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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Abuckatatime who wrote (17098)	3/10/1998 3:44:00 PM
From: Henry Niman	Respond to of 32384

Greg Thanks for the heads up. For those who forget to get over there: Leptin Johan Auwerx, Bart Staels Lancet 1998; 351: 737-42 Laboratoire de Biologie des R‚gulations chez les Eucaryotes (U325 INSERM), D‚partement d'Ath‚roscl‚rose, Institut Pasteur, 1 rue Calmette, 59019 Lille, France (J Auwerx MD, B Staels PhD) Correspondence to: Dr Johan Auwerx (e-mail johan.auwerx@pasteur-lille.fr) Leptin, cytokine acting as adipostat Sites of action Leptin as signal of plenty A regulatory role, again? Regulation of leptin expression Leptin's future References Leptin (from the Greek leptos=thin) was identified only 3 years ago. It has attracted huge attention both scentifically, with more than 600 publications, and in the media, where this protein has been portrayed as the way to a cure for obesity. Indeed, leptin was first described as an adipocyte-derived signalling factor, which, after interaction with its receptors, induced a complex response including control of bodyweight and energy expenditure. Leptin seems in addition to its role in metabolic control to have important roles in reproduction and neuroendocrine signalling. Human obesity is a complex disorder, with many factors playing a part; the pathophysiology of leptin is not as simple as it seems to be in rodent models of obesity. Few proteins have received such intense scientific and media coverage as leptin. Since its discovery at the end of 1994, more than 600 papers have appeared, moving modern biology into the field of obesity research. Almost monthly, new molecules with an important role in energy homoeostasis are identified (panel 1), and this new knowledge has changed views on obesity profoundly.1,2 Even so a lot of questions remain to be answered before the complex polygenic nature of human obesity can be understood. In this review we summarise developments with leptin and highlight the important scientific issues that still need to be addressed. We cannot cite every important contribution to research on leptin, and readers seeking more extensive coverage should go to other reviews.1,3-6 Panel 1: Newly identified molecules with important roles in energy balance Molecule Year Notes Leptin 1994 Subject of this review GLP-1 1996 Glucagon-like peptide 1 MCH 1996 Melanin-concentrating hormone M-4-R 1997 Melanocortin-4 receptor MSH, Agouti 1992 Melanocyte-stimulating hormone PPAR 1994 Peroxisome proliferator-activated receptor CRF, Urocortin 1990s Corticotropin-releasing factor UCP-1-3 1997 Uncoupling protein 1-3 Agrp 1997 Agouti-related peptide Leptin, cytokine acting as adipostat Leptin, a 167 aminoacid protein transcribed from the ob gene, was originally cloned in the mouse during research directed at identifying the molecular defect in an obesity-prone strain, the ob/ob mouse.7 The name leptin is derived from the Greek leptos which means thin. The human leptin gene is on chromosome 7q31; its DNA has more than 15000 base-pairs and there are three exons, the major coding sites driving protein synthesis. Leptin is mainly produced in white adipose tissue; very small amounts are found in brown adipose tissue. At first leptin was seen as an adipocyte-derived signalling molecule, which limits food intake and increases energy expenditure7 (figure 1). Evidence supporting the claim that leptin was an adiposat was provided by the decrease in bodyweight and the improvement in metabolic control in rodents with genetic8-12 or diet-induced8 obesity that were injected with leptin. One remarkable effect of leptin is its capacity to improve glucose homoeostasis when injected into laboratory animals9-12 or inserted via adenovirus-mediated gene therapy.13,14 Kamohara and colleagues15 suggested that the improvement in glucose homoeostasis was mediated at least partly by the central nervous system. Figure 1: Schematic model of signalling pathways in which leptin is implicated Neuroendocrine effects include effects on reproductive system as well as on thyroid and adrenal axis; metabolic effects include those on glucose homoeostasis, mediated either via central nervous system or periphery. Leptin achieves most of its metabolic effects by interacting with specific receptors located in the central nervous system and in peripheral tissues (figure 2).16-18 This leptin receptor is a class I cytokine receptor, a family that also includes interleukin-2 receptor, the interferon receptor and the growth hormone receptor (reviewed by Ihle19). The receptor transmits the leptin signal via janus kinase 220 to three signal transducers and activators of transcription (STATS 3, 5, and 6),21-23 a STAT subset known as the "fat-STATS".24 The receptor is encoded by a complex gene generating multiple splice variants17,18,25 and it is mutated in the diabetes-prone db/db mouse,17,18,25 the Zucker fatty rat (fa/fa),25-28 and the spontaneously hypertensive obese Koletsky rat29 but not mutated in the ob/ob mouse and obese mouse. Figure 2: Leptin receptor Binding of leptin to its receptor will induce diverisation of receptor and the Janus kinases (JAK) associated with receptor will induce phosphorylation of tyrosine (Y) residues on the cytoplasmic domains of the receptor, creating phosphotyrosine docking sites for the STAT proteins. After phosphorylation and tyrosine residues of these STAT proteins they will dissociate from the receptor and from dimers, which contribute the active transciptional regulators. After transport into the nucleus, they will bind to STAT responsive elements and the DNA and stimulate transcription of responsive target genes. Sites of action Several lines of evidence suggest that the hypothalamus is a critical target for the satiety effects leptin. Induction of obesity follows experimental lesions of the ventromedial hypothalamus; leptin has a more potent anorectic effect when administered centrally rather than peripherally;8,11 the ob protein is specifically bound to hypothalamic plasma membranes;11 and leptin receptor is expressed in the hypothalamus.16,30 Leptin is transported through the blood/brain barrier via a saturable transport system.21,32 The complete set of genes involved in mediating the downstream effects of activation of the central leptin receptor and of transcription factors on energy metabolism is unknown. One candidate effector molecule is the hypothalamic neuropeptide Y (NPY), a potent stimulator of food intake, of which synthesis is inhibited by leptin.11,33 Studies in animals with a mutated NPY gene show that NPY cannot be the sole mediator of leptin's actions.33,34 Other candidates, of which activity could be modulated by leptin and which are active in the brain, are melanocyte-stimulating hormone and its receptor,35,36 glucagon-like peptide-1,37 corticotropin-releasing hormone or the related factor urocortin,38-40 and melanin-concentrating hormone.41 Evidence is also accumulating for a direct leptin effect on peripheral tissues. Several of the leptin receptor isoforms are expressed in peripheral tissues16-18 and the profound biological responses to leptin in cultured hepatocytes,42 adipocytes,43,45 haemopoietic cells,20,45 and pancreatic islet cells46 supports a peripheral action. The effects on lipid metabolism in cultured cells is especially interesting since it suggests an alternative explanation for the beneficial leptin effects on glucose homoeostasis. Leptin directly inhibits intracellular lipid concentrations by reducing fatty-acid and triglyceride synthesis and concomitantly increasing lipid oxidation.46 This effect on lipid metabolism may be mediated by an inhibitory effect of leptin on acetyl-CoA carboxylase activity, the rate-limiting enzyme in fatty-acid synthesis.43 Inhibition of this enzyme leads to a reduction in malonyl-CoA, an inhibitor of carnitylacyltransferase I and mitochondrial á-oxidation. Inhibition of acetyl-CoA carboxylase will thus block fatty-acid synthesis and favour mitochondrial fatty-acid uptake and oxidation, resulting in lower intracellular fatty-acid and triglyceride concentrations. Unger and coworkers suggest that leptin, by reversing lipid accumulation in several tissues, could have beneficial effects on insulin resistance and á-cell function, ultimately improving glucose homoeostasis.46 It is worth assessing, as Flier5 suggested, whether under conditions of increased fuel oxidation, as seen after leptin, mitochondrial oxidation could be uncoupled from ATP synthesis, resulting in increased thermogenesis. These direct effects of leptin on cellular lipid metabolism are consistent with in vivo studies showing that leptin improves glucose homoeostasis. However, these data are not in line with both the in vitro observation that addition of leptin to cultured hepatoma43 or primary adipocyte44 cells interferes with the insulin-signalling pathway and with the demonstration of a central-nervous-system-mediated effect on glucose homoeostasis.15 These apparent differences between the in vivo and in vitro effects of leptin on insulin signalling and glucose homoeostasis need further study. Leptin as signal of plenty From the evidence summarised above came the suggestion that leptin has an adipostatic function and can decrease bodyweight in obesity. Several observations, however, question whether prevention of obesity or weight gain is leptin's prime or only function. Mutations in the leptin gene in human obesity have proved elusive47,48 and genetic markers flanking the human OB gene seem to be at best only weakly linked to extreme obesity.48-50 This is not too surprising, given the polygenic and complex nature of human obesity. The recently detected frame-shift mutation52 associated with obesity probably accounts for only a minute fraction of the obesity that clinicians encounter. Further clouding optimism about the potential of leptin is the demonstration of high levels of leptin in obesity syndromes in human beings and some laboratory animals. This finding is in sharp contrast to the perceived starvation state in ob/ob mice deficient in leptin.7 Adipose tissue leptin mRNA and plasma leptin levels have been found to be closely correlated with the size of the adipose tissue depot,47,53-57 which suggests that obesity is not caused by an absolute deficiency in leptin levels per se. These findings gave rise to the "leptin resistance" hypothesis,3,4 which argues that obesity is the result of inadequate leptin signalling for a given leptin concentration (figure 3). Evidence for multiple peripheral effects of leptin makes it unlikely that all aspects of leptin resistance can be explained by an impaired transport of leptin into the cerebrospinal fluid.58,59 True "leptin resistance", mediated by a receptor or postreceptor defect, similar to the hypothesis of a defect in insulin resistance, must be involved in explaining some of these effects. A good example of the receptor type of leptin resistance is the db/db mouse which lacks a functional leptin receptor.16 Leptin levels may merely reflect adipose-tissue size and may not be the signalling molecule, as initially thought, and leptin is now seen as a "signal of plenty".3 Figure 3: Leptin resistance in mice (a) and man (b) (a) Inverse relation between leptin level and leptin response in mice, with, at extremes, situation in ob/ob and db/db mice. (b) Relative leptin resistance observed in obese people with high circulating steady-state leptin levels. Low steady-state leptin levels are associated with inadequate adipose tissue mass and can be associated with neuroendocrine disturbances, such as abnormalities of the reproductive system. A final piece of evidence in favour of roles for leptin beyond those of bodyweight and metabolic homoeostasis is that for a significant controlling role in other endocrine and regulatory pathways. Chehab and colleagues60 showed that the sterility defect in homozygous ob/ob female mice could be corrected by leptin administration. Follow-up studies showed that leptin triggered the onset of puberty and sexual maturity in female mice, supporting the hypothesis that fat accumulation enhances maturation of the reproductive tract.61-63 These observations were extended by the work of Ahima and colleagues,64 who found that leptin controls not only reproductive but also other neuroendocrine functions, such as thyroid and adrenal steroid production. Low levels of leptin, as typically occur after weight loss,54,65 are perceived by the body as harmful and lead to adaptive changes mainly mediated through inhibition of the hypothalamopituitary axis. The raising of leptin levels could bypass these effects and restore a normal hypothalamopituitary axis.64 High leptin levels may thus signal that energy reserves are sufficient, whereas low leptin levels inform the brain about limited energy supplies. Leptin is also produced in the placenta, suggesting an important role for it in fetomaternal signalling.66 Finally, a last effect of leptin worth exploring is its effects on the haemopoietic system; studies suggest a role for this cytokine in haemopoiesis and macrophage function.20,47 A regulatory role, again? Most clinical studies of leptin's role in the developing of obesity have indicated an association between established obesity and high levels of leptin mRNA or protein. Conclusions based on steady-state data reflecting the relation between an established obesity and leptin levels are bound to be incomplete and will miss any regulatory or dynamic effects that leptin might have in the early development of changes in bodyweight. Studies of this issue do suggest that there is an important regulatory role for leptin in the control of bodyweight homoeostasis. When leptin levels were measured in Pima Indians, whose weight was prospectively monitored, it was emerged that in people with comparable initial bodyweight, high leptin levels identified those who would remain slim whereas low leptin levels identified individuals predisposed to obesity later on.67 This observation suggests that diminished production of leptin may have a role in the pathogenesis of obesity in the Pima Indians and that leptin levels before the development of obesity do not merely reflect adipose tissue size as had been suggested in the initial steady-state studies. Similar conclusions emerged from a study showing that in children with chronic renal insufficiency, raised leptin levels do not correlate with bodyweight. The high leptin levels in these children, which could be due to disturbed renal clearance,68-67 could underly the anorexia and resulting bodyweight loss associated with chronic renal insufficiency. Proof of such regulatory effects requires longitudinal studies with serial leptin measurements and monitoring of changes in bodyweight. These studies stress the importance of assessing the dynamics of the leptin system rather than relying on a steady-state plasma leptin measurement. Experience with insulin measurement during development of non-insulin-dependent diabetes mellitus (NIDDM) suggests that the measurement of a leptin response to a challenge and serial leptin measurements over time will be more infomative than a single measurement. A final argument supporting a role of leptin in the control of bodyweight was provided by identification of a mutation in the leptin gene in two severely obese children in the same highly consanguineous pedigree.52 Their serum leptin levels were very low and both children had homozygous frame-shift mutations in codon 133 of the leptin gene. Although such mutations are likely to be very rare the severe obesity in these two children does provide direct genetic evidence for a key role for leptin in energy metabolism. Human studies of a regulatory role for leptin in the induction of weight changes are supported by rodent models. A good example is rodents treated with thiazolidinedione insulin sensitizers. Thiazolidinediones, such as troglitazone, bind to and activate the nuclear hormone receptor PPAR. In rodents, these compounds induce weight gain mainly via their stimulatory effects on PPAR, a key trigger for adipocyte differentiation and adipogenesis.1,2 These PPAR activators decrease leptin gene transcription, resulting in a decrease in leptin mRNA and plasma levels.72-74 Thiazolidinediones did not induce weight gain or affect circulating leptin levels in a small study in patients with NIDDM.75 It is important to stress that the decrease in rodent leptin levels after thiazolidinediones compounds occurred despite the fact that these compounds induce weight gain and adipose tissue mass and increase food intake. Other examples in which body mass and leptin levels are regulated in opposite fashion are provided by treatment of animals with bacterial endotoxin,76 cytokines,76 or high doses of glucocorticoids,77 which all induce leptin levels despite a reduction in bodyweight. These clinical and animal studies suggest that one cannot reduce leptin to a simple indicator of adipose tissue mass. Regulation of leptin expression In view of the important potential regulatory role of leptin, it is important to understand the genetic and environmental factors contributing to the variability in basal leptin mRNA and plasma levels. Since leptin expression is restricted to adipose tissue and since basal leptin levels are closely related to triglyceride stores and adipose tissue mass, it was important to define the molecular mechanism underlying adipose-tissue-specific gene expression. The cloning and initial characterisation of the leptin promoter allowed characterisation of the regulatory regions implicated in adipose tissue-specific leptin expression. Leptin gene expression is regulated in an opposite fashion by PPAR and C/EBP, two transcription factors controlling adipocyte differentiation. Leptin gene expression is induced by C/EBP, an effect mediated by a C/EBP-binding site in the proximal leptin gene promoter.78-80 By contrast antidiabetic thiazolidinediones, ligands, and activators of PPAR, decrease leptin expression73,74,81 via a direct effect on the leptin promoter.73,80 Thus, PPAR seems not only to favour adipocyte differentiation at a local adipocyte level but also to trigger a systemic response consisting of a decrease in leptin levels and an associated increase in food intake, which will provide substrate to be stored in these adipocytes. Leptin, therefore, also appears to be functioning in this adipocyte-sustaining positive feedback loop. Also, supporting a role for PPAR in controlling leptin levels is a large genetic study showing that a variant in the PPAR gene is important to determine circulating leptin levels (A Meirhaeghe and colleagues, unpublished). A locus on chromosome 2p21 (D2S1788) also seems to be a major determining factor for circulating leptin.82 Although the gene responsible has not yet been identifed, a candidate is the pro-opiomelanocortin (POMC) gene.82 POMC is a precursor for adrenocorticotropic hormone that regulates the production of glucocorticoid hormones, and these glucocorticoids are known to regulate leptin gene expression.77 Besides the regulation associated with adipose tissue differentiation, the leptin gene expression seems to be tightly controlled by environmental and hormonal factors (summarised in panel 2, more detailed information reviewed elsewhere83). Leptin expression is itself influenced by food intake. In rodents, leptin levels are greatly decreased after fasting and increased by refeeding.65,84-87 These changes in leptin expression with feeding patterns in rodents are accounted for by changes in insulin levels, since leptin gene expression is positively regulated by insulin both in vivo and in vitro.84,88,89 In human beings, fasting also decreases leptin levels,90,91 whereas overfeeding seems to induce leptin levels,92 but short-term food restriction, resulting in a decrease in calorie intake, does not seem to affect leptin expression.54,57 The regulatory mechanisms underlying leptin expression after changes in food intake are less clear in human beings than in rodents. In human beings, acute changes in insulin levels54,57 have little effect on leptin expression and insulin levels must be raised for a longer time to induce leptin expression.93-96 Panel 2: Inducers and suppressors of leptin expression Inducer Effect* Species Feeding + Rodent + man Fasting - Rodent + man Glucocorticoids + Rodent + man Insulin + Rodent c or + Man Pertussis toxin - Rodent cAMP - Rodent á-receptor agonists - Rodent Thiazolidinediones - Rodent Cytokines + Rodent Obesity + Rodent + man *+=induction; -=suppression; c=no change. Leptin's future Leptin was first described as an adipocyte-derived signalling factor which, after interaction with specific receptors, induces a pleiotropic response including control of bodyweight and energy expenditure. Although research has moved ahead rapidly there are still more questions about leptin than there are definite answers. We should soon have the outcome of clinical studies, using leptin or leptinomimetic agents, designed to identify effects on bodyweight and metabolic control in man. Also important is leptin's exact role in neuroendocrine, reproductive, haemopoietic, and metabolic control pathways. We also need to identify which other organ systems are affected, and definition of the full array of downstream effector molecules transducing the leptin signal will be very important here. Finally, we need to determine the regulatory pathways that control leptin since they might provide ways to modulate leptin expression. We thank Mike Briggs, Samir Deeb, Jean Dallongeville, Aline Meirhaeghe, Philippe Amouyel, and Kristina Schoonjans for stimulating discussions and suggestions. The work in our laboratory is supported by grants from INSERM, Institut Pasteur de Lille, R‚gion Nord-Pas de Calais, Association de Recherche pour le Cancer (ARC 6403), and from Fondation pour la Recherche Medicale.

To: Abuckatatime who wrote (17098)	3/10/1998 3:48:00 PM
From: Henry Niman	Respond to of 32384

Here are the leptin references (LGND's is in bold): References 1 Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell 1996; 87: 377-89. 2 Auwerx J, Martin G, Guerre-Millo M, Staels B. Transcription, adipocyte differentiation, and obesity. J Mol Med 1996; 74: 347-52. 3 Caro J, Sinha MK, Kolaczynski LW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes 1996; 45: 1455-62. 4 Campfield LA, Smith FJ, Burn P. The ob protein (leptin) pathway - a link between adipose tissue mass and central neural networks. Horm Metab Res 1996; 28: 619-32. 5 Flier JS. Leptin expression and action: new experimental paradigms. Proc Natl Acad Sci USA 1997; 94: 4242-45. 6 Tartaglia L. The leptin receptor. J Biol Chem 1997; 272: 6093-96. 7 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-32. 8 Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein; evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546-49. 9 Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-46. 10 Pelleymounter MA, Cullen MJ, Baker MB, et al. Effect of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540-43. 11 Stephens TW, Basinski M, Bristow PK, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995; 377: 530-32. 12 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. 13 Chen G, Koyama K, Yuan X, et al. Dissapearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci USA 1996; 93: 14795-99. 14 Muzzin P, Eisensmith RC, Copeland KC, Woo SLC. Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. Proc Natl Acad Sci USA 1996; 93: 14804-08. 15 Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 1997; 389: 379-77. 16 Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83: 1263-1271. 17 Lee GH, Proenca R, Montez JM, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996; 379: 632-35. 18 Chen H, Charlat O, Tartaglia LA, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84: 491-95. 19 Ihle J. STATs: signal transducers and activators of transcription. Cell 1996; 84: 331-34. 20 Ghilardi N, Skoda RC. The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol Endocrinol 1997; 11: 393-399. 21 Baumann H, Morella KK, White DW, et al. The full length leptin receptor has signalling capabilities of interleukin 6-type receptors. Proc Natl Acad Sci USA 1996; 93: 8374-78. 22 Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim MH, Skoda RC. defective STAT signalling by the leptin receptor in diabetic mice. Proc Natl Acad Sci USA 1996; 93: 6231-35. 23 Vaisse C, Halaas JL, Horvath CM, Darnell JE, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996; 14: 95-97. 24 Darnell JE. Reflections on STAT3, STAT5, and STAT6 as fat STATs. Proc Natl Acad Sci USA 1996; 93: 6221-24. 25 Chua SC, Chung WK, Wu-Peng S, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996; 271: 994-96. 26 Philips MS, Liu Q, Hammond HA, et al. Leptin receptor missense mutations in the fatty Zucker rat. Nat Genet 1996; 13: 18-19. 27 Iida M, Murakami T, Ishida K, Mizuno A, Kuwajima M, Shima K. Phenotype-linked amino acid alteration in leptin receptor cDNA from Zucker fatty (fa/fa) rat. Biochem Biophys Res Commun 1996; 222: 19-26. 28 Takaya K, Ogawa Y, Isse N, et al. Molecular cloning of rat leptin receptor isoform complementary DNAs-identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun 1996; 225: 75-83. 29 Takaya K, Ogawa Y, Hiraoka J, et al. Nonsense mutation of the leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Genet 1996; 14: 130-31. 30 Schwartz MW, Seeley RJ, Campfield LA, Burn P. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996; 98: 1101-06. 31 Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides 1996; 17: 305-11. 32 Golden PL, Maccagnan TJ, Pardridge WM. Human blood-barrier leptin receptor; binding and endocytosis in isolated human brain microvessels. J Clin Invest 1997; 99: 14-18. 33 Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 1996; 274: 1704-07. 34 Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 1996; 381: 415-18. 35 Fan W, Boston BA, Kesterton RA, Hruby VJ, Cone RD. Role of melanocotinergic neurons in feeding and the agouti obesity syndrome. Nature 1996; 385: 165-68. 36 Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melancocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131-41. 37 Turton MD, O'Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996; 379: 69-72. 38 Arase K, York DA, Shimizu H, Shargill N, Bray GA. Effect of corticotropin-releasing factor on food intake and brown tissue thermogenesis in rats. Am J Physiol 1988; 255: E255-E259. 39 Spina M, Merlo-Pich E, Chan RKW, et al. Appetite-suppressing effects of urocortin a CRF-related neuropeptide. Science 1996; 273: 1561-1564. 40 Muglia L, Jacobson L, Dikkes P, Majzoub JA. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 1995; 373: 427-32. 41 Qu D, Ludwig DS, Gammeltoft S, et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996; 380: 243-47. 42 Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science 1996; 274: 1185-88. 43 Bai Y, Zhang S, Kim KS, Lee JK, Kim KH. Obese gene expression alters the ability of 30A5 preadipocytes to respond to lipogenic hormones. J Biol Chem 1996; 271: 13939-42. 44 Muller G, Ertl J, Gerl M, Preibisch G. Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J Biol Chem 1997; 272: 10585-93. 45 Gainsford T, Wilson TA, Metcalf D, et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci USA 1996; 93: 14564-68. 46 Shimabukuro M, Koyama K, Chen G, et al. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci USA 1997; 94: 4637-41. 47 Considine RV, Considine EL, Williams CJ, et al. Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. J Clin Invest 1995; 95: 2986-88. 48 Maffei M, et al. Absence of mutations in the human OB gene in obese/diabetic subjects. Diabetes 1996; 45: 679-682. 49 Reed DR, Ding Y, Xu W, Cather C, Green ED, Price RA. Extreme obesity may be linked to markers flanking the human ob gene. Diabetes 1996; 45: 691-94. 50 Stirling B, Cox NJ, Bell GI, Hanis CL, Spielman RS, Concannon P. Identification of microsatellite markers near the human ob gene and linkage studies in NIDDM-affected sib pairs. Diabetes 1995; 44: 999-1001. 51 Clement K, Garner C, Hager J, et al. Indication for linkage of the human ob gene region with extreme obesity. Diabetes 1996; 45: 687-690. 52 Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903-908. 53 Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-95. 54 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. Nature Med 1995; 1: 1155-1161. 55 L”nnqvist F, Arner P, Nordfors L, Schalling M. Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med 1995; 1: 950-53. 56 Hamilton BS, Paglia D, Kwan AYM, Deitel M. Increased obese mRNA expression in omental fat cells from massively obese humans. Nat Med 1995; 1: 954-56. 57 Vidal H, Auboeuf D, De Vos P, et al. The expression of ob gene is not acutely regulated by insulin and fasting in human abdominal subcutaneous adipose tissue. J Clin Invest 1996; 98: 251-55. 58 Caro JF, Kolaczynski JW, Nyce MR, et al. Decreased cerebrospinal fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996; 348: 159-61. 59 Schwartz M, Peskind E, Raskind M, Boyko EJ, Porte D. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 1996; 2: 589-93. 60 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. 61 Chehab FF, Mounzih K, Lu R, Lin ME. Early onset of reproductive function in normal female mice treated with leptin. Science 1997; 275: 88-90. 62 Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 1997; 138: 855-88. 63 Barash IA, Cheung CC, Weigle DS, et al. Leptin is a signal to the reproductive system. Endocrinology 1996; 137: 3144-47. 64 Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382: 250-52. 65 Frederich RC, Lollmann B, Hamann A, et al. Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest 1995; 96: 1658-63. 66 Masuzaki H, Ogawa Y, Sagawa N, et al. Non-adipose tissue production of leptin; leptin as a novel placenta-derived hormone in humans. Nat Med 1997; 3: 1029-33. 67 Ravussin E, Pratley RE, Maffei M, et al. Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat Med 1997; 3: 238-40. 68 Cumin F, Baum HP. Leptin is cleared from the circulation primarily by the kidney. Int J Obes 1996; 20: 1120-26. 69 Merabet E, Dagogo-Jack S, Coyne DW, et al. Increased plasma leptin concentration in end-stage renal disease. J Clin Endocrinol Metab 1997; 82: 847-50. 70 Sharma K, Considine RV, Michael B, et al. Plasma leptin is partly cleared by the kidney and is elevated in hemodialysis patients. Kidney Int 1997; 51: 1980-85. 71 Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR2, a lipid-activated transcription factor. Cell 1994; 79: 1147-56. 72 Zhang B, Graziano MP, Doebber TW, et al. Down-regulation of the expression of the obese gene by antidiabetic thiazolidinedione in Zucker diabetic fatty rats and db/db mice. J Biol Chem 1996; 271: 9455-59. 73 De Vos P, Lefebvre AM, Miller SG, et al. Thiazolidinediones repress ob gene expresson via activation of PPAR. J Clin Invest 1996; 98: 1004-09. 74 Kallen CB, Lazar MA. 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To: Abuckatatime who wrote (17098)	3/10/1998 4:53:00 PM
From: Henry Niman	Read Replies (7) \| Respond to of 32384

Today's close (15 15/16) was the highest since 10/23/97 and home.att.net just passed the 15,000th hit mark. Last week, home.att.net passed the 10,000 hit mark. Viewers (over 25,000 hits) must like what they see. Since the site was set up, a little over a month ago, LGND has gained over 5 points or about 45%.

To: Abuckatatime who wrote (17098)	3/11/1998 8:51:00 AM
From: Henry Niman	Respond to of 32384

Here's what Reuter said about obesity: C H I C A G O, March 8 - Severely overweight people run up much higher medical bills than most people and U.S. health care costs could be significantly reduced if obese people lost excess weight or never put it on. An examination of the medical records of 17,118 members of a large health maintenance organization in 1990 by the health provider, Kaiser Permanente of Oakland, California, found the medical costs of obese people were 44 percent higher than average. Obesity was defined by body mass index (BMI), a number produced by dividing weight in kilograms by the square of height in meters. A woman 5 feet, 6 inches tall and weighing 198 pounds, for example, would have a BMI of 32. A person with a BMI over 30 is considered overweight, and one with an index over 35 is seen as obese. More Hospital Visits The study, which appeared in the journal Archives of Internal Medicine, found that severely overweight people had a 24 percent higher rate of outpatient hospital visits, their hospital stays were 74 percent longer, and their pharmacy costs were 78 percent higher. Moderately overweight people had a 17 percent higher rate of hospital visits, their hospital stays were 34 percent longer, and their pharmacy costs were 60 percent higher. Much of the increased costs incurred by overweight people related to their higher rates of heart disease, hypertension and diabetes, the study found. The 1990 study estimated the direct costs of obesity-associated diseases at $45.8 billion that year, about 6.8 percent of all U.S. health care expenditures. "Given the high prevalence of obesity and the clearly elevated disease risks and increased use of health services, there is a great potential for a reduction in health care expenditures through efforts in weight reduction and prevention of weight gain," study author Charles Quesenberry Jr. wrote.