volume and number respectively. If shifts in adipose surface area provide a signal source regarding organismic mass, and if this surface area reflects the quantity and chronology of antecedent nutritional events, there are obvious implications for the role of nutrition during “critical periods” in the subsequent operation of the complex systems subserving appetite, somatic growth and sexual maturation.
1. Introduction Current theories regarding the physiology of long-term appetite control (Cabanac, Duclaux & Spector, 1971; Panksepp, 1974; Kennedy, 1953; Hervey, 1969; Kennedy, 1966; Kennedy, 1969), the timing of onset of puberty (Kennedy & Mitra, 1963; Frisch & McArthur, 1974), and mechanisms of catch-up growth (Prader, Tanner & von Harnack, 1963 ; Tanner, 1963; Williams, Tanner &Hughes, 1974a,b) all imply that the mammalian organism 291
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is provided with some means of assessing its body mass and of using this information to make various homeostatic adjustments (weight, linear growth) and chronologic ontogenetic decisions (puberty). To varying degrees, the components of these seemingly interrelated bioloops are unknown. As Weiss & Kavanau (1957) have postulated, and as the biology of mammalian hematologic, renal, and various endocrine organs tends to imply, each organ system seems to have intrinsic growth potential and fine closed-loop mechanisms for insuring optimal organ function and size relative to the organism as a whole. Resting above these biologically parochial and intrinsic organ-related interests, however, there appears to be a more generalized integrator of organ size, having access to both primary internal metabolic information as well as certain of the sequelae of the organism’s interaction with its environment. In assessing the cybernetics of a system capable of integrating the long-term biologic information required to mediate these crucial organismic functions, it would seem that the central nervous system (CNS) must represent the primary afferent receptor and efferent agent and that in some manner, data regarding the organism’s long-term thermodynamic status must be available to the CNS. Although the rate of energy loss by conduction, convection, and radiation off the surface may be signaled via direct neural circuits and actual blood temperature to the CNS (Hammel, 1968), there appears to be no such direct mechanism for the signaling of long-term energy stores. 2. Adipose Tissue as Target The major energy store in mammals is adipose tissue. This calorically dense, low-entropy storage material also constitutes a significant percentage of total body mass, a percentage which rises as energy intake exceeds expenditure. Central “knowledge” of the size of this adipose organ could provide the requisite information regarding body mass and long-term thermodynamic status. The signal from this organ might be transmitted via some metabolic product, dilution of a “tracer” (e.g., steroid) with differential water/lipid solubility (Hervey, 1969), or via a radar-type mechanism employing a signal “bounced off” adipose tissue in proportion to some mass-related characteristic of that organ. Insulin, a peptide representing the quintessential mediator of chemical energy flow and storage, would provide an excellent signal for this last system. Because this hormone participates in the anabolic processes of fat, protein, and glycogen containing organs, some correlate of its plasma level could provide “information” bearing directly on the potential chemical energy of the organism.
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3. Insulin as Signal Studies by Liebelt and his colleagues (Liebelt, 1963; Liebelt, Ichnoe & Nicholson, 1965; Liebelt, Vismara & Liebelt, 1968) have shown that in mice adipose tissue behaves as an integrated functional unit whose total mass is regulated by humoral and/or neurogenic mechanisms and that the mass of the adipose organ in turn apparently exerts a regulatory influence on eating behavior. Experiments using parabiosed animals (Hervey, 1959) and direct mechanical exchange of blood between satiated (or hypothalamic ventromedial nucleus lesioned animals) and normal animals (Davis, Gallagher, Ladove & Turausky, 1969) have implied the presence of a humoral satiety (as opposed to hunger) factor. Hoebel & Teitelbaum (1966) showed that hypothalamic ventromedial nucleus lesions in rats already obese secondary to chronic insulin administration did not produce the anticipated hyperphagia, implying inhibition of eating behavior by excessive adipose tissue. Again, the nature of this humoral signal has not been elucidated, but insulin has been considered by some to be the prime candidate for this role (Kennedy, 1966; Kennedy, 1969; Cahill, 1971). Insulin clearly influences the hypothalamus directly (Debons, Krimsky & From, 1970; Szabo & Szabo, 1975) and can, in fact augment the satiety produced by a nutrient ingested immediately before its injection (Lovett & Booth, 1970). The ventromedial nucleus of the hypothalamus, via the vagus, appears to influence insulin production. Kennedy & Parker (1963) have demonstrated beta cell hyperplasiain rats with ventromedial nucleus lesions, and Bergman & Miller (1973), showed increased insulin secretion resulting from increased vagal firing rates in a similar animal model. Insulin exerts its primary effect (probably the acceleration of glucose uptake) on adipose tissue by interaction with a surface receptor on these cells. Although some recent studies have indicated the possible existence of both high (Kd 60 pm) and low (& 3 nm) affinity receptors (or negative co-operativity between receptors of equal affinity) on the adipocyte membrane (Gliemann, Gammeltoft & Vinten, 1975), the great majority (99%) of receptors are of the “low” affinity type. The number of these receptors, but not their affinity constants, appears to decrease as the adipocyte enlarges (Olefsky, 1976), in turn producing diminished insulin binding per unit surface area of adipose cell membrane. Cuatrecasas (1973) estimates that there are 10 000 receptors per adipose cell. Olefsky & Reaven (1975) report 23 + I-5 x lo4 receptor sites per adipose cell in rats at weights of 160 to 220 g and 12 f 1 x lo4 sites per cell in rats which weigh more than 400 g (age has no appreciable effect on the number of sites). Obese humans have adipose cells whose surface area may be more than four times that of a normal weight individual (Amatruda, Livingston & 7.“. 20
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Lockwood, 1975). Olefsky & Reaven (1975) showed that in rats a 30% increment in adipose cell volume resulted in a 20% decrease to insulin binding ability per cell and that appropriate caloric augmentation or deprivation could dramatically alter the number of insulin binding sites within 24 h (5% body weight shifts). Thus, adipocyte insulin receptors are highly sensitive to the degree of obesity and caloric balance. Salans and his colleagues (Salans, Knittle & Hirsch, 1968; Salans & Cushman, 1975) have shown that membrane sensitivity to insulin-mediated glucose translocation falls as adipose surface area is increased. Numerous clinical studies (Bjornstorp, 1972) have demonstrated elevated serum insulin levels in obese patients, a fraction of which may admittedly be dependent upon the status of carbohydrate ingestion (Stern, Johnson, Batchelor, Zucker & Hirsch, 1975). This relative insulin insensitivity of large adipocytes may be the result of an actual decrease in the number of insulin receptors (Soll, Kahn, Neville & Roth, 1975), altered receptor affinity due to changes in surface geometry (Cuatrecasas, 1973), or changes at some point more distal in the transmission of the insulin receptor signal (Livingston, Cuatrecasas & Lockwood, 1972; Amatruda et al., 1975). Regardless of the mechanism of resistance, it appears that large adipose cells, as well as other cells (e.g., muscle), in the obese organism are relatively insulin resistant and that this characteristic is reversed by weight reduction (Salans et al., 1968; Olefsky, 1976). Since adipose tissue accounts for only a small fraction of the body’s glucose consumption (Bjornstorp, 1972), its projected influence on insulin homeostasis must be mediated to a considerable extent via associated effects on the sensitivity of skeletal muscle, liver, etc., to insulin (Nutr. Rev., 1976). This could result from membrane lipid changes secondary to obesity (Cuatrecasas, 1973) or to insulin-mediated feedback effects on surface receptors (Sol1 et al., 1975; Olefsky, 1976; Maugh, 1976). In the latter situation, expansion of adipose surface area might result in moderate insulin level increases which in turn would repress receptor sites in other tissues, including perhaps the CNS satiety region. Such a series of events might explain the apparent upward resetting of the “ponderostat” in exogenous obesity. 4. How Adipose Mass Is “Read” It seems possible, therefore, that as a first-order approximation, adipose mass represents the peripheral structure which is ultimately “read” by the CNS in assessing total body size. The actual “reading” may be obtained by an ongoing assessment of the adipose organ’s total surface area as signaled
HUMORAL Caloric Intake m excess of energy requirements
ASSESSMENT __
t Adipose surface area
301
OF BODY MASS _I
t I per molecule clrcutating glucose I ’ {Receptor site number other peripheral ttssues (muscle, her)
in
Further 4 f per molecule circulating glucose
+ Adlspose surface area
c_
t Intake per meal
A
i Abram (“ponderostat”) glucose, amino acids, neurotransmitter augmented “satiety”per calorie Ingested
FIG. 1. This diagram illustrates the manner in which extant body adipose content might influence per meal food intake. Insulin (I) is used in this figure as the humoral mediator. This system provides the crucial link between short-term appetitive behavior and long-term energy stores.
by absolute insulin level or the relationship of insulin level to some insulin dependent metabolite (e.g., glucose, amino acids) or even glucagon or growth hormone (Woods, Decke & Vasselli, 1974). This biologic radar system may use continuous hepatic glucose monitoring (Russek, 1963) as a determinant of outgoing signal (insulin) intensity with the hypothalamus measuring the “bounced” signal (unknown hormone, insulin, insulin-like peptide, amino acids, insulin/glucose, insulin/glucagon, insulin/growth hormone) whose intensity would vary inversely as adipose cell surface area (and muscle insulin resistance). Wurtman & Fernstrom (1975, 1974), have demonstrated that diet and circulating amino acid levels (modulated by insulin) can influence CNS monoamine synthesis and, therefore, the levels of putative neurotransmitters. Lytle, Messing, Fisher & Phebus (1975) first reported an actual behavioral alteration (shock avoidance) which correlated with diet-induced (low tryptophan) depression of brain serotonin in rats, and Breisch, Zemlan & Hoebel (1976) and Saller & Stricker (1976) have recently demonstrated CNS serotonin-mediated alterations in appetite behavior in rats. There is increasing evidence that the ventromedial and lateral hypothalamic nuclei are not the only, or perhaps even the major, areas of brain subserving appetite behavior (Ahlskog, Randall & Hoebel, 1975; Ziegler & Karten, 1974; Gold, 1973; Grossman, 1975; Nutr. Rev., 1974), and that an integrated, anatomically diverse catechol-mediated system may be of major physiologic import (Ahlskog et al., 1975; Antelman & Szechtman, 1975; Leibowitz, 1971). Insulin, via a direct effect on the CNS transport of neurotransmitter substrates
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(e.g., tryptophan) and/or brain fuels (glucose, ketones, free-fatty acids) or via an indirect effect mediated by peripheral amino acid, glucose, free-fatty acid fluxes, could influence brain chemistry and hence behavior. This peptide could provide the denominator against which neurotransmitter substrate and brain fuel levels are compared, the ratio reflecting the status of adipose and peripheral tissue (body mass). The ontogeny of development would require that the CNS “ponderostat” vary in sensitivity with age in a fashion similar to that of the “gonadostat” (Grumbach, Roth, Kaplan & Kelch, 1974). Stable obesity of any etiology would be characterized by an upward resetting of the “ponderostat.” For a sphere (fat cell) of radius R surface area (A) 4nR2 volume (V) =4/3nRj=i
3
indicating that the surface area per unit volume is minimum cells and,
aA av'
for the largest
2 ii
so that the surface area change per unit cell volume change is maximal for the smallest cells.
5. Appetite Control Such a “lipostatic” system would provide a mechanism whereby shortterm appetite behavior, an obviously crucial pathway for the adjusting of organismic energy stores, could be influenced by the status of these stores. Panksepp & Ritter (1975) have described the experimental basis for the belief that the long-term signal of body energy status has a greater impact on per meal intake than inter-meal interval. The energy balance control loop would be closed by a humoral feedback agent sensitive to the total surface area of adipose tissue in the organism. And this “information” would be used to adjust food intake to a level appropriate to the organism’s ontogenetic energy requirements. Reduced intake and/or increased energy expenditure would result in a reduction of adipose surface area, a reduction in insulin/ substrate per unit calorie ingested and, hence, a reduced CNS satiety signal per meal. Conversely, excessive adipose mass would generate an augmented peripheral satiety signal per meal, tending to reduce caloric intake and hence to return the organism to a genetically coded weight norm for age. This concept provides the crucial link between short-term appetite behavior and long-term organismic energy status.
HUMORAL 5 Adipose compositton
ASSESSMENT
OF BODY
MASS
303
D
C
Hypothalomlc effector
“Ponderostot” reading ---+
-
( I ) Reduced (2) Reduced (3) Puberty
calories per meal growth hormone release (at critcol setting)
(I ) Increased calories per meol (2) Increased growth hormone release (catch-up growth) (3) Delay m puberty, secondary amenorrhea
FIG. 2. Humoral feedback system by which body adipose composition (cell size and number) influences CNS (hypothalamic) “decisions” relevant to body mass. The impact of a fixed number of calories (A) elicits different responses depending on the peripheral tissues’ sensitivity to insulin (or other humoral mediator). This sensitivity is, in turn, the result of total adipose cell surface area and its secondary influence on mediator sensitivity in other tissues (see Fig. 1). As adipose cells enlarge (E), with attendant increases in surface area, the amount of mediator per calorie ingested (Z/C) rises. The mediator (insulin is used m . t hi s I‘11us tra t’Ion ) signals “ponderostat” (C), a hypothetical CNS structure, either directly or via its influence on circulating levels of substrate (glucose) or neurotransmitter precursors (amino acids). The “ponderostat” then orchestrates appropriate homeostatic adjustments (0) in eating behavior, growth and reproductive function.
Ease of weight reduction would depend on the nature of the obesity (hyperplastic or hypertrophic). The hyperplastic obese individual (many smaller adipocytes) would have greater trouble, since the &4/13V for a given reduction in adipose mass would be greater in these individuals than the hypertrophic obese (fewer, larger adipocytes) and any signal would be multiplied by virtue of increased cellularity. Thus, any degree of weight reduction would be associated with a louder peripheral mass reduction “hunger” signal in the hyperplastic as opposed to the hypertrophic obese individual. 6. Catch-up Growth Presumably, this same “ponderostat” system could be used to determine when and to what degree catch-up growth was necessary. Sensing a reduction in fat cell total surface area versus the biologically coded norm for chronologic age, augmented eating behavior would be employed to provide the substrates for accelerated growth. No primary endocrinologic changes would be necessary. So-called “critical periods”, that is, growth periods during
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which caloric deprivation leads to permanent stunting of stature and/or weight (Prader et al., 1963 ; Tanner, 1963 ; Widdowson & McCance, 1975), would result from a permanent disruption (downward resetting) of the sizing mechanism by impact on the CNS sensing device and/or the peripheral signal source. 7. Menarche Finally, menarche, shown by Frisch & McArthur (1974) to be weight (first order) or percent body adiposity (second order) related, could be regulated by the same system. The signal for the achievement of appropriate adiposity could be provided by the mechanisms described earlier. The variance in percent adiposity at menarche noted by Frisch & McArthur could be the result of variable adipose cell size and number producing a relatively constant (for biologic age) total adipose tissue surface area.
8. Summary In summary, the divergence of the adipose signal from an age-appropriate norm could influence “ponderostat” activity and in turn brain centers mediating appetitive and various endocrine systems. Total caloric intake and the timing of this intake with respect to somatic maturity appear to affect adipose cell volume and number respectively (Lemonnier, 1972; Knittle & Hirsch, 1968; Brook, 1972). If shifts in adipose surface area provide a signal source regarding organismic mass, and if this surface area reflects the quantity and chronology of antecedent nutritional events, there are obvious implications for the role of nutrition during “critical periods” in the operation of long-term homeostatic (appetite, growth) and reproductive functions. This hypothesis, that total adipose cell surface area controls the peripheral signal used in the mammal to determine its “mass” and that this information is used to mediate appetite control, menarcheal timing, and catch-up growth, is testable even in the absence of knowledge of the “signal” utilised by this system.-f7 Easiest to study in this regard would be the following. 1. Results of expiration of adipose tissue (inguinal fat organ and gonadal fat organ) in rats rendered obese from force feeding or insulin administration. 2. Results of supetnumery adipose transplants of varying cellular size and number in animals made underweight by starvation. 3. Effects of adipose extirpation on rat estrus. 4. Effects of adipose transplants of varying cellular size and number on the timing of estrus in rats.
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1 am indebted to Drs Arthur Frankel, John D. Crawford and Francis A. Hill for helpful discussions regarding some of the material presented here, and to Drs Philip J. Porter and Robert G. Zwerdling for encouragement and time. Mrs Rheta Stanton provided invaluable library assistance. This work was supported in part by grant No. lR22 HDO!3228-01 from the National Institute of Child Health and Human Development. REFERENCES AHLSKOG, J. E., RANDALL, P. K. & HOEEEL, B. G. (1975). Science, N. Y. 190, 399. AMATRUDA, J. M., LIVINGSTON, J. N. & LOCKWOOD, D. H. (1975). Science, N. Y. 188,264. ANTELMAN, S. M. & SZECHTMAN, S. M. (1975). Science, N. Y. 189, 731. BERGMAN, R. N. & MILLER, R. E. (1973). Am. J. Physioi. 225, 481. BJORNSTORP, P. (1972). In Hunger and Satiety in Health and Disease (F. Reichsman, ed.) Adv. Psychosom. Med. 7, 116-147. Basel: S. Karger. BREISCH, S. T., ZEMLAN, F. P. & HOEBEL, B. G. (1976). Science, N. Y. 192, 382. BROOK, G. C. D. (1972). Lancet ii, 624. CABANAC, A., DUCLAUX, R. & SPECTOR, N. H. (1971). Nature, Land. 229, 125. CAHILL, G. F. (1971). Diabetes 20, 785. CUATRECASAS, P. (1973). Fedn. Proc. Fedn. Am. Sots. exp. Biol. 32, 1838. DAVIS, J. D., GALLAGHER, R. J., LADOVE, R. F. & TURAUSKY, A. J. (1969). J. Cbnlp.
Physiol. Psychol. 67, 407. DEBONS, A. F., KRIMSKY, I. & FROM, A. (1970). Am. J. Physiol. 219, 938. FRISCH. R. E. & MCARTHUR. J. W. (1974). Science. N. Y. 185. 949. GLIEM~NN, J., GAMMELT~FT, s. & V&TEN; J. (1975). J. Biol. dhem. 250, 3368. GOLD, R. M. (1973). Science, N. Y. 182,488. GROSSMAN, S. P. (1975). Psychol. Rev. 82, 200. GRUMBACH, M. M., ROTH, J. C., KAPLAN, S. L. & KELCH, R. P. (1974). In Con&of of the Onset ofpuberty (M. M. Grumbach, G. D. Grave & F. E. Mayer, eds), pp. 115-166. New York: Wiley. HAMMEL, H. T. (1968). Ann. Rev. Physiol. 30, 641. HERVEY, G. R. (1959). J. Physiol. 145, 336. HERVEY, G. R. (1969). Nature, Land. 222, 629. HOEBEL, B. G. & TEITELBAUM, P. (1966). J. Camp. Physiol. Psychol. 61, 189. KENNEDY, G. C. (1953). Proc. R. Sot. Series B 140, 578. KENNEDY, G. C. (1966). Br. Med. BUN. 22, 216. KENNEDY, G. C. (1969). Ann. N. Y. Acad. Sci. 157, 1049. KENNEDY, G. C. & MITRA, J. (1963). J. Physiol. 166, 395. KENNEDY, G. C. &PARKER, R. A. (1963). Lancet ii, 981. KNI~LE, J. L. & HIRSCH, J. (1968):J. &. Invest. b7, 2091. LEIBOWITZ. S. F. (1971). Proc. Natn. Acad. Sci. U.S.A. 68. 332. LEMONNIE~, D. (1572). J. Clin. Invest, 51, 2907. LIEBELT, R. A. (1963). Ann. N. Y. Acad. Sci. 110, 723. LIEBELT, R. A., ICHNOE, S. & NICHOLSON, N. (1965). Ann. N. Y. Acad. Sci. 131, 559. LIEBELT, R. A,, VISMARA, L. & LIEBELT, A. G. (1968). Proc. Sot. exp. Biol. Med. 127,458. LIVINGSTON, J. N., CUATRECASAS, P. & LOCKWOOD, D. H. (1972). Science, N. Y. 177, 626. Love, D. & BOOTH, D. A. (1970). Q. J. exp. Psychol. 22,406. LYTLE, L. D., MESSING, R. B., FISHER, L. & PHEBUS, L. (1975). Science, N. Y. 190, 692. MA~GH, T. H. (1976). Science, N. Y. 193, 220. Nutr. Rev. (1974), 32, 83. Nutr. Rev. (1976), 34, 145. OLEFSKY, J. M. (1976). J. Clin. Invest. 56, 1165. OLEFSKY, J. M. & REAVEN, G. M. (1975). Endocrinology 96, 1486.
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PANKSEPP, J. (1974). Fedn. Proc. Fedn. Am. Sots. exp. Biol. 33, 1150. PANKSEPP, J. & RITTER, M. (1975). J. Comp. Physioi. Psychol. 89, 1019. PRADER, A., TANNER, J. M. & VON HARNACK, G. A. (1963). J. Pediat. 62, f%6. RUSSEK, M. (1963). Nature, Lond. 197, 79, SALANS, L. B. & CUSHMAN, S. W. (1975). In Obesity in Perspective (G. A. Bray, ed.) pp. 245-251. Washington, D.C. : DHEW Publication No. (NIH) 75-708. SALANS, L. B., KNI~LE, J. L. & HIRSCH, J. (1968). J. Ciin. Invest. 47, 153. SALLER, C. F. & STRICKER, E. M. (1976). Science, N. Y. 192, 385. SOLL, A. H., KAHN, C. R., NEVILLE, D. M. & ROTH, J. (1975). J. C/in. Invest. 56, 769. STERN, J. S., JOHNSON, P. R., BATCHELQR, B. R., ZUCKER, L. M. & HIRSCH, J. (1975).
Am. J. Physiol. 228, 543. SZABO, 0. & SZABO, A. J. (1975). Diabetes 24, 328. TANNER, J. M. (1963). ChiId. Devef. 34, 817. WEISS, P. & KAVANAU, J. L. (1957). J. Gen. Physiof. 41, 1. WIDDOWSON, E. M. & MCCANCE, R. A. (1975). Pediat. Res. 9, 154. WILLIAMS, J. P. G., TANNER, J. M. & HUGHES, P. C. R. (1974a). Pediaf. WILLIAMS, J. P. G., TANNER, J. M. & HUGHES, P. C. R. (19746). Pediat. WOODS, S. C., DECKE, E. & VASSELLI, J. R. (1974). Psychol. Rev. 81, 26. WURTMAN, R. J. & FERNSTROM, J. D. (1974). N&r. Rev. 32, 193. WURTMAN, R. J. & FERNSTROM, J. D. (1975). Am. J. Clin. NW. 28, 638. ZIEGLER, H. P. & KARTEN, H. J. (1974). Science, N. Y. 186, 636.
Res. 8, 149. Res. 8, 157.
A Biologic Radar System for the Assessment of Body Mass The Model of a Geometry Sensitive Endocrine System is Presented RUDOLPH L. LEIBEL The Cambridge Hospital, Harvard Medical School, 1493 Cambridge Street, Cambridge, Massachusetts 02139, U.S.A. (Received 21 April 1976, and in revised form 23 July 1976) Appetite control, pubarchal timing, and catch-up growth all seem to depend, to some extent, on body mass. Information regarding this variable may be supplied to the central nervous system (“ponderostat”) by a humoral radar system employing an insulin-like molecule or dependent substrate as a signal. The intensity of this signal would vary as a function of the organism’s total adipose cell surface area, which, in turn, is a product of cell size and number. The geometry of a sphere (adipose cell) is such that surface area change per unit volume change increases as the radius of the sphere is reduced. Signal shifts then are maximal when cell volume is minimal. Divergence of the adipose signal from an age-appropriate norm could influence “ponderostat” activity and, in turn, brain centers mediating appetitive and various endocrine systems. Total caloric intake and the timing of this intake with respect to somatic maturity appear to affect adipose cell volume and number respectively. If shifts in adipose surface area provide a signal source regarding organismic mass, and if this surface area reflects the quantity and chronology of antecedent nutritional events, there are obvious implications for the role of nutrition during “critical periods” in the subsequent operation of the complex systems subserving appetite, somatic growth and sexual maturation.
1. Introduction Current theories regarding the physiology of long-term appetite control (Cabanac, Duclaux & Spector, 1971; Panksepp, 1974; Kennedy, 1953; Hervey, 1969; Kennedy, 1966; Kennedy, 1969), the timing of onset of puberty (Kennedy & Mitra, 1963; Frisch & McArthur, 1974), and mechanisms of catch-up growth (Prader, Tanner & von Harnack, 1963 ; Tanner, 1963; Williams, Tanner &Hughes, 1974a,b) all imply that the mammalian organism 291
298
R.
L.
LEIBEL
is provided with some means of assessing its body mass and of using this information to make various homeostatic adjustments (weight, linear growth) and chronologic ontogenetic decisions (puberty). To varying degrees, the components of these seemingly interrelated bioloops are unknown. As Weiss & Kavanau (1957) have postulated, and as the biology of mammalian hematologic, renal, and various endocrine organs tends to imply, each organ system seems to have intrinsic growth potential and fine closed-loop mechanisms for insuring optimal organ function and size relative to the organism as a whole. Resting above these biologically parochial and intrinsic organ-related interests, however, there appears to be a more generalized integrator of organ size, having access to both primary internal metabolic information as well as certain of the sequelae of the organism’s interaction with its environment. In assessing the cybernetics of a system capable of integrating the long-term biologic information required to mediate these crucial organismic functions, it would seem that the central nervous system (CNS) must represent the primary afferent receptor and efferent agent and that in some manner, data regarding the organism’s long-term thermodynamic status must be available to the CNS. Although the rate of energy loss by conduction, convection, and radiation off the surface may be signaled via direct neural circuits and actual blood temperature to the CNS (Hammel, 1968), there appears to be no such direct mechanism for the signaling of long-term energy stores. 2. Adipose Tissue as Target The major energy store in mammals is adipose tissue. This calorically dense, low-entropy storage material also constitutes a significant percentage of total body mass, a percentage which rises as energy intake exceeds expenditure. Central “knowledge” of the size of this adipose organ could provide the requisite information regarding body mass and long-term thermodynamic status. The signal from this organ might be transmitted via some metabolic product, dilution of a “tracer” (e.g., steroid) with differential water/lipid solubility (Hervey, 1969), or via a radar-type mechanism employing a signal “bounced off” adipose tissue in proportion to some mass-related characteristic of that organ. Insulin, a peptide representing the quintessential mediator of chemical energy flow and storage, would provide an excellent signal for this last system. Because this hormone participates in the anabolic processes of fat, protein, and glycogen containing organs, some correlate of its plasma level could provide “information” bearing directly on the potential chemical energy of the organism.
HUMORAL
ASSESSMENT
OF
BODY
MASS
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3. Insulin as Signal Studies by Liebelt and his colleagues (Liebelt, 1963; Liebelt, Ichnoe & Nicholson, 1965; Liebelt, Vismara & Liebelt, 1968) have shown that in mice adipose tissue behaves as an integrated functional unit whose total mass is regulated by humoral and/or neurogenic mechanisms and that the mass of the adipose organ in turn apparently exerts a regulatory influence on eating behavior. Experiments using parabiosed animals (Hervey, 1959) and direct mechanical exchange of blood between satiated (or hypothalamic ventromedial nucleus lesioned animals) and normal animals (Davis, Gallagher, Ladove & Turausky, 1969) have implied the presence of a humoral satiety (as opposed to hunger) factor. Hoebel & Teitelbaum (1966) showed that hypothalamic ventromedial nucleus lesions in rats already obese secondary to chronic insulin administration did not produce the anticipated hyperphagia, implying inhibition of eating behavior by excessive adipose tissue. Again, the nature of this humoral signal has not been elucidated, but insulin has been considered by some to be the prime candidate for this role (Kennedy, 1966; Kennedy, 1969; Cahill, 1971). Insulin clearly influences the hypothalamus directly (Debons, Krimsky & From, 1970; Szabo & Szabo, 1975) and can, in fact augment the satiety produced by a nutrient ingested immediately before its injection (Lovett & Booth, 1970). The ventromedial nucleus of the hypothalamus, via the vagus, appears to influence insulin production. Kennedy & Parker (1963) have demonstrated beta cell hyperplasiain rats with ventromedial nucleus lesions, and Bergman & Miller (1973), showed increased insulin secretion resulting from increased vagal firing rates in a similar animal model. Insulin exerts its primary effect (probably the acceleration of glucose uptake) on adipose tissue by interaction with a surface receptor on these cells. Although some recent studies have indicated the possible existence of both high (Kd 60 pm) and low (& 3 nm) affinity receptors (or negative co-operativity between receptors of equal affinity) on the adipocyte membrane (Gliemann, Gammeltoft & Vinten, 1975), the great majority (99%) of receptors are of the “low” affinity type. The number of these receptors, but not their affinity constants, appears to decrease as the adipocyte enlarges (Olefsky, 1976), in turn producing diminished insulin binding per unit surface area of adipose cell membrane. Cuatrecasas (1973) estimates that there are 10 000 receptors per adipose cell. Olefsky & Reaven (1975) report 23 + I-5 x lo4 receptor sites per adipose cell in rats at weights of 160 to 220 g and 12 f 1 x lo4 sites per cell in rats which weigh more than 400 g (age has no appreciable effect on the number of sites). Obese humans have adipose cells whose surface area may be more than four times that of a normal weight individual (Amatruda, Livingston & 7.“. 20
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Lockwood, 1975). Olefsky & Reaven (1975) showed that in rats a 30% increment in adipose cell volume resulted in a 20% decrease to insulin binding ability per cell and that appropriate caloric augmentation or deprivation could dramatically alter the number of insulin binding sites within 24 h (5% body weight shifts). Thus, adipocyte insulin receptors are highly sensitive to the degree of obesity and caloric balance. Salans and his colleagues (Salans, Knittle & Hirsch, 1968; Salans & Cushman, 1975) have shown that membrane sensitivity to insulin-mediated glucose translocation falls as adipose surface area is increased. Numerous clinical studies (Bjornstorp, 1972) have demonstrated elevated serum insulin levels in obese patients, a fraction of which may admittedly be dependent upon the status of carbohydrate ingestion (Stern, Johnson, Batchelor, Zucker & Hirsch, 1975). This relative insulin insensitivity of large adipocytes may be the result of an actual decrease in the number of insulin receptors (Soll, Kahn, Neville & Roth, 1975), altered receptor affinity due to changes in surface geometry (Cuatrecasas, 1973), or changes at some point more distal in the transmission of the insulin receptor signal (Livingston, Cuatrecasas & Lockwood, 1972; Amatruda et al., 1975). Regardless of the mechanism of resistance, it appears that large adipose cells, as well as other cells (e.g., muscle), in the obese organism are relatively insulin resistant and that this characteristic is reversed by weight reduction (Salans et al., 1968; Olefsky, 1976). Since adipose tissue accounts for only a small fraction of the body’s glucose consumption (Bjornstorp, 1972), its projected influence on insulin homeostasis must be mediated to a considerable extent via associated effects on the sensitivity of skeletal muscle, liver, etc., to insulin (Nutr. Rev., 1976). This could result from membrane lipid changes secondary to obesity (Cuatrecasas, 1973) or to insulin-mediated feedback effects on surface receptors (Sol1 et al., 1975; Olefsky, 1976; Maugh, 1976). In the latter situation, expansion of adipose surface area might result in moderate insulin level increases which in turn would repress receptor sites in other tissues, including perhaps the CNS satiety region. Such a series of events might explain the apparent upward resetting of the “ponderostat” in exogenous obesity. 4. How Adipose Mass Is “Read” It seems possible, therefore, that as a first-order approximation, adipose mass represents the peripheral structure which is ultimately “read” by the CNS in assessing total body size. The actual “reading” may be obtained by an ongoing assessment of the adipose organ’s total surface area as signaled
HUMORAL Caloric Intake m excess of energy requirements
ASSESSMENT __
t Adipose surface area
301
OF BODY MASS _I
t I per molecule clrcutating glucose I ’ {Receptor site number other peripheral ttssues (muscle, her)
in
Further 4 f per molecule circulating glucose
+ Adlspose surface area
c_
t Intake per meal
A
i Abram (“ponderostat”) glucose, amino acids, neurotransmitter augmented “satiety”per calorie Ingested
FIG. 1. This diagram illustrates the manner in which extant body adipose content might influence per meal food intake. Insulin (I) is used in this figure as the humoral mediator. This system provides the crucial link between short-term appetitive behavior and long-term energy stores.
by absolute insulin level or the relationship of insulin level to some insulin dependent metabolite (e.g., glucose, amino acids) or even glucagon or growth hormone (Woods, Decke & Vasselli, 1974). This biologic radar system may use continuous hepatic glucose monitoring (Russek, 1963) as a determinant of outgoing signal (insulin) intensity with the hypothalamus measuring the “bounced” signal (unknown hormone, insulin, insulin-like peptide, amino acids, insulin/glucose, insulin/glucagon, insulin/growth hormone) whose intensity would vary inversely as adipose cell surface area (and muscle insulin resistance). Wurtman & Fernstrom (1975, 1974), have demonstrated that diet and circulating amino acid levels (modulated by insulin) can influence CNS monoamine synthesis and, therefore, the levels of putative neurotransmitters. Lytle, Messing, Fisher & Phebus (1975) first reported an actual behavioral alteration (shock avoidance) which correlated with diet-induced (low tryptophan) depression of brain serotonin in rats, and Breisch, Zemlan & Hoebel (1976) and Saller & Stricker (1976) have recently demonstrated CNS serotonin-mediated alterations in appetite behavior in rats. There is increasing evidence that the ventromedial and lateral hypothalamic nuclei are not the only, or perhaps even the major, areas of brain subserving appetite behavior (Ahlskog, Randall & Hoebel, 1975; Ziegler & Karten, 1974; Gold, 1973; Grossman, 1975; Nutr. Rev., 1974), and that an integrated, anatomically diverse catechol-mediated system may be of major physiologic import (Ahlskog et al., 1975; Antelman & Szechtman, 1975; Leibowitz, 1971). Insulin, via a direct effect on the CNS transport of neurotransmitter substrates
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(e.g., tryptophan) and/or brain fuels (glucose, ketones, free-fatty acids) or via an indirect effect mediated by peripheral amino acid, glucose, free-fatty acid fluxes, could influence brain chemistry and hence behavior. This peptide could provide the denominator against which neurotransmitter substrate and brain fuel levels are compared, the ratio reflecting the status of adipose and peripheral tissue (body mass). The ontogeny of development would require that the CNS “ponderostat” vary in sensitivity with age in a fashion similar to that of the “gonadostat” (Grumbach, Roth, Kaplan & Kelch, 1974). Stable obesity of any etiology would be characterized by an upward resetting of the “ponderostat.” For a sphere (fat cell) of radius R surface area (A) 4nR2 volume (V) =4/3nRj=i
3
indicating that the surface area per unit volume is minimum cells and,
aA av'
for the largest
2 ii
so that the surface area change per unit cell volume change is maximal for the smallest cells.
5. Appetite Control Such a “lipostatic” system would provide a mechanism whereby shortterm appetite behavior, an obviously crucial pathway for the adjusting of organismic energy stores, could be influenced by the status of these stores. Panksepp & Ritter (1975) have described the experimental basis for the belief that the long-term signal of body energy status has a greater impact on per meal intake than inter-meal interval. The energy balance control loop would be closed by a humoral feedback agent sensitive to the total surface area of adipose tissue in the organism. And this “information” would be used to adjust food intake to a level appropriate to the organism’s ontogenetic energy requirements. Reduced intake and/or increased energy expenditure would result in a reduction of adipose surface area, a reduction in insulin/ substrate per unit calorie ingested and, hence, a reduced CNS satiety signal per meal. Conversely, excessive adipose mass would generate an augmented peripheral satiety signal per meal, tending to reduce caloric intake and hence to return the organism to a genetically coded weight norm for age. This concept provides the crucial link between short-term appetite behavior and long-term organismic energy status.
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D
C
Hypothalomlc effector
“Ponderostot” reading ---+
-
( I ) Reduced (2) Reduced (3) Puberty
calories per meal growth hormone release (at critcol setting)
(I ) Increased calories per meol (2) Increased growth hormone release (catch-up growth) (3) Delay m puberty, secondary amenorrhea
FIG. 2. Humoral feedback system by which body adipose composition (cell size and number) influences CNS (hypothalamic) “decisions” relevant to body mass. The impact of a fixed number of calories (A) elicits different responses depending on the peripheral tissues’ sensitivity to insulin (or other humoral mediator). This sensitivity is, in turn, the result of total adipose cell surface area and its secondary influence on mediator sensitivity in other tissues (see Fig. 1). As adipose cells enlarge (E), with attendant increases in surface area, the amount of mediator per calorie ingested (Z/C) rises. The mediator (insulin is used m . t hi s I‘11us tra t’Ion ) signals “ponderostat” (C), a hypothetical CNS structure, either directly or via its influence on circulating levels of substrate (glucose) or neurotransmitter precursors (amino acids). The “ponderostat” then orchestrates appropriate homeostatic adjustments (0) in eating behavior, growth and reproductive function.
Ease of weight reduction would depend on the nature of the obesity (hyperplastic or hypertrophic). The hyperplastic obese individual (many smaller adipocytes) would have greater trouble, since the &4/13V for a given reduction in adipose mass would be greater in these individuals than the hypertrophic obese (fewer, larger adipocytes) and any signal would be multiplied by virtue of increased cellularity. Thus, any degree of weight reduction would be associated with a louder peripheral mass reduction “hunger” signal in the hyperplastic as opposed to the hypertrophic obese individual. 6. Catch-up Growth Presumably, this same “ponderostat” system could be used to determine when and to what degree catch-up growth was necessary. Sensing a reduction in fat cell total surface area versus the biologically coded norm for chronologic age, augmented eating behavior would be employed to provide the substrates for accelerated growth. No primary endocrinologic changes would be necessary. So-called “critical periods”, that is, growth periods during
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which caloric deprivation leads to permanent stunting of stature and/or weight (Prader et al., 1963 ; Tanner, 1963 ; Widdowson & McCance, 1975), would result from a permanent disruption (downward resetting) of the sizing mechanism by impact on the CNS sensing device and/or the peripheral signal source. 7. Menarche Finally, menarche, shown by Frisch & McArthur (1974) to be weight (first order) or percent body adiposity (second order) related, could be regulated by the same system. The signal for the achievement of appropriate adiposity could be provided by the mechanisms described earlier. The variance in percent adiposity at menarche noted by Frisch & McArthur could be the result of variable adipose cell size and number producing a relatively constant (for biologic age) total adipose tissue surface area.
8. Summary In summary, the divergence of the adipose signal from an age-appropriate norm could influence “ponderostat” activity and in turn brain centers mediating appetitive and various endocrine systems. Total caloric intake and the timing of this intake with respect to somatic maturity appear to affect adipose cell volume and number respectively (Lemonnier, 1972; Knittle & Hirsch, 1968; Brook, 1972). If shifts in adipose surface area provide a signal source regarding organismic mass, and if this surface area reflects the quantity and chronology of antecedent nutritional events, there are obvious implications for the role of nutrition during “critical periods” in the operation of long-term homeostatic (appetite, growth) and reproductive functions. This hypothesis, that total adipose cell surface area controls the peripheral signal used in the mammal to determine its “mass” and that this information is used to mediate appetite control, menarcheal timing, and catch-up growth, is testable even in the absence of knowledge of the “signal” utilised by this system.-f7 Easiest to study in this regard would be the following. 1. Results of expiration of adipose tissue (inguinal fat organ and gonadal fat organ) in rats rendered obese from force feeding or insulin administration. 2. Results of supetnumery adipose transplants of varying cellular size and number in animals made underweight by starvation. 3. Effects of adipose extirpation on rat estrus. 4. Effects of adipose transplants of varying cellular size and number on the timing of estrus in rats.
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