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Growth factors, feeding regulation and the nervous system
Life Sciences, Vol. 45, pp. 1207-1217 Printed in the U.S.A.
G R O W T H FACTORS,
Pergamon Press
MINIREVIEW FEEDING REGULATION AND THE NERVOUS SYSTEM
Carlos
R.
D e p a r t m e n t of P s y c h o l o g y U n i v e r s i t y of D e l a w a r e ,
Plata-Salaman
and I n s t i t u t e for N e u r o s c i e n c e , Newark, D e l a w a r e 19716, U.S.A.
(Received in final form July 24, 1989) S-mmary
A variety of growth factors and their receptors are present in the nervous syst~n. Growth factors can modulate specific nervous system functions others than those related to growth, development, and tissue repair. The presence of growth factors in the brain and cerebrospinal fluid is the result of local synthesis (by neuronal, glial, vascular, and mononuclear phagocyte components), and uptake from the peripheral blood through the blood-brain barrier (in specific cases) and circumventricular organs. This paper focuses on the effects of a heterogeneous group of growth factors (acidic and basic fibrcblast wzowth factors, insulinlike ~ z ~ t h factors, epidermal growth factor, platelet-derived factor, interleukin-1 and others) on the central nervous system (flUS), in particular, on feeding regulation. Recent evidence supporting participation of growth factors in the regulation of feeding by a direct action at the level of the CNS is reviewed. Various growth factors have the ability to suppress short- and long-term food intake (FI), whereas others affect only short-term FI, or do not affect FI. Acute and chronic pathological processes stimulate the synthesis and release of growth factors in various cellular systems, and monitoring of growth factors by the CNS could be part of the regulatory signals that induce FI suppression frequently accompanying acute and chronic disease. Thus, it is proposed that a system regulating FI through growth factor-dependent mechanisms may be operative during specific physiological or pathological conditions. Introduction Feeding behavior is regulated by complex mechanisms involving humoral and neuronal factors. A variety of neuroregulators (neurotran~nitters and neuromodulators) have been implicated as feeding modulators. Neuroregulators which have been found to suppress feeding cc~prehend: i) neurotransmitters including epinephrine (I), serotonin (2,3), and dopamine (3); ii) hypothalamic and hypoph~ seal peptides including corticotropin-releasing hormone (3), thyrotropin-releasing hormone (3), and scmatostatin (3); iii) gut-brain peptides including cholecystokinin (3,4,), insulin (5-7), glucagon (3), bombesin (3), vasoactive intestinal peptide (3), and neurotensin (3,8); iv) other peptides including calcitonin (9,10 ), calcitcnin gene-related peptide (3) and satietin (3) ; v) other endogenous non-peptide substances such as prostaglandins (3 ), purines (3 ), and organic acids (11 ). On the other hand, neuroregulators which have been found to facilitate 0024-3205/89 $3.00 + .00 Copyright (c) 1989 Pergamon Press plc
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feeding include norepinephrine (3 ), dopamine (low doses ) (3 ), pro-opiomelanocortin derivatives and other endogenous opioids (3,4,12 ), neuropeptide Y (3 ), galanin (3), and growth hormone-releasing factor (3). Recent studies indicate that various growth factors also modulate feeding by a direct action in the CNS (13-18). Growth factors are heterogeneous substances, which are typically peptides, that coordinate different aspects of the cell growth, proliferation, differentiation and morpho-functional maintenance by inducing replicative DNA synthesis and cell division (19). A multi-interaction of growth factors is required for the normal and neoplastic cells to progress through the cell cycle (20,21). Growth factors can act in an autocrine manner (on the same cell that produces them) and/or paracrine manner (on neighbor cell.~ and/or endocrine manner (on distant target sites)(22) via specific receptors present at the target cells. A variety of growth factors are present in the C~qS due to local synthesis and/or uptake from the peripheral circulation (transcytosis through the bloodbrain barrier and uptake and transport across the circumventricularorgans, 22). Growth factors acting as neuroregulators can specifically regulate a wide variety of CNS functions. This paper focuses on the effects of various growth factors on the CNS, in particular, on feeding regulation; evidence supporting participation of growth factors in the regulation of feeding is summarized, m e discussion presented here also proposes that growth factors released during acute and chronic diseases may be part of the regulatory signals that induce FI suppression during disease, by a direct action in specific CNS target sites. Fibroblast
growth
factor
(FGF)
FGF is a potent mesodermal cell mitogen (23) which has been identified throughout the nervous system of various mammals (24,25). Two forms of FGF, acidic and basic, have been purified, their amino acid sequences determined and their cDNAs cloned and sequenced (23,26-28). Acidic and basic FGFs are two related peptides with a 53% absolute homology (27) and similar range of biological activities (29). A c i d i c FGF (aFGF) aFGF is a polypeptide composed of 140 amino acids (MW of about 16,000)(27) which has been isolated from neural tissues including whole brain, hypothalamus and retina (23,26,30,31). Brain-derived aFGF acts as a survival and neurotrophic agent for central and peripheral neurons (23,29,32-36), and exhibits mitogenic activity for glial and vascular cells (23,37,38). These evidences suggest a role of aFGF in fINS development (39,40); aFGF stimulates angiogenesis (38) and may participate in tissue repair since aFGF has a potent chemotactic activity for fibroblasts and astrocytes. Evidence shows that aFGF acts directly in the CNS to suppress FI. A phasic aFllF-like activity increase is detected in the cerebrospinal fluid (CSF)of rats after feeding (16,17 ), or after an intraperitoneal (IP) administration of glucose (16,41). The intracerebroventricular (ICV) administration of aFGF (106 and 220 ng/rat) suppresses the 2 hr (short-term, from 2000 to 2200 hr) and night-time (long-term, from 2000 to 0800 hr) FI (16,41). Daytime FI increases suggesting compensation for the previous night-time FI decrease. ICV administration of inactivated aF(~ and IP administration of aFGF in doses equivalent to or higher than those administered centrally have no effect on FI (16,41). Electrophysiological studies in the lateral hypothalamic area (LHA), an important site for the regulation of feeding, have shown that electrophoretically applied aFGF specifically suppresses the neuronal activity in 75% of the glucose-sensitive neurons tested, but has little effect on glucose-insensitive neurons (16,41). This evidence supports that aFGF acts directly and specifically in the C~qS to suppress FI.
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The participation of hypothalamic feeding-associated sites in the suppression of FI by aF(~ may interact with other factors. For example, plasma concentrations of glucagon, insulin, and calcitonin --factors which suppress FI (3,6,7,9,10)--and CSF concentrations of aFGF change dynamically during and after feeding (I 6,17 ). This may indicate a hormonal interaction inducing satiety. The increase of aFGF in the CSF after feeding might also participate in other processes such as cerebral arteriosclerosis (42), since aFGF is a potent angiogenic factor stimulating mitosis for endothelial and vascular smooth muscle cells (23,38,43). B a s i c FGF (bFGF) bFGF is a polypeptide ~ s e d of 146 amino acids (MW of about 16,000)(23, 44 ) which has been isolated from neuro-endocrine tissues including whole brain, pituitary and retina (23,29); bFGF has also been isolated from other tissues and cell components such as adrenal glands, macrophages, thymus, and endothelial cells (23). Brain-derived bFGF is of neuronal (25,45) and glial (46) origin. Binding sites and specific receptors for bFGF on neuronal and glial ccmponents have been identified (47-49). Similar to aFGF, bFGF acts as a survival and neurotrophic agent for central and peripheral neurons (29,33-35,50-53), and exhibits mitogenic activity for glial and other cells (23); bFGF also stimulates angiogenesis (23, 29 ), and may participate in the homeostatic mechanisms that regulate the secretion of prolactin and thyrotropin (54). Evidence shows that bF(~ acts directly in the CNS to suppress FI. ICVadministration of bFGF (25 to 250 ng/rat) suppresses the 2 hr and night-time FI, whereas daytime FI increases (1 3). ICV administration of inactivated bFGF and IP administration of bFGF in doses higher than those administered centrally have no effect on FI (13 ). f~ronic ICV administration of bFGF from osmotic minipL~ps (30 ng/rat/24 hr) had no significant effect on night-time or daytime FI (13). On the basis of the amino acid homology between ~ and bFGF (27), bFGF may modulate hypothalamic feeding-associated sites to suppress feeding. Interleukin-1 (an i m m o l a t o r with growth-promoting activity)(14) also shows a sequence homology with aFGF and bFGF of about 27% (27,37,55), and interleukin-1 also suppresses FI by a direct and specific action in the ~ (14 ). Insulin-like
growth
factors
(IGFs)
There are two molecular forms of IGFs: somatomedin-C/IGF-I or IGF-I and IGF-II. IGF-I is a peptide ~m,posed of 70 amino acids (MW of 7649)(22,56,57), and IGF-II is composed of 67 amino acids ( ~ of 7471)(58). The sequence homology between IGF-I and -II is 62% and both IGFs have a high structural homology with pro-insulin (22). The liver is the major source of IGFs (22). IGF-I and -II have also been isolated from the nervous system (22,59); a variant form of IGF-I is present in the human brain (60,61), and mRNA for IGF-I is synthesized by embryonic neurons and glia throughout the nervous system (62). IGF-II has alsoobeenisolated from the human brain (60,61,63) ; thehypothalamus contains high concentrations of IGF-II (18,63) and evidence indicating C~qS synthesis of IGF-II include the presence of IGF-II mRNA in the brain (22,62-64). IGF-I and -II have also been detected in the CSF (22,65), and specific receptors for IGF-I and -If have been localized in specific brain sites (22). In the nervous system, IGF-I and -II participate in the neuronal and glial precursor cell division (22) enhancing cell replication, differentiation and neurite outgrowth (22) as well as neuronal survival (22 ). Evidence shows that IGF-II acts directly in the CNS to suppress FI. Initial studies reported that ICV administration of a preparation enriched of IGFs suppressed 24 hr FI (66). In more recent studies, ICV administration of purified IGF-II (33 to 300 ng/rat) dose-dependently suppressed 24 hr FI (18), whereas IGF-I had no effect on FI (18). In the same study, IGF-II but not IGF-I was
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localized in hypothalamic areas usually associated with FI regulation (18 ). Thus, IGF-II may contribute to the regulation of FI, but the action mechanism(s) and interaction with other satiety signals are unknown. It is established that IGFs and their receptors are under nutritional regulation (22,67) suggesting that circulating nutrients may act as signals for (]qS synthesis and/or release of IGFs. This nutritional regulation may be a determinant of a direct IGF-II modulation of feeding. In general, i n s u l i n and IGFs exert the same biological effects at appropriate concentrations (22). The major difference is that, insulin is more potent in affecting metabolic events, whereas IGFs are more potent in growth-promoting activity (22). Insulin also acts as a short- and long-term feeding modulator (6). Endogenous insulin is released prior to meal initiation, before absorption of nutrients and during feeding (6); CSF insulin content also changes during normal meals. A~ninistration of high doses of insulin increases FI due to hypoglycemia and other metabolic effects (6), whereas chronic ac~ninistration of small amounts of insulin suppresses FI by direct action in the fINS (5,6). Insulin also interacts with other satiety factors to suppress FI (6), and insulin andits receptors are present in brain areas important in the control of FI (6). Several action mechanisms of insulin on FI regulation have been proposed (6), and it has also been suggested that a malfunction of the brain-insulin regulatory system may participate in some types of obesity. Epidermal
9rowth
factor
(EGF)
EGF (urogastrone) is a peptide composed of 53 amino acids (MW of 6045)(68). EGF has been isolated from the CNS (69-71) and CSF (68). EGF is synthesized in the QqS as has been demonstrated by immunocytochemical studies (69,79 ) and by the presence of EGF mRNA in the C~qS (80,81). EGF immunoreactive neurons (71,82) and specific EGF receptors (82-86) are widely distributed in the CNS. EGF acts as a mitogen for glial cells (68,72-74) and survival and neurotrophic (75-77) as well as morphogenic (78) agent. Effects induced by EGF through a CNS modulation include: inhibition of gastric acid secretion (68,87,88), regulation of growth hormone secretion (89), protein phosphorylation (90) and other actions (91,92). Evidence shows that EGF acts directly in the C~qS to suppress FI. Administration of EGF sustaining its pla~na concentrations at about 20 ng/ml Dr exceeding this) for 1 5 t o 2 4 h r resulted in a suppression of FI in sheep (93). More recent studies show that ICV administration of EGF (100 and 200 ng/rat) suppresses the 2 hr, night-time and total daily FI, whereas daytime FI does not change or increase (13 ). ICV ac~ninistration of inactivated EGF and IP ac~ninistration of EGF in doses higher than those administered centrally have no effect on FI (13). The action mechanism of EGF suppressing FI is unknown. However, an increase in the circulating levels of somatostatin (93)and changes in calcium regulation (94) have been observed after peripheral administration of EGF; these effects may participate in the FI suppression by EGF since somatostatin and calcium changes have been shown to suppress FI (3,95). Platelet-derived
growth
factor
(PDGF)
PDGF is a protein consisting of two disulphide linked chains (A and B) of about equal size (MW of about 30,000)(96,97). PDGF is synthesized in platelets, stored in the alpha granules and released in conjunction with the plateletrelease reaction (96,97); PDGF is also synthesized in endothelial cells and mononuclear phagocytes (monocytes/macrophages)(96,97,105), as well as in a variety of transformed cells (106). PDGF exhibits mitogenic and chemotactic activity for glial and other cells (98-104), and it is proposed that PDGFparticipates in embryogenesis, growth and development (100), in wound healing (97) and reactive
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gliosis (101), and in the pathogenesis of arteriosclerosis (96,105-107). Evidence shows that PDGF may act directly in the CNS to modulate short-term FI. ICV administration of PDGF (0.8and I .2 ng/rat) suppresses only the shortterm (2 hr) FI (13). IPadministration of PDGF in doses higher than those administered centrally has no effect on FI (13). C~-x~lic ICV administration of PDGF from osmotic minipLmps (0.8 and I .5 ng/rat/24 hr) had no significant effect on night-time or daytime FI (1 3). Transforming
growth
factors
(TGFs)
TGFs are polypeptides that have a high ability to induce acute phenotypic transformations in several normal cells (108,109 ). Tnere are two molecular forms of TGFs: TGF-alpha which binds to the EGF receptor with high affinity and is composed of 50 amino acids (M~ of about 6000~I09-111), and TGF-beta which does not bind to the EGF receptor, is not structurally related to TGF-alpha, and is composed of a dimer constituted by two identical chains of 112 amino acids (MW of about 25,000)(109,110,112). TGF-alpha immunoreactive cell bodies (113) and TGF-alpha mRNA have been identified in the rat brain (114). TGF-beta is also synthesized in the CNS by normal (108)andneoplastic (115)cells, although the major source of TGF-beta is the alpha granules of platelets (116). TGF-beta controls proliferation, differentiation and other functions in normal and neoplastic cells (I 17); it may function as a mediator of inflammation and repair (110 ) and as a stimulator of angiogenesis (110), since TGF-beta is released frcm platelets (11 0 ), activated macrophages (110 ), and T-lymphocytes (118 ). Evidence shows that TGF-beta does not affect short- or long-term FI after ICV administration (14). The effect(s) of TGF-alpha on FI is not known. However, TGF-alpha is about 40% homologous to EGF (111,11 9) and TGF-alpha produces the same biological signals in target cells as EGF (111); these signals are mediated through the EGF receptor (111,120). These similarities between TGF-alpha and EGF indicate that these peptides possess a similar mechanism(s) of action dependent on an hcmologous region, probably also inducing a FI suppression. Nerve
growth
factor
(NGF)
NGF is an oligcmeric protein cc~plex consisting of three subunits: alpha-2, beta and gamma (MW of about 130,000)(121); the beta-subunit (a dimer of two chains of 118 amino acids) exerts biological activities (121). NGF is synthesized by the target organs innervated by sympathetic and sensory neurons, taken up by these neurons and transported retrogradely to their cell bodies (122,123); NGF is essential for the survival and maintenance of these sympathetic and sensory neurons (122-124). In the C~S, astrocytes are able to synthesize NGF (125); NGF mRNA has been found in specific brain regions (122). Target cells for NGF in the CNS include cholinergic, adrenergic, indoleaminergic, and peptidergic neurons (123,124). Preliminary studies show that NGF does not affect FI. ICV administration of NGF (100 to 200 ng/rat) does not significantly affect short-or long-term FI (I 3). Immunomodulators
Various peptide immunomodulators have growth factor activity. The immune system and its immunoactive humoral cc~ponents can modulate specific nervous system functions; in particular, immunopeptides (which are synthesized and released in the immune and nervous systems and are referred as immuno-neuromodulators) provide the basis for this immuno-neuro communication (13-15).
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A typical example of these immunomodulators-growth factors is interleukin-1 (IL-I). IL-I is present in two molecular forms, IL-I~ and IL-I~ (126). IL-I~ consists of 159 amino acids (MW of about 17,500) and IL-I~ of 153 amino acids (MW of about 17,500 )(126,127). IL-I~ and IL-I~ induce similar biological effects on a wide variety of systems (127). IL-I participates in the activation and differentiation of lymphocytes (129), and induces specific effects in the CNS (14). IL-I is produced by phagocytes, lymphocytes, brain (by astrocytes, microglia, endothelial cells and intrinsic macrophages) and other cells (14,127,128, 130,131 ). Evidence shows that IL-I~ acts directly in the CNS to suppress FI. ICV administration of IL-I~ (I .0 to 13.0 ng/rat) suppresses 2 hr, night-time and total daily FI, dose-dependently, whereas daytime FI increases (14). ICV administration of inactivated IL-I~ and IP administration of II,-1@ in doses equivalent to or higher than those administered centrally have no effect on FI (1 4). The FI suppression induced by IL-I~ is a result of a direct effect in the C~qS; electrophysiological studies show that electrophoretically applied IL-I~ specifically suppresses the neuronal activity of the glucose-sensitive neurons in the IBA (14 ). Based on amino acid and carboxyl terminal sequence data, it has been shown that a sequence homology exists between IL-I~ and aFGF or bFGF (approximately 27% and 25%, respectively)(27,37,55). The similarities between IL-I~, ~ and bFGF in amino acid sequence, biosynthesis in brain, effects on FI and on LHA, and other CNS functions may indicate that these peptides possess a similar mechanism(s) of action or function dependent on a specific homologous region present in all three peptides. For a more detailed description about immunomodulators and feeding regulation see ref. 13-15. Growth factors r feedin 9 regulation integrative view
and
the n e r v o u s
system:
An
Several points arise from the discussion concerning growth factors, feeding regulation and the nervous system: I) A system regulating FI by direct action of growth factors in the CNS is proposed. The presence of growth factors in the CNS is due to the contribution of local synthesis by neuronal, glial, vascular, and mononuclear phagocyte cc~ponents, and uptake from the peripheral circulation. Various growth factors (e.g., EGF, aFGF, bFGF, and PDGF) which are effective in the rat also suppress the feeding response of the hydra (a freshwater coelenterate) (1 6, 132); thus, this postulated system modulating FI might be operant frfxn lower invertebrates (hydra) to mammals (rat). 2) The specificity of action of growth factors suppressing short- and long-term FI after exogenous administration in the rat is suggested because: i) ICV administration of inactivated growth factors has no effect on FI (13-15); ii) FI is suppressed only during the night-time (i.e., during the period of physiologic hyperphagia in the rat), whereas it does not change or increase during the daytime; iii) peripheral administration of growth factors in doses equivalent to or higher than those administered centrally have no effect on either short- or long-term FI (1 3-1 5 ). The fact that FI suppression is observed only after ICV administration of grc~4th factors and not after peripheral administration indicates an effect in the CNS and not in the periphery; iv) some growth factors do not affect FI (13,14), whereas others affect only shortterm FI (13) ; v) different growth factors have different potencies suppressing FI (13,14); vi) a decrease in food-to-water intake ratios (14) and no alteration of the dipsogenesis induced by angiotensin II (I 4) suggest that a modification in water intake after ICV interleukin-1 administration is a result of prandial drinking; vii) as described previously, a variety of specific responses in the CNS are induced by growth factors.
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3) Xhe action mechanism of growth factors suppressing FI involves the hypothalamic feeding-associated sites (1 3-17,41 ). Electrophysiological studies show that one mechanism by which various growth factors suppress FI involves a specific and direct inhibition of the glucose-sensitive neurons in the LHA (considered as a "hunger center")(14,16,41 ). Tne feeding patterns induced by these growth factors are also consistent with this action mechanism on I~HA. At present it is unknown whether other mechanisms also participate in the FI suppression induced by growth factors. 4) The effect of some growth factors (e.g., bFGF) de not show a dose-response pattern (6,13), i.e., the decrease of FI by a growth factor diminishes at higher concentrations suggesting desensitization, and/or activation of other neural system(s) within the brain with increased concentrations, and/or a negative cooperation to maintain peptide sensitivity at low concentrations, but attenuation of responses to higher concentrations. 5) The doses of growth factors administered ICV are estimated not to be out of the predicted concentrations (in specific brain target sites/areas) occurring in some physiological or clinical conditions (6,13-16). 6) Since various growth factors which affect FI are released together under specific conditions, an interaction of growth factors modulating FI might be a plausible possibility. 7) Acute and chronic pathological processes stimulate the synthesis and release of growth factors in various cell systems. Monitoring of growth factors by the CNS could be part of the regulatory signals that induce FI suppression frequently accompanying acute and chronic disease. Examples of growth factor production during disease include: i) mononuclear phagocytes (monocytes/ macrophages) which synthesize and release bFGF, IGF-I, EGF, PDGF, TGF-beta, IL-I and other immunomodulators during chronic inflammatory processes (14,29, 100,133). The CNS also contains blood-derived and intrinsic mononuclear phagocytes (134,135) and T-lymphocytes (15) which serve as a link between the immune and nervous systems; ii) immune and nervous system cells which synthesize and release a variety of ~ l a t o r s (which suppress FI)(14, 15) during infection, injury, toxins, inrm/nological reactic~s, malignancy and inflammatory processes (14,15,128,129 ) ; iii ) stimulated platelets which release various growth factors contained in the alpha granules including bFGF, EGF, PDGF, and TGF-beta (96,97), and increasing evidence supports a role of platelets in acute inflammation; iv) various t~nor cell lines which have the ability to synthesize and release bFGF (e.g., neuroblastoma, hepatoma, m e l ~ , chondrosarooma and rhabdc~yosarcoma) (23,29), and/or PDGF (e.g., neuroblastoma, gliema, bepatema, teratocarcinoma, osteosarcoma and rhabdomyosarcoma)(97,100). EGF is also involved in carcinogenic processes; increased EGF immunoreactive concentrations (136) and increased EGF receptor concentrations (137-141) have been observed in various brain tumors, e.g., glioblastoma multiforme (malignant astrocytoma grade IV, a very aggressive cancer of the CNS)(136). It has also been demonstrated that EGF potentiates chemical and viral transformation (142), and induces cytogenetic alterations (143) and proliferative responses (139,140). EGF is also increased in other neurological diseases (141 ). Thus, FI suppression by growth factors by direct action in the C~S may be operant during acute and chronic disease. In the case of infection, a reduction of the availability of nutrients essential to the growth of pathogenic organisms (I 44 ) might be one of the biological roles of the FI suppression induced by immunomodulators-growth factors (14,15).
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References I. V. HINTON, M. ESGUERRA, N. FARHOODY, J. GRANGER and N. GEARY, Physiol. Behav. 40 109-115 (1987). 2. J. PANKSEPP, P. BISHOP and J. ROSSI III, Psychoneuroendocrinology, 4 89-106 (1979). 3. J.E. MORLEY, Endocr. Rev. 8 256-287 (1987). 4. C.A. BAILE, C.L. MclAUGHLIN and M.A. DETIA-F~RA, Physiol. Rev. 66 172-234 (1986). 5. S.C. WOODS and D. PORTE Jr, Adv. Metab. Disord. 10 457-468 (1983). 6. C.R. PLATA-SALAMAN, Y. OOMURAandN. SHIMIZU, Physio-~. Behav. 37 717-734 (1986). 7. C.R. PLATA-SALAMAN and Y. OCMURA, Physiol. Behav. 37 735-739 (1986). 8. M.F. HAWKINS, Physiol. Behav. 36 I-8 (1986). 9. C.R. PIATA-SALAMAN and Y. OOMURA, Physiol. Behav. 40 501-513 (1987). 10. C.R. PLATA-SAIAMAN and Y. ~ , Physiol. Behav. 40 515-521 (1987). 11. C.R. PLATA-SALAMAN, Y. 00MURA and N. SHIMIZU, Physiol. Behav. 38 359-373 (1986). 12. A.S. LEVINE and R.L. ATKINSON, Fed. Proc. 46 159-162 (1987). 13. C.R. PLATA-SALAMAN, Neurosci. Lett. 94 161-166 (1988). 14. C.R. PLATA-SAIAMAN, Y. OOMURA and Y. KAI, Brain Res. 448 106-114 (1988). 15. C.R. P L A T A - S ~ , Neurosci. Res. C~mr,~n. 3 159-165 (1988). 16. K. HANAI, Y. OOMURA, Y. KAI, K. NISHIKAWA, N. SHIMIZU, H. MORITA and C.R. PLATA-SAIAMAN, Am. J. Physiol. 256 R217-R223 (1989). 17. C.R. P I A T A - S ~ , Y. OOMURA, and K. HANAI, J. Physiol. Soc. Jpn. 49 418 (1987). 18. T.J. IAUTERIO, L. MARSON, W.H. DAUGHADAY and C.A. BAILE, Physiol. Behav. 40 755-758 (1987). 19. E. ROZENGURT, Science 234 161-166 (1986). 20. D.T. G~AVES, A.J. ~ and H.N. ANXONIADES, Cancer Res. 43 83-87 (1983). 21. J.M. ROWE and H.G. FRIESI~q, Rev. Endocrinol. Rel. Cancer 18 27-35 (1984). 22. Y. ~ and C.R. PLATA-SALAMAN, Insulin, Insulin-like Growth Factors, and their Receptors in the Central Nervous System, p. 215-244, Plenum Press, New York (1987). 23. D. GOSIK)ID}~0WICZ, G. NEUFELD and L. S(]{WEIGE~RER, Mol. Cell, Endocrinol. 46 187-204 (1986). 24. A. LOGAN and S.D. ~ , Neurosci. Lett. 69 162-165 (1986). 25. T. JANET, C. ~ , B. PETPMANN, K. UNSIf~
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38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76.
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J. RODKEY and S. FITZPATRICK, Proc. Natl. Acad. Sci. U.S.A. 8__226409-6413 (1985). J. FOIZMAN and M. KLAGSERUN, Science 235 442-447 (1987). C.G. CADAY, A. MIRZABEGIAN, J. PROSSER, M. KLAGSE~rUN and S.P. ~ . ~ ' P E ~ , Soc. Neurosci. Abst. 14 363 (1988). G. FE~RARI, M.-C. MINOZZI, C. SORANZO, G. X I ~ A N O and S.D. SKAPER., Soc. Neurosci. Abst. 14 301 (1988). C.R. PLATA-SALAMAN, K. HANAI, Y. OOMURA and Y. KAI, Jpn. Neurosci. Soc. 138 2C07 (1987). R. ROSS, Acta Meal. Scand. Suppl. 715 33-38 (1987). J. FOLKMAN and M. KLAGSBRUN, Nature 329 671-672 (1987). F. ESC~q, A. BAIRD, et.al., Proc. Natl. Acad. Sci. U.S.A. 82 6507-6511 (1985). B. PETIMANN, G. IABOURDETrE, M. WEIRI~. a n d M. S ~ N ~ , Neurosci. Lett. 68 175 (1986). M.E. HAR'I~, M. LYNCh, J. JOSEPH-SILV~RSTEIN, D. MOSCATELLI and D.B. RIFKIN, Soc. Neurosci. Abst. 13 194 (1987). P.A. WALICKE, Soc. Neurosci. Abst. 13 1605 (1987). P.A. WALICKE, J.J. FEIGE and A. BAIRD, Soc. Neurosci. Abst. 14 364 (1988). W.F. HERRTJN, R.G. KRAUSE and J.S. SC~WABER, Soc. Neurosci. Abst.14 104(1988). R.S. MORRISON, A. SHARMA, J. De VELLIS and R.A. ~ W , Proc. Natl. Acad. Sci. U.S.A. 83 7537-7541 (1986). J.L. McMANAMAN, F.G. CRAWFORD, J.O. RIC~KER and R.C. CLARK, Soc. Neurosci. Abst. 14 686 (1988). D.L. NEEDEI~ and C.W. COTMAN, Soc. Neurosci. Abst. 14 363 (1988). K.J. ANDE~ON, D. DAM, S. LE~ and C.W. Cl)TMAN, Nature 332 360-361 (1988). A. BAIRD, P. MORMEDE, et al. Proc. Natl. Acad. Sci. U.S.A. 82 5545-5549(1985). G. GIMENEZ-GALLEGO, J. RIMDKEY, C. ~ , M. R I O S - C A N D ~ , J. DiSALVO and K. THOMAS, Science 230 1385-1388 (1985). J. ZAPF, C.H. SCHMID and E.R. FROESC~, Clin. Endocrinol. Metab. 13 3-30(1984). J.J. Van WYK, Human Proteins and Peptides, Academic Press, New York (1984). L.E. UNDERWOOD, et al., Clin. Endocrinol. Metab. 15 59-77 (1986). T. NCK~JC~I, L.M. KURATA and T. SUGISAKI, Neuroendocrinology 46 277-282(1987). V.R. SARA, et al., Proc. Natl. Acad. Sci. U.S.A. 83 4904-4907 (1986). C. ~ - S K W I R U T , et al., FEBS Lett. 201 46-50 (1986). P. R ~ I N , S.K. BURGESS, J.D. MILBRANDT and J.E. KRAUSE, Proc. Natl. Acad. Sci. U.S.A. 85 265-269 (1988). G.K. HASEL~ACHER, M.E. SCHWAB, A. PASI and R.E. HL~4BEL, Proc. Natl. Acad. Sci. U.S.A. 82 2153-2157 (1985). P.K. LUND, et al., J. Biol. C ~ . 261 14539-14544 (1986). F. S T Y L I ~ , J. HERBERT, M.B. SOARES and A. EFSTRATIADIS, Proc. Natl. Acad. Sci. U.S.A. 85 141-145 (1988). G.S. T ~ U M , H.J. ~JYDA and B.I. POSNI~R, Science 220 77-79 (1983). N.J. ~ , E.S. CORP, B.J. WILCOX, D.P. F I ~ C Z , D.M. DORSA and D.G. BASKIN, Endocrinology 122 1940-1947 (1988). G. CARP~VPER, J. Cell. SC±. Suppl. 3 1-9 (1985). J. LAKSHMANAN, W.E. WEIC~SEL Jr. and D.A. FISHER, J. ~ . 46 10811085 (1986). R.S. MORRISON, R. KEATING, V.K. £%F~HANE and J.R. MOSKAL, Neuroscience 22 $280 (1987). R.P. SC~AUDIES, E.L. CHRISTIAN and CoR. SAVAGE Jr., Fed. Proc. 461995(1987). D.L. SIMPSON, R. MORRISON, J. De Vk~.T.IS and H.R. ~ , J. Neurosci. Res. 8 453-462 (1982). B. WESTERMARK, A. MAGNUSSON and C.H. ~ I N , Prog. Clin. Biol. Res. 118 491-507 (1983). P. HONEGGER, M. TE~K~T and M. JORDI, Neuroscience 22 $279 (1987). P.A. ~ , D.J. G~JNq~3N and D.H. SILBERBERG, Dev. Neurosci. 7 308-322 (1985). G. AI/MAZAN, P. ~ , J.-M. MAXR'HI~3 and B. ~ - I A U B E R , Dev. Brain Res. 21 257-264 (1985).
1216
Growth Factors and Feeding
Vol. 45, No. 14, 1989
77. R.S. MORRIS~N, H.I. KORNBLUM, F.M. LESLIE and R.A. BRADSHAW, Science 238 72-75 (1987). 78. C.A. ERICY~SON and E.A. ~ , Exp. Cell Res. 169 267-279 (1987). 79. J.H. FALL~, K.B. SE~KX)GY, S.E. LOUf~K~IN, R.S. MO~ISON, R.A. BRADSHAW, D.J. KNAUER and D.D. CUNNING~I~M, Science 224 1107-1109 (1984). 80. L.G. RALL, J.SOOTP, G.I. BELL, et al., Nature 313 228-231 (1985). 81. L.M. lAZAR, J.L. ROBERTS and M. BLUM, Soc. Neurosci. Abst. 14 1162 (1988). 82. R. LOY l J.E. SPRINGER and S. KOH, Soc. Neurosci. Abst. 13 575 (1987). 83. F.M. LESLIE t R.S. BROIDE, K.P. CAVANAU~, R.A. BRADSHAW and J.H. FALLON, Soc. Neurosci. Abst. 13 1604 (1987). 84. M. NIETO-SAMPEDRO, F. GOMEZ-PINILLA and D.J. KNAUER, Neuroscience 22 Suppl. $279 (1987). 85. K.HUFF, L.IBRIC and L. SCHULTZ, Soc. Neurosci. Abst. 13 1365 (1987). 86. C. HERTEL, S.J. COULTER and J.P. PERKINS, J. Biol. Chem. 260 12547-12553(1985). 87. A.M. SODERQUIST and G. CARPE~WTER, Fed. Proc. 42 2615-2620 (1983). 88. H. GREGORY, J. Cell Sci. Suppl. 3 11-17 (1985). 89. J.-G. CHAHOT, P. W ~ and G. P~J.ETIER, Peptides 7 45-50 (1986). 90. J.R. MOSKAL and R.S. MORRISON, Soc. Neurosci. Abst. 14 362 (1988). 91. I. TAKAYANAGI, J. Pharm. Pharmacol. 32 228-230 (1980). 92. H.R. ~ , R. GOODMAN, C. C~9~NDLER, D. SIMPSON, D. CAWLEY, R. COLE and J. De VELLTS, Nervous System Regeneration, pp. 79-94, Alan Liss, New York (1 983 ). 93. B.A. PANARETI~, G.P.M. MOORE and D.M. ROBERTSC~, J. Endocrinol. 94 191(1982). 94. G.P.M. MOORE, M. WILKINSON, B.A. P ~ , L.W. Dk~.~RIDGE and S. POSEN, Endocrinology 118 1525-1529 (1986). 95. R.D. MYERS, T.F. LEE and S.E. KING, Brain Res. 266 178-181 (1983). 96. J. NILSSON, Atherosclerosis 62 185-199 (1986). 97. B. WESTERMARK and C.-H. HE[~IN, Acta Med. Scand. 715 19-23 (1987). 98. H.N. ANTONIgH)ES and L.T. WILLIAMS, Fed. Proc. 42 2630-2634 (1983). 99. J.P. BRESSLER, G.R. GROT~kKXgRST, C. LEVITOV and L.M. ~ , Brain Res. 344 249-254 (1985). 100. R. ROSS, Annu. Rev. Med. 38 71-79 (1987). 101. F. BESNARD, F. PERRAUD, M. S~SEI%~E~[ER and G. LABOURDETrE, Neurosci. Lett. 73 287-292 (1987). 102. T. KOSCHINSKY, C.E. BL%rfING, R.RUTYER and F.A. GRIES, Diab. Metab. 13 318-325 (1987). 103. W.D. RICHARDSON, et al., Cell 53 309-319 (1988). 104. M. NOBLE, K. MURRAY, P. STROOBANT, M.D. WATERFIELD and P. RIDDLE, Nature 333 560-562 (1988). 105. R. ROSS, Acta Med. Scand.715 33-38 (1987). 106. H.R. BAUMCgLRTNER and M. HOSANG, Experientia 44 109-112 (1988). 107. B.C. BERK, R.W. ALEXANDER, T.A. BROCK, M.A. GIBRONE Jr. and R.C. WI~B, Science 232 87-90 (1986). 108. A.B. ROBerTS, M.A. ANZANO, L.C. LAMB, J.M. SMITH and M.B. SPORN, Proc. Natl. Acad. Sci. U.S.A. 78 5339-5343 (1981). 109. R. GOL-WINKLER, Clin. Endocrinol. Metab. 15 99-115 (1986). 11 0. M.B. SPORN, A.B. ROBERTS, L.M. WAKEFIELD and B. De CRflMBRUGGHE, J. Cell Biol. 105 1039-1045 (1987). 111. G. CARPENTER, Annu. Rev. Biochem. 56 881-914 (1987). 112. J. MASSAGUE, Cell 49 437-438 (1987). 113. R.A. CODE, K.B. SEROOGY and J.H. FAIH/)N, Brain Res. 421 401-405 (1987). 114. D.C. LEE, T.M. ROSE, N.R. WEBB and G.J. TODARO, Nature313 489-491 (1985). 115. W.C. CLARK and J. F~.ESSLER, J. Neurosurg. 68 920-924 (1988). 116. R.K. ASSOIAN, K. KC~ORIYA, C.A. MEYERS, D.M. MITI.ER and M.B. SPORN, J. Biol. Chem. 258 7155-7160 (1983). 117. M.B. SPORN, A.B. ROBERTS, L.M. WAKEFIELD and R.K. ASSOIAN, Science 233 532-534 (1986). 118. J.H. KEHRL, L.M. WAKEFIELD, A.B. ROBERTS, et al., J. Exp. Med. 163 1037-1050 (1986). I
Vol. 45, No. 14, 1989
Growth Factors and Feeding
1217
11 9. H. MARQUARDT, M.W. h"JNEAPITJ.ER, L.E. HOOD and G.J. TODARO, Science 233 1079-1082 (1984). 120. C.-H. HELDIN and B. WES"f~k~RK, Cell 37 9-20 (1984). 121. A. DEKKER, W.H. G I S P ~ and D. De WIED, Life Sci. 41 1667-1678 (1987). 122. S. KORSC~IING, TINS Nov./Dec. 570-573 (1986). 123. R. LEVI-MONTALCINI, ~F~K)J. 6 1145-1154 (1987). 124. S.R. WHIq'I~K)RE and A. SEIG~, Brain Res. Rev. 12 439-464 (1987). 125. R.M. LINDSAY, Nature 282 80-82 (1979). 126. C.J. MARCH, B. MOSLEm, et al., Nature 315 641-647 (1985). 127. M.E.J. BILLIN(~LM, Br. Med. Bull. 43 350-370 (1987). 128. C.A. DINARELTO, J. Clin. Immunol. 5 287-297 (1985). 129. C.A. DINANE~,TO, Immunobiology 172 501-315 (1986). 130. A. FONTANA, E. WF~WR and J.M. DAYER, J. Immunol. 133 1696-1698 (1984). 131. D. GIULIAN, D.G. YOUNG, J. WOODWARD, D.C. BROWN and L.B. LACHMAN, J. Neurosci. 8 709-714 (1988). 132. K. HANAI, H. KATO, S. MATS[fHASHI, H. MORITA, E.W. RAINES and R.ROSS, J. Cell Biol. 104 1675-1681 (1987). 133. D.A. RAPPOLEE, D. MARK, M.J. BANDA and Z. WERB, Science 241 708-712 (1988). 134. C. HAO, A. RIC}{ARDSON and S. FEDOROFF, Soc. Neurosci. Abst. 14 1042 (1988). 135. F.L. JORDAN and W.E. THflMAS, Brain Res. Rev. 13 165-178 (1988). 136. K. STROMBERG, W.R. HUDGINS, L.S. DORMAN, L.E. HI~kK)ERSON, R.C. SOWDER, et al., Cancer Res. 47 1190-1196 (1987). 137. T.A. LIBERMANN, H.R. NUSBAUM, N. RAZON, et al., Nature 313 144-147 (1985). 138. W.J. (~JI~LICK, J.J. MORSDE~q, et al., Cancer Res. 46 285-292 (1986). 139. S.P. BANKS-SCHLEGEL and J. QUINTERO, J. Biol. C ~ . 261 4359-4362 (1986). 140. G.N. GILL, P.J. B~RTICS and J.B. SANTON, Mol. Cell. Endocrinol. 51 169-186 (1987). 141. Y. HIRATA, M. UCHIHASHI, H. NAKAJIMA, T. FIkTITA and S. MATSUKURA, J. Clin. Endocrinol. Metab. 55 1174-1177 (1982). 142. C.M. SRDSCHEC~ and L.E. KING Jr., Cancer Res. 46 1030-1037 (1986). 143. K.T. KET.qEY, H. NAGASAWA, R.S. UMANS and J.B. LITPLE, Carcinogenesis 8 625-627 (1987). 144. M.J. PK~RAY and A.B. MURRAY, Am. J. Clin. Nutr. 32 593-596 (1979).
G R O W T H FACTORS,
Pergamon Press
MINIREVIEW FEEDING REGULATION AND THE NERVOUS SYSTEM
Carlos
R.
D e p a r t m e n t of P s y c h o l o g y U n i v e r s i t y of D e l a w a r e ,
Plata-Salaman
and I n s t i t u t e for N e u r o s c i e n c e , Newark, D e l a w a r e 19716, U.S.A.
(Received in final form July 24, 1989) S-mmary
A variety of growth factors and their receptors are present in the nervous syst~n. Growth factors can modulate specific nervous system functions others than those related to growth, development, and tissue repair. The presence of growth factors in the brain and cerebrospinal fluid is the result of local synthesis (by neuronal, glial, vascular, and mononuclear phagocyte components), and uptake from the peripheral blood through the blood-brain barrier (in specific cases) and circumventricular organs. This paper focuses on the effects of a heterogeneous group of growth factors (acidic and basic fibrcblast wzowth factors, insulinlike ~ z ~ t h factors, epidermal growth factor, platelet-derived factor, interleukin-1 and others) on the central nervous system (flUS), in particular, on feeding regulation. Recent evidence supporting participation of growth factors in the regulation of feeding by a direct action at the level of the CNS is reviewed. Various growth factors have the ability to suppress short- and long-term food intake (FI), whereas others affect only short-term FI, or do not affect FI. Acute and chronic pathological processes stimulate the synthesis and release of growth factors in various cellular systems, and monitoring of growth factors by the CNS could be part of the regulatory signals that induce FI suppression frequently accompanying acute and chronic disease. Thus, it is proposed that a system regulating FI through growth factor-dependent mechanisms may be operative during specific physiological or pathological conditions. Introduction Feeding behavior is regulated by complex mechanisms involving humoral and neuronal factors. A variety of neuroregulators (neurotran~nitters and neuromodulators) have been implicated as feeding modulators. Neuroregulators which have been found to suppress feeding cc~prehend: i) neurotransmitters including epinephrine (I), serotonin (2,3), and dopamine (3); ii) hypothalamic and hypoph~ seal peptides including corticotropin-releasing hormone (3), thyrotropin-releasing hormone (3), and scmatostatin (3); iii) gut-brain peptides including cholecystokinin (3,4,), insulin (5-7), glucagon (3), bombesin (3), vasoactive intestinal peptide (3), and neurotensin (3,8); iv) other peptides including calcitonin (9,10 ), calcitcnin gene-related peptide (3) and satietin (3) ; v) other endogenous non-peptide substances such as prostaglandins (3 ), purines (3 ), and organic acids (11 ). On the other hand, neuroregulators which have been found to facilitate 0024-3205/89 $3.00 + .00 Copyright (c) 1989 Pergamon Press plc
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feeding include norepinephrine (3 ), dopamine (low doses ) (3 ), pro-opiomelanocortin derivatives and other endogenous opioids (3,4,12 ), neuropeptide Y (3 ), galanin (3), and growth hormone-releasing factor (3). Recent studies indicate that various growth factors also modulate feeding by a direct action in the CNS (13-18). Growth factors are heterogeneous substances, which are typically peptides, that coordinate different aspects of the cell growth, proliferation, differentiation and morpho-functional maintenance by inducing replicative DNA synthesis and cell division (19). A multi-interaction of growth factors is required for the normal and neoplastic cells to progress through the cell cycle (20,21). Growth factors can act in an autocrine manner (on the same cell that produces them) and/or paracrine manner (on neighbor cell.~ and/or endocrine manner (on distant target sites)(22) via specific receptors present at the target cells. A variety of growth factors are present in the C~qS due to local synthesis and/or uptake from the peripheral circulation (transcytosis through the bloodbrain barrier and uptake and transport across the circumventricularorgans, 22). Growth factors acting as neuroregulators can specifically regulate a wide variety of CNS functions. This paper focuses on the effects of various growth factors on the CNS, in particular, on feeding regulation; evidence supporting participation of growth factors in the regulation of feeding is summarized, m e discussion presented here also proposes that growth factors released during acute and chronic diseases may be part of the regulatory signals that induce FI suppression during disease, by a direct action in specific CNS target sites. Fibroblast
growth
factor
(FGF)
FGF is a potent mesodermal cell mitogen (23) which has been identified throughout the nervous system of various mammals (24,25). Two forms of FGF, acidic and basic, have been purified, their amino acid sequences determined and their cDNAs cloned and sequenced (23,26-28). Acidic and basic FGFs are two related peptides with a 53% absolute homology (27) and similar range of biological activities (29). A c i d i c FGF (aFGF) aFGF is a polypeptide composed of 140 amino acids (MW of about 16,000)(27) which has been isolated from neural tissues including whole brain, hypothalamus and retina (23,26,30,31). Brain-derived aFGF acts as a survival and neurotrophic agent for central and peripheral neurons (23,29,32-36), and exhibits mitogenic activity for glial and vascular cells (23,37,38). These evidences suggest a role of aFGF in fINS development (39,40); aFGF stimulates angiogenesis (38) and may participate in tissue repair since aFGF has a potent chemotactic activity for fibroblasts and astrocytes. Evidence shows that aFGF acts directly in the CNS to suppress FI. A phasic aFllF-like activity increase is detected in the cerebrospinal fluid (CSF)of rats after feeding (16,17 ), or after an intraperitoneal (IP) administration of glucose (16,41). The intracerebroventricular (ICV) administration of aFGF (106 and 220 ng/rat) suppresses the 2 hr (short-term, from 2000 to 2200 hr) and night-time (long-term, from 2000 to 0800 hr) FI (16,41). Daytime FI increases suggesting compensation for the previous night-time FI decrease. ICV administration of inactivated aF(~ and IP administration of aFGF in doses equivalent to or higher than those administered centrally have no effect on FI (16,41). Electrophysiological studies in the lateral hypothalamic area (LHA), an important site for the regulation of feeding, have shown that electrophoretically applied aFGF specifically suppresses the neuronal activity in 75% of the glucose-sensitive neurons tested, but has little effect on glucose-insensitive neurons (16,41). This evidence supports that aFGF acts directly and specifically in the C~qS to suppress FI.
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1209
The participation of hypothalamic feeding-associated sites in the suppression of FI by aF(~ may interact with other factors. For example, plasma concentrations of glucagon, insulin, and calcitonin --factors which suppress FI (3,6,7,9,10)--and CSF concentrations of aFGF change dynamically during and after feeding (I 6,17 ). This may indicate a hormonal interaction inducing satiety. The increase of aFGF in the CSF after feeding might also participate in other processes such as cerebral arteriosclerosis (42), since aFGF is a potent angiogenic factor stimulating mitosis for endothelial and vascular smooth muscle cells (23,38,43). B a s i c FGF (bFGF) bFGF is a polypeptide ~ s e d of 146 amino acids (MW of about 16,000)(23, 44 ) which has been isolated from neuro-endocrine tissues including whole brain, pituitary and retina (23,29); bFGF has also been isolated from other tissues and cell components such as adrenal glands, macrophages, thymus, and endothelial cells (23). Brain-derived bFGF is of neuronal (25,45) and glial (46) origin. Binding sites and specific receptors for bFGF on neuronal and glial ccmponents have been identified (47-49). Similar to aFGF, bFGF acts as a survival and neurotrophic agent for central and peripheral neurons (29,33-35,50-53), and exhibits mitogenic activity for glial and other cells (23); bFGF also stimulates angiogenesis (23, 29 ), and may participate in the homeostatic mechanisms that regulate the secretion of prolactin and thyrotropin (54). Evidence shows that bF(~ acts directly in the CNS to suppress FI. ICVadministration of bFGF (25 to 250 ng/rat) suppresses the 2 hr and night-time FI, whereas daytime FI increases (1 3). ICV administration of inactivated bFGF and IP administration of bFGF in doses higher than those administered centrally have no effect on FI (13 ). f~ronic ICV administration of bFGF from osmotic minipL~ps (30 ng/rat/24 hr) had no significant effect on night-time or daytime FI (13). On the basis of the amino acid homology between ~ and bFGF (27), bFGF may modulate hypothalamic feeding-associated sites to suppress feeding. Interleukin-1 (an i m m o l a t o r with growth-promoting activity)(14) also shows a sequence homology with aFGF and bFGF of about 27% (27,37,55), and interleukin-1 also suppresses FI by a direct and specific action in the ~ (14 ). Insulin-like
growth
factors
(IGFs)
There are two molecular forms of IGFs: somatomedin-C/IGF-I or IGF-I and IGF-II. IGF-I is a peptide ~m,posed of 70 amino acids (MW of 7649)(22,56,57), and IGF-II is composed of 67 amino acids ( ~ of 7471)(58). The sequence homology between IGF-I and -II is 62% and both IGFs have a high structural homology with pro-insulin (22). The liver is the major source of IGFs (22). IGF-I and -II have also been isolated from the nervous system (22,59); a variant form of IGF-I is present in the human brain (60,61), and mRNA for IGF-I is synthesized by embryonic neurons and glia throughout the nervous system (62). IGF-II has alsoobeenisolated from the human brain (60,61,63) ; thehypothalamus contains high concentrations of IGF-II (18,63) and evidence indicating C~qS synthesis of IGF-II include the presence of IGF-II mRNA in the brain (22,62-64). IGF-I and -II have also been detected in the CSF (22,65), and specific receptors for IGF-I and -If have been localized in specific brain sites (22). In the nervous system, IGF-I and -II participate in the neuronal and glial precursor cell division (22) enhancing cell replication, differentiation and neurite outgrowth (22) as well as neuronal survival (22 ). Evidence shows that IGF-II acts directly in the CNS to suppress FI. Initial studies reported that ICV administration of a preparation enriched of IGFs suppressed 24 hr FI (66). In more recent studies, ICV administration of purified IGF-II (33 to 300 ng/rat) dose-dependently suppressed 24 hr FI (18), whereas IGF-I had no effect on FI (18). In the same study, IGF-II but not IGF-I was
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Vol. 45, No. 14, 1989
localized in hypothalamic areas usually associated with FI regulation (18 ). Thus, IGF-II may contribute to the regulation of FI, but the action mechanism(s) and interaction with other satiety signals are unknown. It is established that IGFs and their receptors are under nutritional regulation (22,67) suggesting that circulating nutrients may act as signals for (]qS synthesis and/or release of IGFs. This nutritional regulation may be a determinant of a direct IGF-II modulation of feeding. In general, i n s u l i n and IGFs exert the same biological effects at appropriate concentrations (22). The major difference is that, insulin is more potent in affecting metabolic events, whereas IGFs are more potent in growth-promoting activity (22). Insulin also acts as a short- and long-term feeding modulator (6). Endogenous insulin is released prior to meal initiation, before absorption of nutrients and during feeding (6); CSF insulin content also changes during normal meals. A~ninistration of high doses of insulin increases FI due to hypoglycemia and other metabolic effects (6), whereas chronic ac~ninistration of small amounts of insulin suppresses FI by direct action in the fINS (5,6). Insulin also interacts with other satiety factors to suppress FI (6), and insulin andits receptors are present in brain areas important in the control of FI (6). Several action mechanisms of insulin on FI regulation have been proposed (6), and it has also been suggested that a malfunction of the brain-insulin regulatory system may participate in some types of obesity. Epidermal
9rowth
factor
(EGF)
EGF (urogastrone) is a peptide composed of 53 amino acids (MW of 6045)(68). EGF has been isolated from the CNS (69-71) and CSF (68). EGF is synthesized in the QqS as has been demonstrated by immunocytochemical studies (69,79 ) and by the presence of EGF mRNA in the C~qS (80,81). EGF immunoreactive neurons (71,82) and specific EGF receptors (82-86) are widely distributed in the CNS. EGF acts as a mitogen for glial cells (68,72-74) and survival and neurotrophic (75-77) as well as morphogenic (78) agent. Effects induced by EGF through a CNS modulation include: inhibition of gastric acid secretion (68,87,88), regulation of growth hormone secretion (89), protein phosphorylation (90) and other actions (91,92). Evidence shows that EGF acts directly in the C~qS to suppress FI. Administration of EGF sustaining its pla~na concentrations at about 20 ng/ml Dr exceeding this) for 1 5 t o 2 4 h r resulted in a suppression of FI in sheep (93). More recent studies show that ICV administration of EGF (100 and 200 ng/rat) suppresses the 2 hr, night-time and total daily FI, whereas daytime FI does not change or increase (13 ). ICV ac~ninistration of inactivated EGF and IP ac~ninistration of EGF in doses higher than those administered centrally have no effect on FI (13). The action mechanism of EGF suppressing FI is unknown. However, an increase in the circulating levels of somatostatin (93)and changes in calcium regulation (94) have been observed after peripheral administration of EGF; these effects may participate in the FI suppression by EGF since somatostatin and calcium changes have been shown to suppress FI (3,95). Platelet-derived
growth
factor
(PDGF)
PDGF is a protein consisting of two disulphide linked chains (A and B) of about equal size (MW of about 30,000)(96,97). PDGF is synthesized in platelets, stored in the alpha granules and released in conjunction with the plateletrelease reaction (96,97); PDGF is also synthesized in endothelial cells and mononuclear phagocytes (monocytes/macrophages)(96,97,105), as well as in a variety of transformed cells (106). PDGF exhibits mitogenic and chemotactic activity for glial and other cells (98-104), and it is proposed that PDGFparticipates in embryogenesis, growth and development (100), in wound healing (97) and reactive
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Growth Factors and Feeding
1211
gliosis (101), and in the pathogenesis of arteriosclerosis (96,105-107). Evidence shows that PDGF may act directly in the CNS to modulate short-term FI. ICV administration of PDGF (0.8and I .2 ng/rat) suppresses only the shortterm (2 hr) FI (13). IPadministration of PDGF in doses higher than those administered centrally has no effect on FI (13). C~-x~lic ICV administration of PDGF from osmotic minipLmps (0.8 and I .5 ng/rat/24 hr) had no significant effect on night-time or daytime FI (1 3). Transforming
growth
factors
(TGFs)
TGFs are polypeptides that have a high ability to induce acute phenotypic transformations in several normal cells (108,109 ). Tnere are two molecular forms of TGFs: TGF-alpha which binds to the EGF receptor with high affinity and is composed of 50 amino acids (M~ of about 6000~I09-111), and TGF-beta which does not bind to the EGF receptor, is not structurally related to TGF-alpha, and is composed of a dimer constituted by two identical chains of 112 amino acids (MW of about 25,000)(109,110,112). TGF-alpha immunoreactive cell bodies (113) and TGF-alpha mRNA have been identified in the rat brain (114). TGF-beta is also synthesized in the CNS by normal (108)andneoplastic (115)cells, although the major source of TGF-beta is the alpha granules of platelets (116). TGF-beta controls proliferation, differentiation and other functions in normal and neoplastic cells (I 17); it may function as a mediator of inflammation and repair (110 ) and as a stimulator of angiogenesis (110), since TGF-beta is released frcm platelets (11 0 ), activated macrophages (110 ), and T-lymphocytes (118 ). Evidence shows that TGF-beta does not affect short- or long-term FI after ICV administration (14). The effect(s) of TGF-alpha on FI is not known. However, TGF-alpha is about 40% homologous to EGF (111,11 9) and TGF-alpha produces the same biological signals in target cells as EGF (111); these signals are mediated through the EGF receptor (111,120). These similarities between TGF-alpha and EGF indicate that these peptides possess a similar mechanism(s) of action dependent on an hcmologous region, probably also inducing a FI suppression. Nerve
growth
factor
(NGF)
NGF is an oligcmeric protein cc~plex consisting of three subunits: alpha-2, beta and gamma (MW of about 130,000)(121); the beta-subunit (a dimer of two chains of 118 amino acids) exerts biological activities (121). NGF is synthesized by the target organs innervated by sympathetic and sensory neurons, taken up by these neurons and transported retrogradely to their cell bodies (122,123); NGF is essential for the survival and maintenance of these sympathetic and sensory neurons (122-124). In the C~S, astrocytes are able to synthesize NGF (125); NGF mRNA has been found in specific brain regions (122). Target cells for NGF in the CNS include cholinergic, adrenergic, indoleaminergic, and peptidergic neurons (123,124). Preliminary studies show that NGF does not affect FI. ICV administration of NGF (100 to 200 ng/rat) does not significantly affect short-or long-term FI (I 3). Immunomodulators
Various peptide immunomodulators have growth factor activity. The immune system and its immunoactive humoral cc~ponents can modulate specific nervous system functions; in particular, immunopeptides (which are synthesized and released in the immune and nervous systems and are referred as immuno-neuromodulators) provide the basis for this immuno-neuro communication (13-15).
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A typical example of these immunomodulators-growth factors is interleukin-1 (IL-I). IL-I is present in two molecular forms, IL-I~ and IL-I~ (126). IL-I~ consists of 159 amino acids (MW of about 17,500) and IL-I~ of 153 amino acids (MW of about 17,500 )(126,127). IL-I~ and IL-I~ induce similar biological effects on a wide variety of systems (127). IL-I participates in the activation and differentiation of lymphocytes (129), and induces specific effects in the CNS (14). IL-I is produced by phagocytes, lymphocytes, brain (by astrocytes, microglia, endothelial cells and intrinsic macrophages) and other cells (14,127,128, 130,131 ). Evidence shows that IL-I~ acts directly in the CNS to suppress FI. ICV administration of IL-I~ (I .0 to 13.0 ng/rat) suppresses 2 hr, night-time and total daily FI, dose-dependently, whereas daytime FI increases (14). ICV administration of inactivated IL-I~ and IP administration of II,-1@ in doses equivalent to or higher than those administered centrally have no effect on FI (1 4). The FI suppression induced by IL-I~ is a result of a direct effect in the C~qS; electrophysiological studies show that electrophoretically applied IL-I~ specifically suppresses the neuronal activity of the glucose-sensitive neurons in the IBA (14 ). Based on amino acid and carboxyl terminal sequence data, it has been shown that a sequence homology exists between IL-I~ and aFGF or bFGF (approximately 27% and 25%, respectively)(27,37,55). The similarities between IL-I~, ~ and bFGF in amino acid sequence, biosynthesis in brain, effects on FI and on LHA, and other CNS functions may indicate that these peptides possess a similar mechanism(s) of action or function dependent on a specific homologous region present in all three peptides. For a more detailed description about immunomodulators and feeding regulation see ref. 13-15. Growth factors r feedin 9 regulation integrative view
and
the n e r v o u s
system:
An
Several points arise from the discussion concerning growth factors, feeding regulation and the nervous system: I) A system regulating FI by direct action of growth factors in the CNS is proposed. The presence of growth factors in the CNS is due to the contribution of local synthesis by neuronal, glial, vascular, and mononuclear phagocyte cc~ponents, and uptake from the peripheral circulation. Various growth factors (e.g., EGF, aFGF, bFGF, and PDGF) which are effective in the rat also suppress the feeding response of the hydra (a freshwater coelenterate) (1 6, 132); thus, this postulated system modulating FI might be operant frfxn lower invertebrates (hydra) to mammals (rat). 2) The specificity of action of growth factors suppressing short- and long-term FI after exogenous administration in the rat is suggested because: i) ICV administration of inactivated growth factors has no effect on FI (13-15); ii) FI is suppressed only during the night-time (i.e., during the period of physiologic hyperphagia in the rat), whereas it does not change or increase during the daytime; iii) peripheral administration of growth factors in doses equivalent to or higher than those administered centrally have no effect on either short- or long-term FI (1 3-1 5 ). The fact that FI suppression is observed only after ICV administration of grc~4th factors and not after peripheral administration indicates an effect in the CNS and not in the periphery; iv) some growth factors do not affect FI (13,14), whereas others affect only shortterm FI (13) ; v) different growth factors have different potencies suppressing FI (13,14); vi) a decrease in food-to-water intake ratios (14) and no alteration of the dipsogenesis induced by angiotensin II (I 4) suggest that a modification in water intake after ICV interleukin-1 administration is a result of prandial drinking; vii) as described previously, a variety of specific responses in the CNS are induced by growth factors.
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Growth Factors and Feeding
1213
3) Xhe action mechanism of growth factors suppressing FI involves the hypothalamic feeding-associated sites (1 3-17,41 ). Electrophysiological studies show that one mechanism by which various growth factors suppress FI involves a specific and direct inhibition of the glucose-sensitive neurons in the LHA (considered as a "hunger center")(14,16,41 ). Tne feeding patterns induced by these growth factors are also consistent with this action mechanism on I~HA. At present it is unknown whether other mechanisms also participate in the FI suppression induced by growth factors. 4) The effect of some growth factors (e.g., bFGF) de not show a dose-response pattern (6,13), i.e., the decrease of FI by a growth factor diminishes at higher concentrations suggesting desensitization, and/or activation of other neural system(s) within the brain with increased concentrations, and/or a negative cooperation to maintain peptide sensitivity at low concentrations, but attenuation of responses to higher concentrations. 5) The doses of growth factors administered ICV are estimated not to be out of the predicted concentrations (in specific brain target sites/areas) occurring in some physiological or clinical conditions (6,13-16). 6) Since various growth factors which affect FI are released together under specific conditions, an interaction of growth factors modulating FI might be a plausible possibility. 7) Acute and chronic pathological processes stimulate the synthesis and release of growth factors in various cell systems. Monitoring of growth factors by the CNS could be part of the regulatory signals that induce FI suppression frequently accompanying acute and chronic disease. Examples of growth factor production during disease include: i) mononuclear phagocytes (monocytes/ macrophages) which synthesize and release bFGF, IGF-I, EGF, PDGF, TGF-beta, IL-I and other immunomodulators during chronic inflammatory processes (14,29, 100,133). The CNS also contains blood-derived and intrinsic mononuclear phagocytes (134,135) and T-lymphocytes (15) which serve as a link between the immune and nervous systems; ii) immune and nervous system cells which synthesize and release a variety of ~ l a t o r s (which suppress FI)(14, 15) during infection, injury, toxins, inrm/nological reactic~s, malignancy and inflammatory processes (14,15,128,129 ) ; iii ) stimulated platelets which release various growth factors contained in the alpha granules including bFGF, EGF, PDGF, and TGF-beta (96,97), and increasing evidence supports a role of platelets in acute inflammation; iv) various t~nor cell lines which have the ability to synthesize and release bFGF (e.g., neuroblastoma, hepatoma, m e l ~ , chondrosarooma and rhabdc~yosarcoma) (23,29), and/or PDGF (e.g., neuroblastoma, gliema, bepatema, teratocarcinoma, osteosarcoma and rhabdomyosarcoma)(97,100). EGF is also involved in carcinogenic processes; increased EGF immunoreactive concentrations (136) and increased EGF receptor concentrations (137-141) have been observed in various brain tumors, e.g., glioblastoma multiforme (malignant astrocytoma grade IV, a very aggressive cancer of the CNS)(136). It has also been demonstrated that EGF potentiates chemical and viral transformation (142), and induces cytogenetic alterations (143) and proliferative responses (139,140). EGF is also increased in other neurological diseases (141 ). Thus, FI suppression by growth factors by direct action in the C~S may be operant during acute and chronic disease. In the case of infection, a reduction of the availability of nutrients essential to the growth of pathogenic organisms (I 44 ) might be one of the biological roles of the FI suppression induced by immunomodulators-growth factors (14,15).
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References I. V. HINTON, M. ESGUERRA, N. FARHOODY, J. GRANGER and N. GEARY, Physiol. Behav. 40 109-115 (1987). 2. J. PANKSEPP, P. BISHOP and J. ROSSI III, Psychoneuroendocrinology, 4 89-106 (1979). 3. J.E. MORLEY, Endocr. Rev. 8 256-287 (1987). 4. C.A. BAILE, C.L. MclAUGHLIN and M.A. DETIA-F~RA, Physiol. Rev. 66 172-234 (1986). 5. S.C. WOODS and D. PORTE Jr, Adv. Metab. Disord. 10 457-468 (1983). 6. C.R. PLATA-SALAMAN, Y. OOMURAandN. SHIMIZU, Physio-~. Behav. 37 717-734 (1986). 7. C.R. PLATA-SALAMAN and Y. OCMURA, Physiol. Behav. 37 735-739 (1986). 8. M.F. HAWKINS, Physiol. Behav. 36 I-8 (1986). 9. C.R. PIATA-SALAMAN and Y. OOMURA, Physiol. Behav. 40 501-513 (1987). 10. C.R. PLATA-SAIAMAN and Y. ~ , Physiol. Behav. 40 515-521 (1987). 11. C.R. PLATA-SALAMAN, Y. 00MURA and N. SHIMIZU, Physiol. Behav. 38 359-373 (1986). 12. A.S. LEVINE and R.L. ATKINSON, Fed. Proc. 46 159-162 (1987). 13. C.R. PLATA-SALAMAN, Neurosci. Lett. 94 161-166 (1988). 14. C.R. PLATA-SAIAMAN, Y. OOMURA and Y. KAI, Brain Res. 448 106-114 (1988). 15. C.R. P L A T A - S ~ , Neurosci. Res. C~mr,~n. 3 159-165 (1988). 16. K. HANAI, Y. OOMURA, Y. KAI, K. NISHIKAWA, N. SHIMIZU, H. MORITA and C.R. PLATA-SAIAMAN, Am. J. Physiol. 256 R217-R223 (1989). 17. C.R. P I A T A - S ~ , Y. OOMURA, and K. HANAI, J. Physiol. Soc. Jpn. 49 418 (1987). 18. T.J. IAUTERIO, L. MARSON, W.H. DAUGHADAY and C.A. BAILE, Physiol. Behav. 40 755-758 (1987). 19. E. ROZENGURT, Science 234 161-166 (1986). 20. D.T. G~AVES, A.J. ~ and H.N. ANXONIADES, Cancer Res. 43 83-87 (1983). 21. J.M. ROWE and H.G. FRIESI~q, Rev. Endocrinol. Rel. Cancer 18 27-35 (1984). 22. Y. ~ and C.R. PLATA-SALAMAN, Insulin, Insulin-like Growth Factors, and their Receptors in the Central Nervous System, p. 215-244, Plenum Press, New York (1987). 23. D. GOSIK)ID}~0WICZ, G. NEUFELD and L. S(]{WEIGE~RER, Mol. Cell, Endocrinol. 46 187-204 (1986). 24. A. LOGAN and S.D. ~ , Neurosci. Lett. 69 162-165 (1986). 25. T. JANET, C. ~ , B. PETPMANN, K. UNSIf~
Vol. 45, No. 14, 1989
38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76.
Growth Factors and Feedlng
1215
J. RODKEY and S. FITZPATRICK, Proc. Natl. Acad. Sci. U.S.A. 8__226409-6413 (1985). J. FOIZMAN and M. KLAGSERUN, Science 235 442-447 (1987). C.G. CADAY, A. MIRZABEGIAN, J. PROSSER, M. KLAGSE~rUN and S.P. ~ . ~ ' P E ~ , Soc. Neurosci. Abst. 14 363 (1988). G. FE~RARI, M.-C. MINOZZI, C. SORANZO, G. X I ~ A N O and S.D. SKAPER., Soc. Neurosci. Abst. 14 301 (1988). C.R. PLATA-SALAMAN, K. HANAI, Y. OOMURA and Y. KAI, Jpn. Neurosci. Soc. 138 2C07 (1987). R. ROSS, Acta Meal. Scand. Suppl. 715 33-38 (1987). J. FOLKMAN and M. KLAGSBRUN, Nature 329 671-672 (1987). F. ESC~q, A. BAIRD, et.al., Proc. Natl. Acad. Sci. U.S.A. 82 6507-6511 (1985). B. PETIMANN, G. IABOURDETrE, M. WEIRI~. a n d M. S ~ N ~ , Neurosci. Lett. 68 175 (1986). M.E. HAR'I~, M. LYNCh, J. JOSEPH-SILV~RSTEIN, D. MOSCATELLI and D.B. RIFKIN, Soc. Neurosci. Abst. 13 194 (1987). P.A. WALICKE, Soc. Neurosci. Abst. 13 1605 (1987). P.A. WALICKE, J.J. FEIGE and A. BAIRD, Soc. Neurosci. Abst. 14 364 (1988). W.F. HERRTJN, R.G. KRAUSE and J.S. SC~WABER, Soc. Neurosci. Abst.14 104(1988). R.S. MORRISON, A. SHARMA, J. De VELLIS and R.A. ~ W , Proc. Natl. Acad. Sci. U.S.A. 83 7537-7541 (1986). J.L. McMANAMAN, F.G. CRAWFORD, J.O. RIC~KER and R.C. CLARK, Soc. Neurosci. Abst. 14 686 (1988). D.L. NEEDEI~ and C.W. COTMAN, Soc. Neurosci. Abst. 14 363 (1988). K.J. ANDE~ON, D. DAM, S. LE~ and C.W. Cl)TMAN, Nature 332 360-361 (1988). A. BAIRD, P. MORMEDE, et al. Proc. Natl. Acad. Sci. U.S.A. 82 5545-5549(1985). G. GIMENEZ-GALLEGO, J. RIMDKEY, C. ~ , M. R I O S - C A N D ~ , J. DiSALVO and K. THOMAS, Science 230 1385-1388 (1985). J. ZAPF, C.H. SCHMID and E.R. FROESC~, Clin. Endocrinol. Metab. 13 3-30(1984). J.J. Van WYK, Human Proteins and Peptides, Academic Press, New York (1984). L.E. UNDERWOOD, et al., Clin. Endocrinol. Metab. 15 59-77 (1986). T. NCK~JC~I, L.M. KURATA and T. SUGISAKI, Neuroendocrinology 46 277-282(1987). V.R. SARA, et al., Proc. Natl. Acad. Sci. U.S.A. 83 4904-4907 (1986). C. ~ - S K W I R U T , et al., FEBS Lett. 201 46-50 (1986). P. R ~ I N , S.K. BURGESS, J.D. MILBRANDT and J.E. KRAUSE, Proc. Natl. Acad. Sci. U.S.A. 85 265-269 (1988). G.K. HASEL~ACHER, M.E. SCHWAB, A. PASI and R.E. HL~4BEL, Proc. Natl. Acad. Sci. U.S.A. 82 2153-2157 (1985). P.K. LUND, et al., J. Biol. C ~ . 261 14539-14544 (1986). F. S T Y L I ~ , J. HERBERT, M.B. SOARES and A. EFSTRATIADIS, Proc. Natl. Acad. Sci. U.S.A. 85 141-145 (1988). G.S. T ~ U M , H.J. ~JYDA and B.I. POSNI~R, Science 220 77-79 (1983). N.J. ~ , E.S. CORP, B.J. WILCOX, D.P. F I ~ C Z , D.M. DORSA and D.G. BASKIN, Endocrinology 122 1940-1947 (1988). G. CARP~VPER, J. Cell. SC±. Suppl. 3 1-9 (1985). J. LAKSHMANAN, W.E. WEIC~SEL Jr. and D.A. FISHER, J. ~ . 46 10811085 (1986). R.S. MORRISON, R. KEATING, V.K. £%F~HANE and J.R. MOSKAL, Neuroscience 22 $280 (1987). R.P. SC~AUDIES, E.L. CHRISTIAN and CoR. SAVAGE Jr., Fed. Proc. 461995(1987). D.L. SIMPSON, R. MORRISON, J. De Vk~.T.IS and H.R. ~ , J. Neurosci. Res. 8 453-462 (1982). B. WESTERMARK, A. MAGNUSSON and C.H. ~ I N , Prog. Clin. Biol. Res. 118 491-507 (1983). P. HONEGGER, M. TE~K~T and M. JORDI, Neuroscience 22 $279 (1987). P.A. ~ , D.J. G~JNq~3N and D.H. SILBERBERG, Dev. Neurosci. 7 308-322 (1985). G. AI/MAZAN, P. ~ , J.-M. MAXR'HI~3 and B. ~ - I A U B E R , Dev. Brain Res. 21 257-264 (1985).
1216
Growth Factors and Feeding
Vol. 45, No. 14, 1989
77. R.S. MORRIS~N, H.I. KORNBLUM, F.M. LESLIE and R.A. BRADSHAW, Science 238 72-75 (1987). 78. C.A. ERICY~SON and E.A. ~ , Exp. Cell Res. 169 267-279 (1987). 79. J.H. FALL~, K.B. SE~KX)GY, S.E. LOUf~K~IN, R.S. MO~ISON, R.A. BRADSHAW, D.J. KNAUER and D.D. CUNNING~I~M, Science 224 1107-1109 (1984). 80. L.G. RALL, J.SOOTP, G.I. BELL, et al., Nature 313 228-231 (1985). 81. L.M. lAZAR, J.L. ROBERTS and M. BLUM, Soc. Neurosci. Abst. 14 1162 (1988). 82. R. LOY l J.E. SPRINGER and S. KOH, Soc. Neurosci. Abst. 13 575 (1987). 83. F.M. LESLIE t R.S. BROIDE, K.P. CAVANAU~, R.A. BRADSHAW and J.H. FALLON, Soc. Neurosci. Abst. 13 1604 (1987). 84. M. NIETO-SAMPEDRO, F. GOMEZ-PINILLA and D.J. KNAUER, Neuroscience 22 Suppl. $279 (1987). 85. K.HUFF, L.IBRIC and L. SCHULTZ, Soc. Neurosci. Abst. 13 1365 (1987). 86. C. HERTEL, S.J. COULTER and J.P. PERKINS, J. Biol. Chem. 260 12547-12553(1985). 87. A.M. SODERQUIST and G. CARPE~WTER, Fed. Proc. 42 2615-2620 (1983). 88. H. GREGORY, J. Cell Sci. Suppl. 3 11-17 (1985). 89. J.-G. CHAHOT, P. W ~ and G. P~J.ETIER, Peptides 7 45-50 (1986). 90. J.R. MOSKAL and R.S. MORRISON, Soc. Neurosci. Abst. 14 362 (1988). 91. I. TAKAYANAGI, J. Pharm. Pharmacol. 32 228-230 (1980). 92. H.R. ~ , R. GOODMAN, C. C~9~NDLER, D. SIMPSON, D. CAWLEY, R. COLE and J. De VELLTS, Nervous System Regeneration, pp. 79-94, Alan Liss, New York (1 983 ). 93. B.A. PANARETI~, G.P.M. MOORE and D.M. ROBERTSC~, J. Endocrinol. 94 191(1982). 94. G.P.M. MOORE, M. WILKINSON, B.A. P ~ , L.W. Dk~.~RIDGE and S. POSEN, Endocrinology 118 1525-1529 (1986). 95. R.D. MYERS, T.F. LEE and S.E. KING, Brain Res. 266 178-181 (1983). 96. J. NILSSON, Atherosclerosis 62 185-199 (1986). 97. B. WESTERMARK and C.-H. HE[~IN, Acta Med. Scand. 715 19-23 (1987). 98. H.N. ANTONIgH)ES and L.T. WILLIAMS, Fed. Proc. 42 2630-2634 (1983). 99. J.P. BRESSLER, G.R. GROT~kKXgRST, C. LEVITOV and L.M. ~ , Brain Res. 344 249-254 (1985). 100. R. ROSS, Annu. Rev. Med. 38 71-79 (1987). 101. F. BESNARD, F. PERRAUD, M. S~SEI%~E~[ER and G. LABOURDETrE, Neurosci. Lett. 73 287-292 (1987). 102. T. KOSCHINSKY, C.E. BL%rfING, R.RUTYER and F.A. GRIES, Diab. Metab. 13 318-325 (1987). 103. W.D. RICHARDSON, et al., Cell 53 309-319 (1988). 104. M. NOBLE, K. MURRAY, P. STROOBANT, M.D. WATERFIELD and P. RIDDLE, Nature 333 560-562 (1988). 105. R. ROSS, Acta Med. Scand.715 33-38 (1987). 106. H.R. BAUMCgLRTNER and M. HOSANG, Experientia 44 109-112 (1988). 107. B.C. BERK, R.W. ALEXANDER, T.A. BROCK, M.A. GIBRONE Jr. and R.C. WI~B, Science 232 87-90 (1986). 108. A.B. ROBerTS, M.A. ANZANO, L.C. LAMB, J.M. SMITH and M.B. SPORN, Proc. Natl. Acad. Sci. U.S.A. 78 5339-5343 (1981). 109. R. GOL-WINKLER, Clin. Endocrinol. Metab. 15 99-115 (1986). 11 0. M.B. SPORN, A.B. ROBERTS, L.M. WAKEFIELD and B. De CRflMBRUGGHE, J. Cell Biol. 105 1039-1045 (1987). 111. G. CARPENTER, Annu. Rev. Biochem. 56 881-914 (1987). 112. J. MASSAGUE, Cell 49 437-438 (1987). 113. R.A. CODE, K.B. SEROOGY and J.H. FAIH/)N, Brain Res. 421 401-405 (1987). 114. D.C. LEE, T.M. ROSE, N.R. WEBB and G.J. TODARO, Nature313 489-491 (1985). 115. W.C. CLARK and J. F~.ESSLER, J. Neurosurg. 68 920-924 (1988). 116. R.K. ASSOIAN, K. KC~ORIYA, C.A. MEYERS, D.M. MITI.ER and M.B. SPORN, J. Biol. Chem. 258 7155-7160 (1983). 117. M.B. SPORN, A.B. ROBERTS, L.M. WAKEFIELD and R.K. ASSOIAN, Science 233 532-534 (1986). 118. J.H. KEHRL, L.M. WAKEFIELD, A.B. ROBERTS, et al., J. Exp. Med. 163 1037-1050 (1986). I
Vol. 45, No. 14, 1989
Growth Factors and Feeding
1217
11 9. H. MARQUARDT, M.W. h"JNEAPITJ.ER, L.E. HOOD and G.J. TODARO, Science 233 1079-1082 (1984). 120. C.-H. HELDIN and B. WES"f~k~RK, Cell 37 9-20 (1984). 121. A. DEKKER, W.H. G I S P ~ and D. De WIED, Life Sci. 41 1667-1678 (1987). 122. S. KORSC~IING, TINS Nov./Dec. 570-573 (1986). 123. R. LEVI-MONTALCINI, ~F~K)J. 6 1145-1154 (1987). 124. S.R. WHIq'I~K)RE and A. SEIG~, Brain Res. Rev. 12 439-464 (1987). 125. R.M. LINDSAY, Nature 282 80-82 (1979). 126. C.J. MARCH, B. MOSLEm, et al., Nature 315 641-647 (1985). 127. M.E.J. BILLIN(~LM, Br. Med. Bull. 43 350-370 (1987). 128. C.A. DINARELTO, J. Clin. Immunol. 5 287-297 (1985). 129. C.A. DINANE~,TO, Immunobiology 172 501-315 (1986). 130. A. FONTANA, E. WF~WR and J.M. DAYER, J. Immunol. 133 1696-1698 (1984). 131. D. GIULIAN, D.G. YOUNG, J. WOODWARD, D.C. BROWN and L.B. LACHMAN, J. Neurosci. 8 709-714 (1988). 132. K. HANAI, H. KATO, S. MATS[fHASHI, H. MORITA, E.W. RAINES and R.ROSS, J. Cell Biol. 104 1675-1681 (1987). 133. D.A. RAPPOLEE, D. MARK, M.J. BANDA and Z. WERB, Science 241 708-712 (1988). 134. C. HAO, A. RIC}{ARDSON and S. FEDOROFF, Soc. Neurosci. Abst. 14 1042 (1988). 135. F.L. JORDAN and W.E. THflMAS, Brain Res. Rev. 13 165-178 (1988). 136. K. STROMBERG, W.R. HUDGINS, L.S. DORMAN, L.E. HI~kK)ERSON, R.C. SOWDER, et al., Cancer Res. 47 1190-1196 (1987). 137. T.A. LIBERMANN, H.R. NUSBAUM, N. RAZON, et al., Nature 313 144-147 (1985). 138. W.J. (~JI~LICK, J.J. MORSDE~q, et al., Cancer Res. 46 285-292 (1986). 139. S.P. BANKS-SCHLEGEL and J. QUINTERO, J. Biol. C ~ . 261 4359-4362 (1986). 140. G.N. GILL, P.J. B~RTICS and J.B. SANTON, Mol. Cell. Endocrinol. 51 169-186 (1987). 141. Y. HIRATA, M. UCHIHASHI, H. NAKAJIMA, T. FIkTITA and S. MATSUKURA, J. Clin. Endocrinol. Metab. 55 1174-1177 (1982). 142. C.M. SRDSCHEC~ and L.E. KING Jr., Cancer Res. 46 1030-1037 (1986). 143. K.T. KET.qEY, H. NAGASAWA, R.S. UMANS and J.B. LITPLE, Carcinogenesis 8 625-627 (1987). 144. M.J. PK~RAY and A.B. MURRAY, Am. J. Clin. Nutr. 32 593-596 (1979).