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A heliocentric view of leptin

Published online by Cambridge University Press:  05 March 2007

Gema Frühbeck*
Affiliation:
Department of Endocrinology, Clínica Universitaria de Navarra and Metabolic Research Laboratory, University of Navarra, 31008 – Pamplona, Spain
*
Corresponding Author: Gema Frühbeck fax +34 948 29 65 00, email [email protected]
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Abstract

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Leptin is significantly broadening our understanding of the mechanisms underlying neuroendocrine function. Initially, based on a rather static view of the hormone, most investigations focused on the effects of leptin on food intake control and body-weight homeostasis, with attention primarily focused on the implications of leptin as a lipostatic factor and central satiety agent. However, the almost ubiquitous distribution of leptin receptors in peripheral tissues provided a fertile area for investigation and a more dynamic view of leptin started to unfold. This adipocyte-derived circulating peptidic hormone, with a tertiary structure resembling that of members of the long-chain helical cytokine family, has generated an enormous interest in the interaction as well as integration between brain targets and peripheral signals. Considerable evidence for systemic effects of leptin on specific tissues and metabolic pathways indicates that leptin operates both directly and indirectly to orchestrate complex pathophysiological processes. Disentangling the biochemical and molecular mechanisms in which leptin is involved represents one of the major challenges ahead.

Type
Nutrition Society Medal Lecture
Copyright
Copyright © The Nutrition Society 2001

References

Ahima, RS & Flier, JS (2000) Leptin. Annual Review of Physiology 62, 413437.CrossRefGoogle ScholarPubMed
Ahren, B, Mansson, S, Gingerich, RL & Havel, PJ (1997) Regulation of plasma leptin in mice: influence of age, high-fat diet, and fasting. American Journal of Physiology 273, R113R120.Google ScholarPubMed
Andersson, K, Gaudiot, N, Ribiere, C, Elizalde, M, Giudicelli, Y & Arner, P (1999) A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo. British Journal of Pharmacology 126, 16391645.CrossRefGoogle ScholarPubMed
Aoki, N, Kawamura, M & Matsuda, T (1999) Lactation-dependent down regulation of leptin production in mouse mammary gland. Biochimica et Biophysica Acta 1427, 298306.CrossRefGoogle ScholarPubMed
Ascherio, A, Rimm, EB, Giovannucci, EL, Colditz, GA, Rosner, B, Willett, WC, Sacks, F & Stampfer, MJ (1992) A prospective study of nutritional factors and hypertension among US men. Circulation 86, 14751484.CrossRefGoogle ScholarPubMed
Bado, A, Levasseur, S, Attoub, S, Kermorgant, S, Laigneau, JP, Bortoluzzi, MN, Moizo, L, Lehy, T, Guerre Millo, M, Le Marchand Brustel, Y & Lewin, MJ (1998) The stomach is a source of leptin. Nature 394, 790793.CrossRefGoogle ScholarPubMed
Bai, Y, Zhang, S, Kim, KS, Lee, JK & Kim, KH (1996) Obese gene expression alters the ability of 30A5 preadipocytes to respond to lipogenic hormones. Journal of Biological Chemistry 271, 1393913942.CrossRefGoogle ScholarPubMed
Baumann, H, Morella, KK, White, DW, Dembski, M, Bailon, PS, Kim, H, Lai, C-F, & Tartaglia, LA (1996) The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proceedings of the National Academy of Sciences USA 93, 83748378.CrossRefGoogle ScholarPubMed
Birkenmeier, G, Kampfer, I, Kratzsch, J & Schellenberger, W (1998) Human leptin forms complexes with a2-macroglobulin which are recognized by the a2-macroglobulin receptor/low density lipoprotein receptor-related protein. European Journal of Endocrinology 139, 224230.CrossRefGoogle Scholar
Bjørbæck, C, El Haschimi, K, Frantz, JD & Flier, JS (1999) The role of SOCS-3 in leptin signaling and leptin resistance. Journal of Biological Chemistry 274, 3005930065.CrossRefGoogle Scholar
Bjørbæck, C, Elmquist, JK, Frantz, JD, Shoelson, SE & Flier, JS (1998) Identification of SOCS-3 as a potential mediator of central leptin resistance. Molecular Cell 1, 619625.CrossRefGoogle Scholar
Bjørbæck, C, Uotani, S, da Silva, B & Flier, JS (1997) Divergent signaling capacities of the long and short isoforms of the leptin receptor. Journal of Biological Chemistry 272, 3268632695.CrossRefGoogle Scholar
Bornstein, SR & Torpy, DJ (1998) Leptin and the renin-angiotensin-aldosterone system. Hypertension 32, 376377.CrossRefGoogle ScholarPubMed
Bouloumie, A, Drexler, HC, Lafontan, M & Busse, R (1998) Leptin, the product of Ob gene, promotes angiogenesis. Circulation Research 83, 10591066.CrossRefGoogle Scholar
Butte, NF, Hopkinson, JM & Nicolson, MA (1997) Leptin in human reproduction: serum leptin levels in pregnant and lactating women. Journal of Clinical Endocrinology and Metabolism 82, 585589.CrossRefGoogle ScholarPubMed
Campfield, LA, Smith, FJ, Guisez, Y, Devos, R & Burn, P (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546549.CrossRefGoogle ScholarPubMed
Cardillo, C, Kilcoyne, CM, Quyyumi, AA, Cannon, RO III & Panza, JA (1998) Selective defect in nitric oxide synthesis may explain the impaired endothelium-dependent vasodilation in patients with essential hypertension. Circulation 97, 851856.CrossRefGoogle ScholarPubMed
Caro, JF, Kolaczynski, JW, Nyce, MR, Ohannesian, JP, Opentanova, I, Goldman, WH, Lynn, RB, Zhang, PL, Sinha, MK & Considine, RV (1996a) Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159161.CrossRefGoogle ScholarPubMed
Caro, JF, Sinha, MK, Kolaczynski, JW, Zhang, PL & Considine, RV (1996b) Leptin: the tale of an obesity gene. Diabetes 45, 14551462.CrossRefGoogle ScholarPubMed
Casabiell, X, Piñeiro, V, Tomé, MA, Peinó, R, Diéguez, C & Casanueva, FF (1997) Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake. Journal of Clinical Endocrinology and Metabolism 82, 42704273.CrossRefGoogle ScholarPubMed
Casto, RM, VanNess, JM & Overton, JM (1998) Effects of central leptin administration on blood pressure in normotensive rats. Neuroscience Letters 246, 2932.CrossRefGoogle ScholarPubMed
Chagnon, YC, Chung, WK, Perusse, L, Chagnon, M, Leibel, RL & Bouchard, C (1999) Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Quebec Family Study. International Journal of Obesity 23, 278286.CrossRefGoogle ScholarPubMed
Chehab, FF (2000) Leptin as a regulator of adipose mass and reproduction. Trends in Pharmacological Science 21, 309314.CrossRefGoogle ScholarPubMed
Chehab, FF, Lim, ME & Lu, RH (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics 12, 318320.CrossRefGoogle ScholarPubMed
Chehab, FF, Mounzih, K, Lu, R & Lim, ME (1997) Early onset of reproductive function in normal female mice treated with leptin. Science 275, 8890.CrossRefGoogle ScholarPubMed
Chen, G, Koyama, K, Yuan, X, Lee, Y, Zhou, YT, O'Doherty, R, Newgard, CB & Unger, RH (1996) Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proceedings of the National Academy of Sciences USA 93, 1479514799.CrossRefGoogle ScholarPubMed
Chua, SC, Chung, WK & Wu-Peng, XS (1996) Phenotypes of mouse diabetes and rat fatty mutations in the OB (leptin) receptor. Science 271, 994996.CrossRefGoogle ScholarPubMed
Chung, WK, Power Kehoe, L, Chua, M, Chu, F, Aronne, L, Huma, Z, Sothern, M, Udall, JN, Kahle, B & Leibel, RL (1997) Exonic and intronic sequence variation in the human leptin receptor gene (LEPR). Diabetes 46, 15091511.CrossRefGoogle ScholarPubMed
Cioffi, JA, Shafer, AW, Zupancic, TJ, Smith-Gbur, J, Mikhail, A, Platika, D & Snodgrass, HR (1996) Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nature Medicine 2, 585589.CrossRefGoogle ScholarPubMed
Clement, K, Vaisse, C, Lahlou, N, Cabrol, S, Pelloux, V, Cassuto, D, Gourmelen, M, Dina, C, Chambaz, J, Lacorte, JM, Basdevant, A, Bougneres, P, Lebouc, Y, Froguel, P & Guy-Grand, B (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398401.CrossRefGoogle ScholarPubMed
Cohen, SL, Halaas, JL, Friedman, JM, Chait, BT, Bennett, L, Chang, D, Hecht, R & Collins, F (1996) Human leptin characterization. Nature 382, 589.CrossRefGoogle ScholarPubMed
Coleman, DL (1973) Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294298.CrossRefGoogle ScholarPubMed
Coleman, DL (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14, 141148.CrossRefGoogle ScholarPubMed
Coleman, DL & Hummel, KP (1969) Effects of parabiosis of normal with genetically diabetic mice. American Journal of Physiology 217, 12981304.CrossRefGoogle ScholarPubMed
Considine, RV, Considine, EL, Williams, CJ, Hyde, TM & Caro, JF (1996a) The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations. Diabetes 45 992994.CrossRefGoogle ScholarPubMed
Considine, RV, Sinha, MK, Heiman, ML, Kriauciunas, A, Stephens, TW, Nyce, MR, Ohannesian, JP, Marco, CC, McKee, LJ, Bauer, TL & Caro, JF (1996b) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine 334, 292295.CrossRefGoogle ScholarPubMed
De Vos, P, Lefebvre, AM, Miller, SG, Guerre-Millo, M, Wong, K, Saladin, R, Hamann, LG, Staels, B, Briggs, MR & Auwerx, J (1996) Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor g. Journal of Clinical Investigation 98, 10041009.CrossRefGoogle Scholar
Diamond, FB Jr, Eichler, DC, Duckett, G, Jorgensen, EV, Shulman, D & Root, AW (1997) Demonstration of a leptin binding factor in serum. Biochemical and Biophysical Research Communications 233, 818822.CrossRefGoogle Scholar
Diekman, MJ, Romijn, JA, Endert, E, Sauerwein, H & Wiersinga, WM (1998) Thyroid hormones modulate serum leptin levels: observations in thyrotoxic and hypothyroid women. Thyroid 8, 10811086.CrossRefGoogle ScholarPubMed
Ducy, P, Amling, M, Takeda, S, Priemel, M, Schilling, AF, Beil, FT, Shen, J, Vinson, C, Rueger, JM & Karsenty, G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100, 195207.CrossRefGoogle ScholarPubMed
Dunbar, JC, Hu, Y & Lu, H (1997) Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes 46, 20402043.CrossRefGoogle ScholarPubMed
Echwald, SM, Sorensen, TD, Sorensen, TI, Tybjaerg Hansen, A, Andersen, T, Chung, WK, Leibel, RL & Pedersen, O (1997) Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity. Biochemical and Biophysical Research Communications 233, 248252.CrossRefGoogle ScholarPubMed
Farooqi, IS, Jebb, SA, Langmack, G, Lawrence, E, Cheetham, CH, Prentice, AM, Hughes, IA, McCamish, MA & O'Rahilly, S (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine 341, 879884.CrossRefGoogle Scholar
Fisker, S, Vahl, N, Hansen, TB, Jørgensen, JOL, Hagen, C, Ørskov, H & Christiansen, JS (1997) Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year. Metabolism 46, 812817.CrossRefGoogle ScholarPubMed
Flier, JS (1995) The adipocyte: storage depot or node on the energy information superhighway? Cell 80, 1518.CrossRefGoogle ScholarPubMed
Flier, JS (1998) What's in a name? In search of leptin's physiologic role. Journal of Clinical Endocrinology and Metabolism 83, 14071413.Google Scholar
Florkowski, CM, Collier, GR, Zimmet, PZ, Livesey, JH, Espiner, EA & Donald, RA (1996) Low-dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency. Clinical Endocrinology 45, 769773.CrossRefGoogle ScholarPubMed
Francke, S, Clement, K, Dina, C, Inoue, H, Behn, P, Vatin, V, Basdevant, A, Guy Grand, B, Permutt, MA, Froguel, P & Hager, J (1997) Genetic studies of the leptin receptor gene in morbidly obese French Caucasian families. Human Genetics 100, 491496.CrossRefGoogle ScholarPubMed
Frank, S, Stallmeyer, B, Kämpfer, H, Kolb, N & Pfeilschifter, J (2000) Leptin enhances wound re-epithelialization and constitutes a direct function of leptin in skin repair. Journal of Clinical Investigation 106, 501509.CrossRefGoogle ScholarPubMed
Frühbeck, G (1997) Leptin involvement in reproductive performance. Journal of Nutrition 127, 1533.CrossRefGoogle ScholarPubMed
Frühbeck, G (1999) Pivotal role of nitric oxide in the control of blood pressure following leptin administration. Diabetes 48, 903908.CrossRefGoogle ScholarPubMed
Frühbeck, G, Aguado, M, Gómez-Ambrosi, J & Martínez, JA (1998a) Lipolytic effect of in vivo leptin administration on adipocytes of lean and ob/ob mice, but not db/db mice. Biochemical and Biophysical Research Communications 250, 99102.CrossRefGoogle Scholar
Frühbeck, G, Aguado, M & Martínez, JA (1997) In vitro lipolytic effect of leptin on mouse adipocytes: evidence for a possible autocrine-paracrine role of leptin. Biochemical and Biophysical Research Communications 240, 590594.CrossRefGoogle ScholarPubMed
Frühbeck, G, Díez-Caballero, A, Salvador, J & Alvarez-Cienfuegos, J (2000) Chronobiology of recombinant leptin therapy. Journal of the American Medical Association 283, 1567.CrossRefGoogle ScholarPubMed
Frühbeck, G, García-Granero, M & Martínez, JA (1998b) Age-related differences in the thermogenic and ponderal effects following the administration of fragment peptides from the rat ob protein. Regulatory Peptides 73, 8387.CrossRefGoogle ScholarPubMed
Frühbeck, G & Gómez-Ambrosi, J (2000a) Involvement of nitric oxide in the lipolytic effect of leptin. European Journal of Clinical Investigation 30, Suppl. 1, 43Abstr.Google Scholar
Frühbeck, G & Gómez-Ambrosi, J (2000b) Lipolytic effect of leptin and nitric oxide on isolated white adipocytes. International Journal of Obesity 24, Suppl. 1, S46Abstr.Google Scholar
Frühbeck, G, Gómez-Ambrosi, J & Martínez, JA (1999) Pre- and postprandial expression of the leptin receptor splice variants OB-Ra and OB-Rb in murine peripheral tissues. Physiological Research 48, 189195.Google ScholarPubMed
Frühbeck, G, Jebb, SA & Prentice, AM (1998c) Leptin: physiology and pathophysiology. Clinical Physiology 18, 399419.CrossRefGoogle ScholarPubMed
Frühbeck, G & Salvador, J (2000a) Relation between leptin and glucose metabolism. Diabetologia 43, 110.Google ScholarPubMed
Frühbeck, G & Salvador, J (2000b) Is leptin involved in the signaling cascade after myocardial ischemia and reperfusion? Circulation 101, e194.CrossRefGoogle ScholarPubMed
Gainsford, T, Willson, TA, Metcalf, D, Handman, E, McFarlane, C, Ng, A, Nicola, NA, Alexander, WS & Hilton, DJ (1996) Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proceedings of the National Academy of Sciences USA 93, 1456414568.CrossRefGoogle ScholarPubMed
Garcia-Mayor, RV, Andrade, MA, Rios, M, Lage, M, Dieguez, C & Casanueva, FF (1997) Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. Journal of Clinical Endocrinology and Metabolism 82, 28492855.Google ScholarPubMed
Gaudiot, N, Jaubert, A-M, Charbonnier, E, Sabourault, D, Lacasa, D, Giudicelli, Y & Ribière, C (1998) Modulation of white adipose tissue lipolysis by nitric oxide. Journal of Biological Chemistry 273, 1347513481.CrossRefGoogle ScholarPubMed
Gavrilova, O, Barr, V, Marcus-Samuels, B & Reitman, M (1997) Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor. Journal of Biological Chemistry 272, 3054630551.CrossRefGoogle ScholarPubMed
Ghilardi, N, Ziegler, S, Wiestner, A, Stoffel, R, Heim, MH & Skoda, R (1996) Defective STAT signaling by the leptin receptor in diabetic mice. Proceedings of the National Academy of Sciences USA 93, 62316235.CrossRefGoogle ScholarPubMed
Gotoda, T, Manning, BS, Goldstone, AP, Imrie, H, Evans, AL, Strosberg, AD, McKeigue, PM, Scott, J & Aitman, TJ (1997) Leptin receptor gene variation and obesity: lack of association in a white British male population. Human and Molecular Genetics 6, 869876.CrossRefGoogle Scholar
Grasso, P, Leinung, MC, Ingher, SP & Lee, DW (1997) In vivo effects of leptin-related synthetic peptides on body weight and food intake in female ob/ob mice: localization of leptin activity to domains between amino acid residues 106–140. Endocrinology 138, 14131418.CrossRefGoogle ScholarPubMed
Grunfeld, C, Zhao, C, Fuller, J, Pollack, A, Moser, A, Friedman, J & Feingold, KR (1996) Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. Journal of Clinical Investigation 97, 21522157.CrossRefGoogle ScholarPubMed
Gualillo, O, Lago, F, Garcia, M, Menendez, C, Senaris, R, Casanueva, FF & Dieguez, C (1999) Prolactin stimulates leptin secretion by rat white adipose tissue. Endocrinology 140, 51495153.CrossRefGoogle ScholarPubMed
Halaas, JL, Gajiwala, KS, Maffei, M, Cohen, SL, Chait, BT, Rabinowitz, D, Lallone, RL, Burley, SK & Friedman, JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543546.CrossRefGoogle ScholarPubMed
Hall, JE (1994) Renal and cardiovascular mechanisms of hypertension in obesity. Hypertension 23, 381394.CrossRefGoogle ScholarPubMed
Hall, JE, Brands, MW & Henegar, JR (1999) Mechanisms of hypertension and kidney disease in obesity. Annals of the New York Academy of Sciences 892, 91107.CrossRefGoogle ScholarPubMed
Hamilton, BS, Paglia, D, Kwan, AY & Deitel, M (1995) Increased obese mRNA expression in omental fat cells from massively obese humans. Nature Medicine 1, 953956.CrossRefGoogle ScholarPubMed
Hardie, L, Trayhurn, P, Abramovich, D & Fowler, P (1997) Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy. Clinical Endocrinology 47, 101106.CrossRefGoogle ScholarPubMed
Harigaya, A, Nagashima, K, Nako, Y & Morikawa, A (1997) Relationship between concentration of serum leptin and fetal growth. Journal of Clinical Endocrinology and Metabolism 82, 32813284.CrossRefGoogle ScholarPubMed
Harris, RBS (2000) Leptin – much more than a satiety signal. Annual Review of Nutrition 20, 4575.CrossRefGoogle ScholarPubMed
Hausberger, FX (1959) Parabiosis and transplantation experiments in hereditarily obese mice. Anatomical Record 130, 313.Google Scholar
Haynes, WG, Morgan, DA, Walsh, SA, Mark, AL & Sivitz, WI (1997) Receptor-mediated regional sympathetic nerve activation by leptin. Journal of Clinical Investigation 100, 270278.CrossRefGoogle ScholarPubMed
He, Y, Chen, H, Quon, MJ & Reitman, M (1995) The mouse obese gene. Genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein a. Journal of Biological Chemistry 270, 2888728891.CrossRefGoogle Scholar
Heaney, ML & Golde, DW (1993) Soluble hormone receptors. Blood 82, 19451948.CrossRefGoogle ScholarPubMed
Hervey, GR (1959) The effects of lesions in the hypothalamus in parabiotic rats. Journal of Physiology 145, 336352.CrossRefGoogle ScholarPubMed
Himms-Hagen, J (1999) Physiological roles of the leptin endocrine system: differences between mice and humans. Critical Reviews in Clinical Laboratory Sciences 36, 575655.CrossRefGoogle ScholarPubMed
Hoggard, N, Hunter, L, Lea, RG, Trayhurn, P & Mercer, JG (2000) Ontogeny of the expression of leptin and its receptor in the murine fetus and placenta. British Journal of Nutrition 83, 317326.CrossRefGoogle ScholarPubMed
Hoggard, N, Hunter, L, Trayhurn, P, Williams, LM & Mercer, JG (1998) Leptin and reproduction. Proceedings of the Nutrition Society 57, 421427.CrossRefGoogle ScholarPubMed
Hoggard, N, Mercer, JG, Rayner, DV, Moar, K, Trayhurn, P & Williams, LM (1997) Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization. Biochemical and Biophysical Research Communications 232, 383387.CrossRefGoogle ScholarPubMed
Holness, MJ, Munns, MJ & Sugden, MC (1999) Current concepts concerning the role of leptin in reproductive function. Molecular and Cellular Endocrinology 157, 1120.CrossRefGoogle ScholarPubMed
Houseknecht, KL, Mantzoros, CS, Kuliawat, R, Hadro, E, Flier, JS & Kahn, BB (1996) Evidence for leptin binding proteins in serum of rodents and humans: modulation with obesity. Diabetes 45, 16381643.CrossRefGoogle ScholarPubMed
Howard, JK, Lord, GM, Matarese, G, Vendetti, S, Ghatei, MA, Ritter, MA, Lechler, RI & Bloom, SR (1999) Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. Journal of Clinical Investigation 104, 10511059.CrossRefGoogle ScholarPubMed
Hsueh, WA & Buchanan, TA (1994) Obesity and hypertension. Endocrine Hypertension 23, 405427.Google ScholarPubMed
Hwa, JJ, Fawzi, AB, Graziano, MP, Ghibaudi, L, Williams, P, Van-Heek, M, Davis, H, Rudinski, M, Sybertz, E & Strader, CD (1997) Leptin increases energy expenditure and selectively promotes fat metabolism in ob/ob mice. American Journal of Physiology 272, R1204R1209.Google ScholarPubMed
Jackson, EK & Li, P (1997) Human leptin has natriuretic activity in the rat. American Journal of Physiology 272, F333F338.Google ScholarPubMed
Jenkins, AB, Markovic, TP, Fleury, A & Campbell, LV (1997) Carbohydrate intake and short-term regulation of leptin in humans. Diabetologia 40, 348351.CrossRefGoogle ScholarPubMed
Kennedy, A, Gettys, TW, Watson, P, Wallace, P, Ganaway, E, Pan, Q & Garvey, T (1997) The metabolic significance of leptin in humans: gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. Journal of Clinical Endocrinology and Metabolism 82, 12931300.Google ScholarPubMed
Kirchgessner, TG, Uysal, KT, Wiesbrock, SM, Marino, MW & Hotamisligil, GS (1997) Tumor necrosis factor a contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. Journal of Clinical Investigation 100, 27772782.CrossRefGoogle ScholarPubMed
Lau, DCW, Shillabeer, G, Li, Z-H, Wong, K-L, Varzaneh, FE & Tough, SC (1996) Paracrine interactions in adipose tissue development and growth. International Journal of Obesity 23, Suppl. 3,S16S25.Google Scholar
Lee, G-H, Proenca, R, Monte, JM, Carroll, KM, Darvishzadeh, JG, Lee, JI & Friedman, JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632635.CrossRefGoogle ScholarPubMed
Levin, N, Nelson, C, Gurney, A, Vandlen, R & de Sauvage, F (1996) Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proceedings of the National Academy of Sciences USA 93, 17261730.CrossRefGoogle Scholar
Licinio, J, Mantzoros, C, Negrao, AB, Cizza, G, Wong, M-L, Bongiorno, PB, Chrousos, GP, Karp, B, Allen, C, Flier, JS & Gold, PW (1997) Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nature Medicine 3, 575579.CrossRefGoogle ScholarPubMed
Lönnqvist, F, Arner, P, Nordfors, L & Schalling, M (1995) Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nature Medicine 1, 950953.CrossRefGoogle ScholarPubMed
Lord, GM, Matarese, G, Howard, JK, Baker, RJ, Bloom, SR & Lechler, RI (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897901.CrossRefGoogle ScholarPubMed
Lyons, D, Roy, S, Patel, M, Benjamin, N & Swift, CG (1997) Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age. Clinical Science 93, 519523.CrossRefGoogle ScholarPubMed
MacDougald, OA, Hwang, C-S, Fan, H & Lane, MD (1995) Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3 adipocytes. Proceedings of the National Academy of Sciences USA 92, 90349037.CrossRefGoogle Scholar
Madej, T, Boguski, MS & Bryant, SH (1995) Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Letters 373, 1318.CrossRefGoogle ScholarPubMed
Maffei, M, Halaas, J, Ravussin, E, Pratley, RE, Lee, GH, Zhang, Y, Fei, H, Kim, S, Lallone, R, Ranganathan, S, Kern, PA & Friedman, JM (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine 1, 11551161.CrossRefGoogle ScholarPubMed
Mantzoros, CS, Flier, JS & Rogol, AD (1997a) A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. Journal of Clinical Endocrinology and Metabolism 82, 10661070.Google Scholar
Mantzoros, CS, Moschos, S, Avramopoulos, I, Kaklamani, V, Liolios, A, Doulgerakis, DE, Griveas, I, Katsilambros, N & Flier, JS (1997b) Leptin concentrations in relation to body mass index and the tumor necrosis factor-a system in humans. Journal of Clinical Endocrinology and Metabolism 82, 34083413.Google Scholar
Mantzoros, CS, Rosen, HN, Greenspan, SL, Flier, JS & Moses, AC (1997c) Short-term hyperthyroidism has no effect on leptin levels in man. Journal of Clinical Endocrinology and Metabolism 82, 497499.Google ScholarPubMed
Mark, AL, Correia, M, Morgan, DA, Shaffer, RA & Haynes, WG (1999) State-of-the-art-lecture: Obesity-induced hypertension: new concepts from the emerging biology of obesity. Hypertension 33, 537541.CrossRefGoogle ScholarPubMed
Masuzaki, H, Ogawa, Y, Isse, N, Satoh, N, Okazaki, T, Shigemoto, M, Mori, K, Tamura, N, Hosoda, K, Yoshimasa, Y, Jingami, H, Kawada, T & Nakao, K (1996) Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 44, 855858.CrossRefGoogle Scholar
Masuzaki, H, Ogawa, Y, Sagawa, N, Hosoda, K, Matsumoto, T, Mise, H, Nishimura, H, Yoshimasa, Y, Tanaka, I, Mori, T & Nakao, K (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nature Medicine 3, 10291033.CrossRefGoogle ScholarPubMed
Matsuda, J, Yokota, I, Iida, M, Murakami, T, Naito, E, Ito, M, Shima, K & Kuroda, Y (1997) Serum leptin concentration in cord blood: relationship to birth weight and gender. Journal of Clinical Endocrinology and Metabolism 82, 16421644.CrossRefGoogle Scholar
Matsuoka, N, Ogawa, Y, Hosoda, K, Matsuda, J, Masuzaki, H, Miyawaki, T, Azuma, N, Natsui, K, Nishimura, H, Yoshimasa, Y, Nishi, S, Thompson, DB & Nakao, K (1997) Human leptin receptor gene in obese Japanese subjects: evidence against either obesity causing mutations or association of sequence variants with obesity. Diabetologia 40, 12041210.CrossRefGoogle ScholarPubMed
Miller, SG, De Vos, P, Guerre-Millo, M, Wong, K, Hermann, T, Staels, B, Briggs, MR & Auwerx, J (1996) The adipocyte specific transcription factor C/EBPa modulates human ob gene expression. Proceedings of the National Academy of Sciences USA 93, 55075511.CrossRefGoogle Scholar
Montague, CT, Farooqi, IS, Whitehead, JP, Soos, MA, Rau, H, Wareham, NJ, Sewter, CP, Digby, JE, Mohammed, SN, Hurst, JA, Cheetham, CH, Earley, AR, Barnett, AH, Prins, JB & O'Rahilly, S (1997a) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903908.CrossRefGoogle ScholarPubMed
Montague, CT, Prins, JB, Sanders, L, Digby, JE & O'Rahilly, S (1997b) Depot- and sex-specific differences in human leptin mRNA expression. Implications for the control of regional fat distribution. Diabetes 46, 342347.CrossRefGoogle ScholarPubMed
Morley, JE & Mattammal, MB (1996) Nitric oxide synthase levels in obese Zucker rats. Neuroscience Letters 209, 137139.CrossRefGoogle ScholarPubMed
Mounzih, K, Lu, R & Chehab, FF (1997) Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 138, 11901193.CrossRefGoogle ScholarPubMed
Ozata, M, Ozdemir, IC & Licinio, J (1999) Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. Journal of Clinical Endocrinology and Metabolism 84, 36863695.CrossRefGoogle Scholar
Ozata, M, Ozisik, G, Bingol, N, Corakci, A & Gundogan, MA (1998) The effects of thyroid status on plasma leptin levels in women. Journal of Endocrinological Investigation 21, 337341.CrossRefGoogle ScholarPubMed
Pelleymounter, MA, Cullen, MJ, Baker, MB, Hecht, R, Winters, D, Boone, T & Collins, F (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540543.CrossRefGoogle ScholarPubMed
Pinkney, JH, Goodrick, SJ, Katz, J, Johnson, AB, Lightman, SL, Coppack, SW & Mohamed-Ali, V (1998) Leptin and the pituitary-thyroid axis: a comparative study in lean, obese, hypothyroid and hyperthyroid subjects. Clinical Endocrinology 49, 583588.CrossRefGoogle Scholar
Rau, H, Reaves, BJ, O'Rahilly, S & Whitehead, JP (1999) Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport. Endocrinology 140, 17181723.CrossRefGoogle ScholarPubMed
Ribière, C, Jaubert, AM, Gaudiot, N, Sabourault, D, Marcus, ML, Boucher, JL, Denis-Henriot, D & Giudicelli, Y (1996) White adipose tissue nitric oxide synthase: a potential source for NO production. Biochemical and Biophysical Research Communications 222, 706712.CrossRefGoogle ScholarPubMed
Rolland, V, Clement, K, Dugail, I, Guy Grand, B, Basdevant, A, Froguel, P & Lavau, M (1998) Leptin receptor gene in a large cohort of massively obese subjects: no indication of the fa/fa rat mutation. Detection of an intronic variant with no association with obesity. Obesity Research 6, 122127.CrossRefGoogle Scholar
Rosenbaum, M, Nicolson, M, Hirsch, J, Heymsfield, SB, Gallagher, D, Chu, F & Leibel, RL (1996) Effects of gender, body composition, and menopause on plasma concentrations of leptin. Journal of Clinical Endocrinology and Metabolism 81, 34243427.Google ScholarPubMed
Ruige, JB, Dekker, JM, Blum, WF, Stehouwer, CD, Nijpels, G, Mooy, J, Kostense, PJ, Bouter, LM & Heine, RJ (1999) Leptin and variables of body adiposity, energy balance, and insulin resistance in a population-based study. The Hoorn Study. Diabetes Care 22, 10971104.CrossRefGoogle Scholar
Russell, JC, Graham, SE, Dolphin, PJ, Amy, RM, Wood, GO & Brindley, DN (1997) Antiatherogenic effects of long-term benfluorex treatment in male insulin resistant JCR:LA-cp rats. Atherosclerosis 132, 187197.CrossRefGoogle ScholarPubMed
Saad, MF, Damani, S, Gingerich, RL, Riad-Gabriel, MG, Khan, A, Boyadjian, R, Jinagouda, SD, El-Tawil, K, Rude, RK & Kamdar, V (1997) Sexual dimorphism in plasma leptin concentration. Journal of Clinical Endocrinology and Metabolism 82, 579584.Google ScholarPubMed
Saladin, R, De Vos, P, Guerre-Millo, M, Leturque, A, Girard, J, Staels, B & Auwerx, J (1995) Transient increase in obese gene expression after food intake or insulin administration. Nature 377, 527529.CrossRefGoogle ScholarPubMed
Schorr, U, Blaschke, K, Turan, S, Distler, A & Sharma, AM (1998) Relationship between angiotensinogen, leptin and blood pressure levels in young normotensive men. Journal of Hypertension 16, 14751480.CrossRefGoogle ScholarPubMed
Schubring, C, Kiess, W, Englaro, P, Rascher, W, Dötsch, J, Hanitsch, S, Attanasio, A & Blum, WF (1997) Levels of leptin in maternal serum, amniotic fluid, and arterial and venous cord blood: relation to neonatal and placental weight. Journal of Clinical Endocrinology and Metabolism 82, 14801483.CrossRefGoogle ScholarPubMed
Serrero, G & Lepak, N (1996) Endocrine and paracrine negative regulators of adipose differentiation. International Journal of Obesity 23, Suppl. 3, S58S64.Google Scholar
Shek, EW, Brands, MW & Hall, JE (1998) Chronic leptin infusion increases arterial pressure. Hypertension 31, 409414.CrossRefGoogle ScholarPubMed
Shimabukuro, M, Koyama, K, Chen, G, Wang, MY, Trieu, F, Lee, Y, Newgard, CB & Unger, RH (1997) Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proceedings of the National Academy of Sciences USA 94, 46374641.CrossRefGoogle ScholarPubMed
Shimizu, H, Shimomura, Y, Nakanishi, Y, Futawatari, T, Ohtani, K, Sato, N & Mori, M (1997) Estrogen increases in vivo leptin production in rats and human subjects. Journal of Clinical Endocrinology 154, 285292.Google ScholarPubMed
Sierra-Honigmann, MR, Nath, AK, Murakami, C, Garcia-Cardena, G, Papapetropoulos, A, Sessa, WC, Madge, LA, Schechner, JS, Schwabb, MB, Polverini, PJ & Flores-Riveros, JR (1998) Biological action of leptin as an angiogenic factor. Science 281, 16831686.CrossRefGoogle ScholarPubMed
Silver, K, Walston, J, Chung, WK, Yao, F, Parikh, VV, Andersen, R, Cheskin, LJ, Elahi, D, Muller, D, Leibel, RL & Shuldiner, AR (1997) The Gln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate with traits related to obesity. Diabetes 46, 18981900.CrossRefGoogle Scholar
Sinha, MK, Ohannesian, JP, Heiman, ML, Kriauciunas, A, Stephens, TW, Magosin, S, Marco, C & Caro, JF (1996a) Nocturnal rise of leptin in lean, obese and non-insulin-dependent diabetes mellitus subjects. Journal of Clinical Investigation 97, 13441347.CrossRefGoogle ScholarPubMed
Sinha, MK, Opentanova, I, Ohannesian, JP, Kolaczynski, JW, Heiman, ML, Hale, J, Becker, GW, Bowsher, RR, Stephens, TW & Caro, JF (1996b) Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. Journal of Clinical Investigation 98, 12771282.CrossRefGoogle ScholarPubMed
Sinha, MK, Sturis, J, Ohannesian, J, Magosin, S, Stephens, T, Heiman, ML, Polonsky, KS & Caro, JF (1996c) Ultradian oscillations of leptin secretion in humans. Biochemical and Biophysical Research Communications 228, 733738.CrossRefGoogle ScholarPubMed
Strobel, A, Issad, T, Camoin, L, Ozata, M & Strosberg, AD (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genetics 18, 213215.CrossRefGoogle ScholarPubMed
Suter, PM, Locher, R, Hasler, E & Vetter, W (1998) Is there a role for the ob gene product leptin in essential hypertension? American Journal of Hypertension 11, 13051311.CrossRefGoogle Scholar
Tartaglia, LA (1997) The leptin receptor. Journal of Biological Chemistry 272, 60936096.CrossRefGoogle ScholarPubMed
Tartaglia, LA, Dembski, M, Weng, X, Deng, N, Culpepper, J, Devos, R, Richards, GJ, Campfield, LA, Clark, FT, Deeds, J, Muir, C, Sanker, S, Moriarty, A, Moore, KJ, Smutko, JS, Mays, GG, Woolf, EA, Monroe, CA & Tepper, RI (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 12631271.CrossRefGoogle ScholarPubMed
Thompson, DB, Ravussin, E, Bennett, PH & Bogardus, C (1997) Structure and sequence variation at the human leptin receptor gene in lean and obese Pima Indians. Human and Molecular Genetics 6, 675679.CrossRefGoogle ScholarPubMed
Trayhurn, P (1996) New insights into the development of obesity: obese genes and the leptin system. Proceedings of the Nutrition Society 55, 783791.CrossRefGoogle ScholarPubMed
Trayhurn, P, Duncan, JS & Rayner, DV (1995a) Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice: mediation by the sympathetic system. Biochemical Journal 311, 729733.CrossRefGoogle Scholar
Trayhurn, P, Hoggard, N, Mercer, JG & Rayner, DV (1999) Leptin: fundamental aspects. International Journal of Obesity 23, Suppl. 1, 2228.CrossRefGoogle ScholarPubMed
Trayhurn, P, Thomas, MEA, Duncan, JS & Rayner, DV (1995b) Effects of fasting and refeeding on ob gene expression in white adipose tissue of lean and obese (ob/ob) mice. FEBS Letters 368, 488490.Google Scholar
Tritos, NA & Mantzoros, CS (1997) Leptin: its role in obesity and beyond. Diabetologia 40, 13711379.CrossRefGoogle ScholarPubMed
Vaisse, C, Halaas, JL, Horvath, CM, Darnell, JE Jr, Stoffel, M & Friedman, JM (1996) Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nature Genetics 14, 9597.CrossRefGoogle Scholar
Van Cauter, E (1990) Diurnal and ultradian rhythms in human endocrine function: a minireview. Hormone Research 34, 4553.CrossRefGoogle ScholarPubMed
Villarreal, D, Reams, G, Freeman, RH & Taraben, A (1998) Renal effects of leptin in normotensive, hypertensive, and obese rats. American Journal of Physiology 275, R2056R2060.Google ScholarPubMed
Wang, J, Liu, R, Hawkins, M, Barzilai, N & Rossetti, L (1998) A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393, 684688.CrossRefGoogle ScholarPubMed
Wang, M-Y, Lee, Y & Unger, RH (1998) Novel form of lipolysis induced by leptin. Journal of Biological Chemistry 274, 1754117544.CrossRefGoogle Scholar
Wang, Z-W, Zhou, Y-T, Lee, Y, Higa, M, Kalra, SP & Unger, RH (1999) Hyperleptinemia depletes fat from denervated fat tissue. Biochemical and Biophysical Research Communications 260, 653657.CrossRefGoogle ScholarPubMed
Weigle, DS, Duell, B, Connor, WE, Steiner, RA, Soules, MR & Kuijper, JL (1997) Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. Journal of Clinical Endocrinology and Metabolism 82, 561565.Google ScholarPubMed
White, DW, Wang, DW, Chua, SC Jr, Morgenstern, JP, Leibel, RL, Baumann, H & Tartaglia, LA (1997) Constitutive and impaired signaling of leptin receptors containing the Gln ® Pro extracellular domain fatty mutation. Proceedings of the National Academy of Sciences USA 94, 1065710662.CrossRefGoogle ScholarPubMed
Wiesner, G, Vaz, M, Collier, G, Seals, D, Kaye, D, Jennings, G, Lambert, G, Wilkinson, D & Esler, M (1999) Leptin is released from the human brain: influence of adiposity and gender. Journal of Clinical Endocrinology and Metabolism 84, 22702274.Google ScholarPubMed
Wu, X, Makynen, H, Kahonen, M, Arvola, P & Porsti, I (1996) Mesenteric arterial function in vitro in three models of experimental hypertension. Journal of Hypertension 14, 365372.CrossRefGoogle ScholarPubMed
Zamorano, PL, Mahesh, VB, De Sevilla, LM, Chorich, LP, Bhat, GK & Brann, DW (1997) Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat. Neuroendocrinology 65, 223228.CrossRefGoogle ScholarPubMed
Zhang, F, Basinski, MB, Beals, JM, Briggs, SL, Churgay, LM, Clawson, DK, DiMarchi, RD, Furman, TC, Hale, JE, Hsiung, HM, Schoner, BE, Smith, DP, Zhang, XY, Wery, J-P, & Schevitz, RW (1997) Crystal structure of the obese protein leptin-E100. Nature 387, 206209.CrossRefGoogle ScholarPubMed
Zhang, Y, Proenca, R, Maffei, M, Barone, M, Leopold, L & Friedman, JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425432.CrossRefGoogle ScholarPubMed
Zimmet, P, Boyko, EJ, Collier, GR & de Courten, M (1999) Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players. Annals of the New York Academy of Sciences 892, 2544.CrossRefGoogle ScholarPubMed