Model for the regulation of energy balance and adiposity by the central nervous system

American Journal of Clinical Nutrition

Volumn 69, Issue 4, 1999, Pages 584-596

  Schwartz, Michael W ^a   Baskin, Denis G ^a   Kaiyala, Karl J ^a   Woods, Stephen C ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

Author keywords

Adipose tissue; Arcuate nucleus; Body weight; Central effector pathways; Central nervous system; Energy balance; Food intake; Glucocorticoids; Homeostasis; Insulin; Leptin; Neuropeptide Y; Obesity; Paraventricular nucleus; Review

Indexed keywords

INSULIN; LEPTIN; NEUROPEPTIDE Y;

BODY WEIGHT; CENTRAL NERVOUS SYSTEM; ENERGY BALANCE; ENERGY EXPENDITURE; FOOD INTAKE; OBESITY; REVIEW;

EID: 0032963304     PISSN: 00029165     EISSN: None     Source Type: Journal    
DOI: 10.1093/ajcn/69.4.584     Document Type: Review

References (180)

1. Kaiyala KJ, Woods SC, Schwartz MW. New model for the regulation of energy balance and adiposity by the central nervous system. Am J Clin Nutr 1995;62(suppl):1123S-34S.
2. Keesey RE, Powley TL. The regulation of body weight. Annu Rev Psychol 1986;37:109-33.
3. Keesey RE. A set-point theory of obesity. In: Brownell KD, Foreyt JP, eds. Handbook of eating disorders: physiology, psychology, and treatment of obesity, anorexia, and bulimia. New York: Basic Books, 1986:63-87.
4. Stallone DD, Stunkard AJ. The regulation of body weight: evidence and clinical implications. Ann Behav Med 1991;13:220-30.
5. Drenick EJ, Johnson D. Weight reduction by fasting and semistarvation in morbid obesity: long-term follow-up. Int J Ohes 1978;2:123-32.
6. Garner DM, Wooley SC. Confronting the failure of behavorial and dietary treatments for obesity. Clin Psychol Rev 1991;11:729-80.
7. Faust IM, Johnson PR. Hirsch J. Adipose tissue regeneration following lipectomy. Science 1977;197:391-3.
8. Larson KA, Anderson DB. The effects of lipectomy on remaining adipose tissue depots in the Sprague Dawley rat. Growth 1978;42:469-77.
9. Chlouverakis C, Hojnicki D. Lipectomy in obese hyperglycemic mice (ob/ob). Metabolism 1974;23:133-7.
10. Bernstein IL, Lotter EC, Kulkosky PJ. Effect of force-feeding upon basal insulin levels in rats. Proc Soc Exp Biol Med 1975;150:546-8.
11. Sims EAH. Experimental obesity, diet-induced thermogenesis and their clinical implications. Clin Endocrinol Metab 1976:5:377-95.
12. Edholm OG. Energy balance in man. J Hum Nutr 1977;31:413-31.
13. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci 1953;140:579-92.
14. Woods SC, Porte D Jr. Insulin and the set-point regulation of body weight. In: Novin D, Bray GA. Wyrwichka W, eds. Hunger: basic mechanisms and clinical implications, New York: Raven Press, 1976:273-80.
15. Zhang Y, Proenca R, Maffie M, Barone M, Leopold L, Friedman J. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-32.
16. Woods S, Seeley R. Porte DJ, Schwartz M. Signals that regulate food intake and energy homeostasis. Science 1998;280:1378-3.
17. Bray GA, Fisler J, York DA. Neuroendocrine control of the development of obesity: understanding gained from studies of experimental animal models. Front Neuroendocrinol 1990;11:128-81.
18. Bray G. Peptides affect the intake of specific nutrients and the sympathetic nervous system. Am J Clin Nutr 1992;55(suppl):265S-71S.
19. Scheurink AJ, Steffens AB. Central and peripheral control of sympathoadrenal activity and energy metabolism in rats. Physiol Behav 1990;48:909-20.
20. Leibowitz SF. Hypothalamic neuropeptide Y, galanin, and amines: concepts of coexistence in relation to feeding behavior. In: Proceedings of the New York Academy of Sciences. New York: Academy of Sciences, 1990:221-35.
21. Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 1986;7:1189-92.
22. Morley JE. Neuropeptide regulation of appetite and weight. Endocr Rev 1987;8:256-87.
23. Billington CJ, Briggs JE, Grace M, Levine AS. Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. Am J Physiol 1991;260:R321-7.
24. Zarjevski N, Cusin I, Vetter R, Rohner-Jeanrenaud F, Jeanrenaud B. Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 1993:133:1753-8.
25. White JD, Kershaw M. Increased hypothalamic neuropeptide Y expression following food deprivation. Mol Cell Neurosci 1989:1:41-8.
26. Schwartz MW, Sipols AJ, Marks JL, et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 1992;130:3608-16.
27. Schwartz MW. Sipols AJ, Grubin CE. Baskin DG. Differential effect of fasting on hypothalamic expression of genes encoding neuropeptide Y, galanin and glutamic acid decarboxylase. Brain Res Bull 1993:31:361-7.
28. Sahu A, Kalra PS, Kalra SP. Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus, Peptides 1988;9:83-6.
29. Leedom LJ, Meehan WP. The psychoneuroendocrinology of diabetes mellitus in rodents. Psychoneuroendocrinology 1989;14:275-94.
30. White JD, Olchovsky D, Kershaw M, Berelowitz M. Increased hypothalamic content of preproneuropeptide-Y messenger ribonucleic acicl in streptozotocin-diabetic rats. Endocrinology 1990;126:765-72.
31. Sipols AJ, Baskin DG, Schwartz MW. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 1995;44:147-51.
32. Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra P. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci U S A 1991;88:10931-5.
33. Williams G, Gill JS, Lee YC, Cardoso HM, Okpere BE, Bloom SR. Increased neuropeptide Y concentrations in specific hypothalamic regions of streptozocin-induced diabetic rats. Diabetes 1989;38:321-7.
34. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996;98:1101-6.
35. Dallman MF, Strack AM, Akana SF, et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol 1993;14:303-47.
36. Strack AM, Sebastian RJ, Schwartz MW, Dallman MF. Glucocorticoids and insulin: reciprocal signals for energy balance. Am J Physiol 1995;268:142-9.
37. Beck B, Burlet A, Nicolas JP, Burlet C. Hypothalamic neuropeptide Y (NPY) in obese Zucker rats: implications in feeding and sexual behaviors. Physiol Behav 1990;47:449-53.
38. Sanacora G, Kershaw M, Finkelstein JA, White JD. Increased hypothalamic content of preproneuropeptide Y mRNA in genetically obese Zucker rats and its regulation by food deprivation. Endocrinology 1990;127:730-7.
39. Wilding JPH, Gilbey SG, Bailey CJ, et al. Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse. Endocrinology 1993;132:1939-44.
40. Chua SC, Brown AW, Kim J, Hennessey KL, Leibel RL, Hirsch J. Food deprivation and hypothalamic neuropeptide gene expression: effects of strain background and the diabetes mutation. Mol Brain Res 1991;11:291-9.
41. Akabayashi A, Wahlestedt C, Alexander JT, Leibowitz SF. Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Brain Res 1994;21:55-61.
42. Schaffhauser A. Stricker-Kongrad A, Brunner L, et al. Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. Diabetes 1997;46:1792-8.
43. 1 receptor mediating this peptide's effect. Peptides 1992;13:581-7.
44. Shibasaki T, Oda T, Imaki T, Ling N, Demura H. Injection of antineuropeptide Y γ-globulin into the hypothalamic paraventricular nucleus decreases food intake in rats. Brain Res 1993:601:313-6.
45. Gerald C, Walker MW, Criscione L, et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 1996;382:168-71.
46. Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 1996;381:415-8.
47. Marsh D, Hollopeter G, Kafer K, Palmiter R, Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat Med 1998;4:718-21.
48. Pedrazzini T, Seydoux J, Kunstner P, et al. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat Med 1998;4:722-6.
49. Qu D, Ludwig DS, Gammeltoft S, et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996;380:243-7.
50. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G-protein-coupled receptors that regulate feeding behavior. Cell 1998;92:573-85.
51. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998;95:322-7.
52. Baskin DG, Wilcox BJ, Figlewicz DP, Dorsa DM. Insulin and insulin-like growth factors in the CNS. Trends Neurosci 1988;11:107-11.
53. Jegou S, Balsquez C, Delbende C, Bunel DT, Vaudry H. Regulation of alpha-melanocyte stimulating hormone release from hypothalamic neurons. Ann N Y Acad Sci 1993;680:260-78.
54. Mountjoy K, Mortrud M, Low M, Simerly R, Cone R. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomie control circuits in the brain. Mol Endocrinol 1994;8:1298-308.
55. Huszar D, Lynch C, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997;88:131-41.
56. Fan W, Boston B, Kesterson R, Hruby V, Cone R. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997;385:165-8.
57. Schwartz M, Seeley R, Woods S, et al. Leptin increases hypothalamic proopiomelanocortin (POMC) mRNA expression in the rostral arcuate nucleus. Diabetes 1997;46:2119-23.
58. Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997;138:4489-92.
59. Seeley R, Thiele T, van Dijk G, et al. Melanocortin receptors in leptin effects. Nature 1997;390:349.
60. Cone R, Lu D, Koppula S, et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res 1996;51:287-318.
61. Shutter J, Graham M, Kinsey A, Scully S, Luthy R, Stark K. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997;11:593-602.
62. Ollmann M, Wilson B, Yang Y, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997;278:135-8.
63. Hahn T, Breininger JF, Baskin DG, Schwanz MW. Coexpression of AgRP and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1998;1:271-2.
64. Arase K, York DA, Shimizu H, Shargil NS, Bray GA. Effects of corticotropin releasing factor on food intake and brown adipose tissue thermogenesis in rats. Am J Physiol 1988;255:E255-9.
65. Egawa H, Yoshimatsu H, Bray GA. Effect of corticotropin releasing hormone and neuropeptide Y on electrophysiological activity of sympathetic nerves to interscapular brown adipose tissue. Neuroscience 1990;34:771-5.
66. Rothwell N. Central effects of CRF on metabolism and energy balance. Neurosci Biobehav Rev 1989;14:263-71.
67. Arase K, Shargill NS, Bray GA. Effects of intraventricular infusion of corticotropin-releasing factor on VMH-lesioned obese rats. Am J Physiol 1989;256:R751-6.
68. Arase K, Shargill NS, Bray GA. Effect of corticotropin releasing factor on genetically obese (fatty) rats. Physiol Behav 1989;45:565-70.
69. Glowa J, Gold P. Corticotropin releasing hormone produces profound anorexigenic effects in the rhesus monkey. Neuropeptides 1991;18:55-61.
70. Seeley RJ, Matson CA, Chavez M, Woods SC, Dallman MF, Schwartz MW. Behavioral, endocrine, and hypothalamic responses to involuntary overfeeding. Am J Physiol 1996;271:R819-23.
71. Uehara A, Sekiya C, Takasugi Y, Namiki M, Arimura A. Anorexia induced by interleukin 1: involvement of corticotropin-releasing factor. Am J Physiol 1989;257:613-7.
72. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 1987;238:522-6.
73. Brady LS, Smith MA, Gold PW, Herkenham M. Altered expression of hypothalamic neuropeptide mRNAs in food restricted and food-deprived rats. Neuroendocrinology 1990;52:441-7.
74. Bray GA. Autonomic and endocrine factors in the regulation of food intake. Int J Obes 1989;13:327-35.
75. Zakrzewska KE, Cusin I, Sainsbury A, Rohner-Jeanrenaud F, Jeanrenaud B. Glucocorticoids as counterregulatory hormones of leptin. Diabetes 1997;46:717-9.
76. Kristensen P, Judge M, Thim L, et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 1998;393:72-6.
77. Couceyro P, Koylu E, Kuhar M. Further studies on the anatomical distribution of CART by in situ hybridization. J Chem Neuroanat 1997;12:229-41.
78. Lambert P, Couceyro P, McGirr K, Vechia S, Smith Y, Kuhar M. CART peptides in the central control of feeding and interactions with neuropeptide Y. Synapse 1998;29:1-6.
79. Young JB, Landsberg L. Stimulation of the sympathetic nervous system during sucrose feeding. Nature 1977;269:615-7.
80. Ravussin E, Swinburn BA. Pathophysiology of obesity. Lancet 1992;340:404-8.
81. Rothwell NJ, Stock MJ. Effects of feeding a palatable 'cafeteria' diet on energy balance in young and adult lean (+/-) Zucker rats. Br J Nutr 1982;47:461-71.
82. Rothwell NJ, Stock MJ. Brown adipose tissue and diet-induced thermogenesis. In: Trayhurn P, Nicholls DG, eds. Brown adipose tissue. New York: Edward Arnold Publishers. 1986:269-98.
83. Gong DW, He Y, Karas M, Reitman M. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem 1997;272:24129-32.
84. Fleury C, Neverova M, Collins S, et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997;15:269-72.
85. Lowell BB, Susulic VS, Hamann A, et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993;366:740-2.
86. Thomas SA, Palmiter RD. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature 1997;387:94-7.
87. Enerback S, Jacobsson A, Simpson E, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997;387:27-8.
88. Hamann A, Flier J, Lowell B. Decreased brown fat markedly enhances susceptibility to diet-induced obesity, diabetes and hyperlipidemia. Endocrinology 1996;137:21-9.
89. Hamann A, Büsing B, Kausch C, et al. Chronic leptin treatment does not prevent the development of obesity in transgenic mice with brown fat deficiency. Diabetologia 1997;40:810-5.
90. Langhans W, Scharrer E. Metabolic control of eating, energy expenditure and bioenergetics of obesity. In: Simopoulos AP, ed. World review of nutrition and dietetics. Basel, Switzerland: Karger, 1992:1-67.
91. Mayer J, Thomas DW. Regulation of food intake and obesity. Science 1967;7156:328-37.
92. Stellar E. The physiology of motivation. Psychol Rev 1954;61:5-22.
93. King BM, Grossman SP. Response to glucoprivic and hydrational challenges by normal and hypothalamic hyperphagic rats. Physiol Behav 1977;18:463-73.
94. King BM, Stamoutsos BA, Grossman SP. Delayed response to 2-deoxy-D-glucose in hypothalamic obese rats. Pharm Biochem Behav 1978;8:259-62.
95. Teitelbaum P. Disturbances in feeding and drinking behavior after hypothalamic lesions. In: Jones MR, ed. Nebraska Symposium on Motivation. Lincoln, NB: University of Nebraska Press, 1961:39-69.
96. Hoebel BG, Teitelbaum P. Weight regulation in normal and hypothalamic hyperphagic rats. J Comp Physiol Psychol 1966;61:189-93.
97. Lotter EC, Woods SC. Injections of insulin and changes of body weight. Physiol Behav 1977;18:293-7.
98. Grossman SP. The role of glucose, insulin and glucagon in the regulation of food intake and body weight. Neurosci Biobehav Rev 1986;10:295-315.
99. Campfield LA, Smith FJ. Transient declines in blood glucose signal meal initiation. Int J Obes 1990;14:15-33.
100. Woods SC, Strubbe JH. The psychobiology of meals. Psychonomic Bull Rev 1994;1:141-55.
101. Polonsky KS, Given BD, VanCauter E. Twenty-four hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 1988;81:442-8.
102. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and B-cell function in human subjects: evidence for a hyperbolic function. Diabetes 1993;42:1663-72.
103. Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 1973;84:488-95.
104. Greenberg D, Smith GP. Hepatic-portal infusion reduces the satiating potency of CCK-8. Physiol Behav 1988;44:535-8.
105. Gibbs J, Smith GP. The neuroendocrinology of postprandial satiety. Front Neuroendocrinol 1984;8:223-45.
106. Moran TH, McHugh PR. Gastric and non-gastric mechanisms for satiety action of cholecystokinin. Am J Physiol 1988;4:R628-32.
107. Sankaran H, Deveney CW, Goldfine ID, Williams JA. Preparation of biologically active radioiodinated cholecystokinin for radioreceptor assay and radioimmunoassay. J Biol Chem 1979;254:9349-51.
108. Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky KJ. Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 1981;213:1036-7.
109. Smith GP, Jerome E, Norgren R. Afferent axons in abdominal vagus mediate the satiety effect of cholycystokinin in rats. Am J Physiol 1985;249:R638-41.
110. Crawley JN, Kiss JZ, Mezey E. Bilateral midbrain transections block the behavioral effects of cholecystokinin on feeding and exploration in rats. Brain Res 1984;322:316-21.
111. West DB, Fey D, Woods SC. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol 1984;246:R776-87.
112. Figlewicz DP, Stein LJ, West D, Porte D Jr, Woods SC. Intracisternal insulin alters sensitivity to CCK-induced meal suppression in baboons. Am J Physiol 1986;250:R856-60.
113. Matson CA, Wiater M, Kuiper JL, Weigle DS. Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides 1997;18:1275-8.
114. Schwartz M, Seeley R. Neuroendocrine responses to starvation and weight loss. N Engl J Med 1997;336:1802-11.
115. Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155-66.
116. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995;1:1311-4.
117. Sinha MK, Ohannesian JP, Heiman ML, et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 1996;97:1344-7.
118. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-5.
119. McGregor GP, Desaga JF, Ehlenz K, et al. Radioimmunological measurement of leptin in plasma of obese and diabetic human subjects. Endocrinology 1996;137:1501-4.
120. Kolaczynski JW, Nyce MR, Considine RV, et al. Acute and chronic effect of insulin on leptin production in humans. Diabetes 1996;45:699-701.
121. Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M. Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes 1996;45:695-8.
122. Schwartz MW, Peskind E, Raskind M, et al. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 1996;2:589-93.
123. Rentsch JR, Levens N, Chiesi M. Recombinant ob-gene product reduces food intake in fasted mice. Biochem Biophys Res Commun 1995;214:131-6.
124. Stephens TW, Bashinski M, Bristow PK, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995;377:530-4.
125. Campfield L, Smith F, Gulsez Y, Devos R, Burn P. Mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-9.
126. Halaas JL, Gajiwala KS, Maffel M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-6.
127. Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540-3.
128. Levin N, Nelson C, Gurney A, Vandlen R, DeSauvage F. Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci U S A 1996;93:1726-30.
129. Weigle DS, Bukowski TR, Foster DC, et al. Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J Clin Invest 1995;96:2065-70.
130. Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 1996;274:1704-7.
131. Seeley R, van Dijk G, Campfield L, et al. Intraventricular leptin reduces food intake and body weight of lean rats but not Zucker obese rats. Horm Metab Res 1997;28:664-8.
132. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997;100:270-8.
133. Montague C, Farooql I, Whitehead J, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-8.
134. Clement K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:330-1.
135. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996;12:318-20.
136. Barash I, Cheung C, Weigle D, et al. Leptin is a metabolic signal to the reproduction system. Endocrinology 1996;137:3144-7.
137. Ahima R, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250-2.
138. Flier J. What's in a name? In search of leptin's physiologic role. J Clin Endocrinol Metab 1998;83:1407-13.
139. Rossetti L, Massillon D, Barzilai N, et al. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem 1997;272:27758-63.
140. + channels in pancreatic B-cells. Diabetes 1997;46:1087-93.
141. Halaas J, Boozer C, Blair-West J, Fidahusein N, Denton D, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 1997;94:8878-83.
142. Gwo-Hwa L, Proenca R, Montez JM, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632-5.
143. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263-71.
144. White D, Kuropatwinski K, Devos R, Baumann H, Tartaglia L. Leptin receptor (OB-R) signaling. J Biol Chem 1997;272:4065-71.
145. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978;14:141-8.
146. Baskin D, Seeley R, Kuijper J, et al. Increased expression of mRNA for the long form of the leptin receptor (OB-Rb) in the hypothalamus is associated with leptin hypersensitivity and fasting. Diabetes 1998;47:535-43.
147. Stanley BG. Neuropeptide Y in multiple hypothalamic sites controls eating behavior, endocrine, and autonomic systems for energy balance. In: Colmers WF, Wahlestedt C, eds. The biology of neuropeptide Y and related peptides. Ottawa: Humana Press, 1993:457-509.
148. Schwartz MW, Baskin DG, Bukowski TR, et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 1996;45:531-5.
149. Saladin R, De Vos P, Guerre-Millo M, et al. Transient increase in obese gene expression after food intake or insulin administration. Nature 1995;377:527-9.
150. Mizuno TM, Bergen H, Funabashi T, et al. Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet induced) and genetic (yellow agouti) obesity. Proc Natl Acad Sci USA 1996;93:3434-8.
151. MacDougald OA, Hwang C, Fan H, Lane MD. Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3 L1 adipocytes. Proc Natl Acad Sci USA 1995;92:9034-7.
152. Cusin I, Sainsbury A, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. The ob gene and insulin: a relationship leading to clues to the understanding of obesity. Diabetes 1995;44:1467-70.
153. Ogawa Y, Masuzaki H, Isse N, et als. Molecular cloning of rat obese cDNA and augmented gene expression in genetically obese Zucker fatty (fa/fa) rats. J Clin Invest 1995;96:1647-52.
154. Funahashi T, Shimomura I, Hiraoka H, et al. Enhanced expression of rat obese (ob) gene in adipose tissues of ventromedial hypothalamus (VMH)-lesioned rats. Biochem Biophys Res Commun 1995;211:469-75.
155. Frederich RC, Lollmann B, Hamann A, et al. Expression of ob mRNA and its encoded protein in rodents. J Clin Invest 1996;96:1658-63.
156. Rosenbaum M, Leibel R, Hirsch J. Regulation of energy storage, intake and expenditure. N Engl J Med 1997;337:396-407.
157. Mueller W, Gregoire F, Stanhope K, et al. Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes. Endocrinology 1998;139:551-8.
158. Slicker LJ, Sloop KW, Surface PL, et al. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 1996;271:5301-4.
159. De Vos P, Saladin R, Auwerx J, Staels B. Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J Biol Chem 1995;270:15958-61.
160. Havel P, Uriu-Hare J, Liu T, et al. Marked and rapid decreases of circulating leptin in streptozotocin diabetic rats: reversal by insulin. Am J Physiol 1998;274:R1482-91.
161. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest 1967;46:1549-57.
162. Woods SC, Stein LJ, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 1979;282:503-5.
163. Brief DJ, Davis JD. Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res Bull 1984;12:571-5.
164. Ikeda H, West DB, Pustek JJ, et al. Intraventricular insulin reduces food intake and body weight of lean but not obese Zucker rats. Appetite 1986;7:381-6.
165. Foster LA, Ames NK, Emery RS. Food intake and serum insulin responses to intraventricular infusions of insulin and IGF-I. Physiol Behav 1991;50:745-9.
166. Florant GL, Singer L, Scheurink AJ, Park CR, Richardson RD, Woods SC. Intraventricular insulin reduces food intake and body weight of marmots during the summer feeding period. Physiol Behav 1991;49:335-8.
167. Baskin DG, Sipols AJ, Schwartz MW, White MF. Immunocytochemical detection of insulin receptor substrate-1 (IRS-1) in rat brain: colocalization with phosphotyrosine. Regul Pept 1993;48:257-66.
168. Steffens AB, Scheurink AJ, Porte D Jr, Woods SC. Penetration of peripheral glucose and insulin into cerebrospinal fluid in the rat. Am J Physiol 1988;255:R200-4.
169. Schwartz MW, Bergman RN, Kahn SE, et al. Evidence for uptake of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. J Clin Invest 1991;88:1272-81.
170. Schwartz MW, Sipols AJ, Kahn SE, et al. Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol 1990;259:E378-83.
171. Wallum BJ, Taborsky GJ Jr, Porte D Jr, et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 1987;64:190-4.
172. Stein LJ, Dorsa DM, Baskin DG, Figlewicz DP, Porte D Jr, Woods SC. Reduced effect of experimental peripheral hyperinsulinemia to elevate cerebrospinal fluid insulin concentrations of obese Zucker rats. Endocrinology 1987;121:1611-5.
173. Baura G, Foster D, Porte D Jr, et al. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo: a mechanism for regulated insulin delivery to the brain. J Clin Invest 1993;92:1824-30.
174. Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 1987;420:32-8.
175. Wu D, Yang J, Pardridge W. Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor. J Clin Invest 1997;100:1804-12.
176. The DCCT Study Group. Weight gain associated with intensive therapy in the Diabetes Control and Complications Trial. Diabetes Care 1988;11:567-73.
177. Riedy CA, Chavez M, Figlewicz DP, Woods SC. Central insulin enhances sensitivity to cholecystokinin. Physiol Behav 1995;58:755-60.
178. Schwartz MW, Dallman MF, Woods SC. The hypothalamic response to starvation: implications for the study of wasting disorders. Am J Physiol 1995;269:R949-57.
179. Chavez M, Seeley R, Green P, Wilkinson C, Schwartz M, Woods S. Adrenalectomy increases sensitivity to central insulin. Physiol Behav 1997;62:631-4.
180. Ponsalle P, Srivastava LS, Uht RM, White JD. Glucocorticoids are required for food deprivation-induced increases in hypothalamic neuropeptide Y expression. J Neuroendocrinol 1993;4:585-91.