The Leptin Receptor (1997)

INTRODUCTIONOf the many genetic obesity syndromes, none have been as intensively studied as ob/ob and db/db mice. These two mutant mice were originally identified over 30 years ago (1Hummel K.P. Dickie M.M. Coleman D.L. Science. 1966; 153: 1127-1128Crossref PubMed Scopus (736) Google Scholar, 2Ingalls A.M. Dickie M.M. Snell G.D. J. Hered. 1950; 41: 317-318Crossref PubMed Scopus (642) Google Scholar) and shown to be a result of two distinct single gene mutations residing on mouse chromosomes 6 (ob) and 4 (db). The phenotypes and pathophysiologies of these two mice have been studied for decades and described in well over 1000 publications. However, the nature of the lesions or primary defects was not revealed until very recently.Perhaps the most informative early studies on the nature of the ob and db primary defects were the parabiosis experiments (partial connection of the circulatory systems of animals through grafting) performed throughout the 1970s (3Coleman D.L. Diabetologia. 1973; 9: 294-298Crossref PubMed Scopus (547) Google Scholar) (reviewed in Ref. 4Coleman D.L. Diabetologia. 1978; 14: 141-148Crossref PubMed Scopus (1074) Google Scholar). Parabiosis of an ob/ob mouse and a lean control resulted in partial normalization of body weight in the ob/ob mutant mouse. This led to the proposal that ob/ob mice were deficient in a circulating factor that could be restored through the blood of the lean animal. However, db/db mice that underwent parabiosis with lean controls did not exhibit body weight normalization. This suggested that db/db mice may be defective in their ability to respond to the putative satiety factor, perhaps because they were defective in the receptor for this molecule.The Obese (ob) Gene and Its Product, LeptinDespite intensive interest in the nature of the putative satiety factor missing in ob/ob mice, biochemical strategies failed to identify it. It was not until a genetic/positional cloning strategy was employed that the gene corresponding to the ob locus and its gene product were ultimately identified (5Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-431Crossref PubMed Scopus (11625) Google Scholar). The wild type ob gene encodes a protein of about 16 kDa that is preceded by a secretory hydrophobic signal peptide. It is expressed in adipose tissue in multiple mammalian species including mice and humans. The development of antibody reagents confirmed that this factor (leptin) is found at high levels in blood, consistent with the previous parabiosis studies (6Maffei M. Halaas J. Ravussin E. Pratley R.E. Lee G.H. Zhang Y. Fei H. Kim S. Lallone R. Ranganathan S. Kern P.A. Freidman J.M. Nat. Med. 1995; 1: 1155-1161Crossref PubMed Scopus (3292) Google Scholar).Since the cloning of the ob gene numerous studies have described the regulation of the leptin mRNA and protein. Although the purpose of this review is not to comprehensively examine the growing literature on the regulation of the leptin ligand, it is important to briefly summarize a few aspects of leptin expression and regulation that are key in interpreting the biology of the leptin receptor. The leptin transcript appears to be expressed fairly specifically in adipose tissue (5Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-431Crossref PubMed Scopus (11625) Google Scholar), although it is also detectable in human placenta on poly(A)- Northern blots. 1X. Weng and L. A. Tartaglia, unpublished observations. Steady state levels of the leptin mRNA and protein are elevated in a variety of rodent obesity models (6Maffei M. Halaas J. Ravussin E. Pratley R.E. Lee G.H. Zhang Y. Fei H. Kim S. Lallone R. Ranganathan S. Kern P.A. Freidman J.M. Nat. Med. 1995; 1: 1155-1161Crossref PubMed Scopus (3292) Google Scholar, 7Frederich R.C. Löllmann B. Hamann A. Napolitano-Rosen A. Kahn B.B. Lowell B.B. Flier J.S. J. Clin. Invest. 1995; 96: 1658-1663Crossref PubMed Scopus (551) Google Scholar, 8Maffei M. Halaas J. Ravussin E. Pratley R.E. Lee G.H. Zhang Y. Fei H. Kim S. Lallone R. Ranganathan S. Kern P.A. Freidman J.M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6957-6960Crossref PubMed Scopus (414) Google Scholar, 9Mizuno T.M. Bergen H. Funabashi T. Kleopoulos S.P. Zhong Y.G. Bauman W.A. Mobbs C.V. Proc. Natl. Acad. Sci U. S. A. 1996; 93: 3434-3438Crossref PubMed Scopus (173) Google Scholar). These observations have led to the proposal that leptin serves as an “adipostat,” informing the body of the status of energy storage in the adipose tissue so that appropriate changes in appetite, metabolism, and nutrient partitioning can be signaled via the leptin receptor. Dramatic regulation of the leptin transcript and protein has also been observed in response to short term alterations in food intake (7Frederich R.C. Löllmann B. Hamann A. Napolitano-Rosen A. Kahn B.B. Lowell B.B. Flier J.S. J. Clin. Invest. 1995; 96: 1658-1663Crossref PubMed Scopus (551) Google Scholar, 9Mizuno T.M. Bergen H. Funabashi T. Kleopoulos S.P. Zhong Y.G. Bauman W.A. Mobbs C.V. Proc. Natl. Acad. Sci U. S. A. 1996; 93: 3434-3438Crossref PubMed Scopus (173) Google Scholar, 10Saladin R. De Vos P. Guerre-Millo M. Leturque A. Girard J. Staels B. Auwerx J. Nature. 1995; 377: 527-529Crossref PubMed Scopus (1088) Google Scholar, 11Frederich R.C. Hamann A. Anderson S. Lollmann B. Lowell B.B. Flier J.S. Nat. Med. 1995; 1: 1311-1314Crossref PubMed Scopus (1394) Google Scholar); fasting results in dramatic down-regulation, and excessive caloric intake results in up-regulation. It is therefore plausible that an important role for leptin is mediating the response to starvation (12Ahima R.S. Prabakaran D. Mantzoros C. Qu D. Lowell B. Maratos-Flier E. Flier J.S. Nature. 1996; 382: 250-252Crossref PubMed Scopus (2662) Google Scholar). Acute effects on leptin mRNA and protein have also been observed in response to a variety of stimuli including glucocorticoids, cytokines, and insulin (10Saladin R. De Vos P. Guerre-Millo M. Leturque A. Girard J. Staels B. Auwerx J. Nature. 1995; 377: 527-529Crossref PubMed Scopus (1088) Google Scholar, 13Slieker L.J. Sloop K.W. Surface P.L. Kriauciunas A. LaQuier F. Manetta J. Bue-Valleskey J. Stephens T.W. J. Biol. Chem. 1996; 271: 5301-5304Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, 14Grunfeld C. Zhao C. Fuller J. Pollack A. Moser A. Friedman J. Feingold K.R. J. Clin. Invest. 1996; 97: 2152-2157Crossref PubMed Scopus (824) Google Scholar).There has now also been considerable analysis of leptin regulation in humans. The leptin mRNA is regulated in humans by both changes in the percentage of body fat as well as changes in food intake (6Maffei M. Halaas J. Ravussin E. Pratley R.E. Lee G.H. Zhang Y. Fei H. Kim S. Lallone R. Ranganathan S. Kern P.A. Freidman J.M. Nat. Med. 1995; 1: 1155-1161Crossref PubMed Scopus (3292) Google Scholar, 15Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marco C.C. McKee L.J. Bauer T.L. Caro J.F. N. Engl. J. Med. 1996; 334: 292-295Crossref PubMed Scopus (5488) Google Scholar, 16Considine R.V. Considine E.L. Williams C.J. Nyce M.R. Magosin S.A. Bauer T.L. Rosato E.L. Colberg J. Caro J.F. J. Clin. Invest. 1995; 95: 2986-2988Crossref PubMed Scopus (426) Google Scholar, 17Hamilton B.S. Paglia D. Kwan A.T.M. Deitel M. Nat. Med. 1995; 1: 953-956Crossref PubMed Scopus (508) Google Scholar, 18Lonnqvist F. Arner P. Nordfors L. Shalling M. Nat. Med. 1995; 1: 950-953Crossref PubMed Scopus (690) Google Scholar). However, the degree of mRNA regulation in humans is less impressive than that seen in rodents. Importantly, at the protein level human leptin is dramatically regulated, with changes approaching those seen in the rodent obesities and fasting (6Maffei M. Halaas J. Ravussin E. Pratley R.E. Lee G.H. Zhang Y. Fei H. Kim S. Lallone R. Ranganathan S. Kern P.A. Freidman J.M. Nat. Med. 1995; 1: 1155-1161Crossref PubMed Scopus (3292) Google Scholar, 15Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marco C.C. McKee L.J. Bauer T.L. Caro J.F. N. Engl. J. Med. 1996; 334: 292-295Crossref PubMed Scopus (5488) Google Scholar). The protein is much higher in individuals with an increased percentage of body fat and is down-regulated during body weight loss. This parallel regulation in mice and humans may imply that leptin is functioning in humans as it is in rodents, although further studies are required to directly address this.An obvious and important question has been whether a significant portion of human obesity can be due to mutations in the ob gene. The ob coding region has been sequenced from hundreds of human individuals, but mutations have not been found (16Considine R.V. Considine E.L. Williams C.J. Nyce M.R. Magosin S.A. Bauer T.L. Rosato E.L. Colberg J. Caro J.F. J. Clin. Invest. 1995; 95: 2986-2988Crossref PubMed Scopus (426) Google Scholar, 19Maffei M. Stoffel M. Barone M. Moon B. Dammerman M. Ravussin E. Bogardus C. Ludwig D.S. Flier J.S. Talley M. Auerbach S. Friedman J.M. Diabetes. 1996; 45: 679-682Crossref PubMed Scopus (177) Google Scholar, 20Niki T. Mori H. Tamori Y. Kishimoto-Hashirmoto M. Ueno H. Araki S. Masugi J. Sawant N. Majithia H.R. Rais N. Hashiramoto M. Taniguchi H. Kasuga M. Diabetes. 1996; 45: 675-678Crossref PubMed Scopus (63) Google Scholar). Although mutations affecting mRNA levels can reside outside of the coding region, individuals with severely reduced leptin mRNA levels have also not yet been described (15Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marco C.C. McKee L.J. Bauer T.L. Caro J.F. N. Engl. J. Med. 1996; 334: 292-295Crossref PubMed Scopus (5488) Google Scholar, 16Considine R.V. Considine E.L. Williams C.J. Nyce M.R. Magosin S.A. Bauer T.L. Rosato E.L. Colberg J. Caro J.F. J. Clin. Invest. 1995; 95: 2986-2988Crossref PubMed Scopus (426) Google Scholar, 17Hamilton B.S. Paglia D. Kwan A.T.M. Deitel M. Nat. Med. 1995; 1: 953-956Crossref PubMed Scopus (508) Google Scholar, 18Lonnqvist F. Arner P. Nordfors L. Shalling M. Nat. Med. 1995; 1: 950-953Crossref PubMed Scopus (690) Google Scholar), suggesting that the number of such individuals will not be high. On the other hand, genotyping of microsatellite markers that span the ob gene region has suggested linkage of this region with extreme human obesity (21Clement K. Garner C. Hager J. Philippi A. LeDuc C. Carey A. Harris T.J.R. Jury C. Cardon L.R. Basdevant A. Demenais F. Guy-Grand B. North M. Froguel P. Diabetes. 1996; 45: 687-690Crossref PubMed Scopus (0) Google Scholar, 22Reed D.R. Ding Y. Xu W. Cather C. Green E.D. Price R.A. Diabetes. 1996; 45: 691-694Crossref PubMed Scopus (0) Google Scholar).Considerable excitement has been generated by the observations that administration of recombinant leptin to rodents results in food intake reduction and weight loss (23Campfield A.L. Smith F.J. Guisez Y. Devos R. Burn P. Science. 1995; 269: 546-549Crossref PubMed Scopus (3060) Google Scholar, 24Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Freidman J.M. Science. 1995; 269: 543-546Crossref PubMed Scopus (4199) Google Scholar, 25Pelleymounter M.A. Cullen M.J. Baker M.B. Hecht R. Winters D. Boone T. Collins F. Science. 1995; 269: 540-543Crossref PubMed Scopus (3849) Google Scholar, 26Stephens T.W. Bashinski M. Bristow P.K. Bue-Valleskey J.M. Burgett S.G. Craft L. Hale J. Hoffmann J. Hsiung H.M. Kriauciunas A. Mackellar W. Rosteck P.R. Schoner B. Smith D. Tinsley F.C. Zhang X.Y. Helman M. Nature. 1995; 377: 530-534Crossref PubMed Scopus (1467) Google Scholar). Although the potency of leptin is highest in mice that are completely deficient in this protein (ob/ob), significant effects can be seen at higher doses in normal mice and mice with diet-induced obesity. Such studies have brought hope that leptin may be an effective treatment even in some obesities that are not due to leptin deficiencies. Of particular interest are studies that have investigated the effects of centrally administered leptin. These studies showed that leptin injection into the lateral or third brain ventricle produced reduction in food intake and weight loss, strongly implying that leptin could act directly on receptors within the central nervous system (23Campfield A.L. Smith F.J. Guisez Y. Devos R. Burn P. Science. 1995; 269: 546-549Crossref PubMed Scopus (3060) Google Scholar, 26Stephens T.W. Bashinski M. Bristow P.K. Bue-Valleskey J.M. Burgett S.G. Craft L. Hale J. Hoffmann J. Hsiung H.M. Kriauciunas A. Mackellar W. Rosteck P.R. Schoner B. Smith D. Tinsley F.C. Zhang X.Y. Helman M. Nature. 1995; 377: 530-534Crossref PubMed Scopus (1467) Google Scholar).Weight loss in rodents following leptin administration appears to be due to not only decreases in food intake but also increases in energy expenditure (24Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Freidman J.M. Science. 1995; 269: 543-546Crossref PubMed Scopus (4199) Google Scholar, 25Pelleymounter M.A. Cullen M.J. Baker M.B. Hecht R. Winters D. Boone T. Collins F. Science. 1995; 269: 540-543Crossref PubMed Scopus (3849) Google Scholar). Although the mechanisms of increased energy utilization are likely to be complex, one important component may involve the activation of brown adipose tissue (27Collins S. Kuhn C. Petro A. Swick A. Chrunyk B. Surwit R. Nature. 1996; 380Google Scholar).The observation that leptin deficiencies are not common in human obesity and, in fact, that leptin levels appear to be up-regulated as the percentage of body fat increases has suggested that resistance to normal or elevated levels of leptin may be more important than inadequate leptin production in human obesity (15Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marco C.C. McKee L.J. Bauer T.L. Caro J.F. N. Engl. J. Med. 1996; 334: 292-295Crossref PubMed Scopus (5488) Google Scholar). This line of thought has been further strengthened by the parallel situation of type II diabetics, many of whom exhibit severe insulin resistance while producing elevated levels of insulin. These observations further stimulated interest in the identification of the receptor for leptin and the analysis of leptin signal reception. They also heightened interest in the db/db mouse, a model of total leptin resistance (23Campfield A.L. Smith F.J. Guisez Y. Devos R. Burn P. Science. 1995; 269: 546-549Crossref PubMed Scopus (3060) Google Scholar, 24Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Freidman J.M. Science. 1995; 269: 543-546Crossref PubMed Scopus (4199) Google Scholar, 25Pelleymounter M.A. Cullen M.J. Baker M.B. Hecht R. Winters D. Boone T. Collins F. Science. 1995; 269: 540-543Crossref PubMed Scopus (3849) Google Scholar, 26Stephens T.W. Bashinski M. Bristow P.K. Bue-Valleskey J.M. Burgett S.G. Craft L. Hale J. Hoffmann J. Hsiung H.M. Kriauciunas A. Mackellar W. Rosteck P.R. Schoner B. Smith D. Tinsley F.C. Zhang X.Y. Helman M. Nature. 1995; 377: 530-534Crossref PubMed Scopus (1467) Google Scholar) and elevated leptin levels (8Maffei M. Halaas J. Ravussin E. Pratley R.E. Lee G.H. Zhang Y. Fei H. Kim S. Lallone R. Ranganathan S. Kern P.A. Freidman J.M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6957-6960Crossref PubMed Scopus (414) Google Scholar).Cloning of the Leptin Receptor (OB-R)The identification of the receptor for the leptin protein was realized through an expression cloning strategy (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar). Tagged versions of leptin were generated either through a traditional iodination strategy or by generating recombinant fusion proteins between leptin and secreted placental alkaline phosphatase. These tagged reagents were then used to identify a tissue source expressing a cell surface leptin binding activity (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar, 29Devos R. Richards J.G. Campfield L.A. Tartaglia L.A. Guisez Y. van der Heyden J. Travernier J. Plaetinck G. Burn P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5668-5673Crossref PubMed Scopus (126) Google Scholar). Significant and specific leptin binding was detected in the mouse choroid plexus. To clone this leptin binding activity a murine choroid plexus cDNA library was constructed, and cells transfected with this library were screened with a leptin-alkaline phosphatase fusion protein. From this screen, cDNAs were identified that encoded a cell surface leptin receptor (OB-R) with an affinity for leptin of about 0.7 nM (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar).Sequencing of the original murine cDNA identified in the expression cloning screen revealed a single membrane-spanning receptor of the class I cytokine receptor family (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar). This observation was consistent with a previous structural prediction indicating that the leptin protein would be expected to fold into a cytokine-like structure (30Madej T. Boguski M.S. Bryant S.H. FEBS Lett. 1995; 373: 13-18Crossref PubMed Scopus (241) Google Scholar). The closest relatives of OB-R were gp130 (31), the G-CSF receptor (32Larsen A. Davis T. Curtis B.M. Gimpel S. Sims J.E. Cosman D. Park L. Sorenson E. March C.J. Smith C.A. J. Exp. Med. 1990; 172: 1559-1570Crossref PubMed Scopus (169) Google Scholar), and the leukemia inhibitory factor receptor (33Gearing D.P. Thut C.J. VandenBos T. Gimpel S.D. Delaney P.B. King J. Price V. Cosman D. Beckmann M.P. EMBO J. 1991; 10: 2839-2848Crossref PubMed Scopus (513) Google Scholar). The predicted extracellular domain of OB-R was quite large, about 816 amino acids, while the predicted intracellular domain was fairly short, 34 amino acids, suggesting that this protein might not have signal-transducing capability. However, further screening and analysis of cDNA libraries using the original OB-R cDNA sequence as a guide soon revealed that there were multiple forms of OB-R in both mice and humans, including a long form with an intracellular domain of about 303 amino acids (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar, 34Chen H. Charlat O. Tartaglia L.A. Woolf E.A. Weng X. Ellis S.J. Lakey N.D. Culpepper J. Moore K.J. Breitbart R.E. Duyk G.M. Tepper R.I. Morgenstern J.P. Cell. 1996; 84: 491-495Abstract Full Text Full Text PDF PubMed Scopus (1918) Google Scholar, 35Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar, 36Cioffi J.A. Shafer A.W. Zupancic T.J. Smith-Gbur J. Mikhail A. Platika D. Snodgrass H.R. Nat. Med. 1996; 2: 585-589Crossref PubMed Scopus (626) Google Scholar) (Fig. 1). The intracellular domain of the long form contained sequence motifs suggestive of intracellular signal-transducing capabilities.The extracellular domains of the short and long forms of OB-R are identical throughout their entire length, since differences in the receptor forms arise from alternative RNA splicing at the most C-terminal coding exon, resulting in OB-R intracellular domains with differing length and sequence composition (34Chen H. Charlat O. Tartaglia L.A. Woolf E.A. Weng X. Ellis S.J. Lakey N.D. Culpepper J. Moore K.J. Breitbart R.E. Duyk G.M. Tepper R.I. Morgenstern J.P. Cell. 1996; 84: 491-495Abstract Full Text Full Text PDF PubMed Scopus (1918) Google Scholar, 35Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar) (see short intracellular domain forms have now been of the of (34Chen H. Charlat O. Tartaglia L.A. Woolf E.A. Weng X. Ellis S.J. Lakey N.D. Culpepper J. Moore K.J. Breitbart R.E. Duyk G.M. Tepper R.I. Morgenstern J.P. Cell. 1996; 84: 491-495Abstract Full Text Full Text PDF PubMed Scopus (1918) Google Scholar, 35Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar, 36Cioffi J.A. Shafer A.W. Zupancic T.J. Smith-Gbur J. Mikhail A. Platika D. Snodgrass H.R. Nat. Med. 1996; 2: 585-589Crossref PubMed Scopus (626) Google Scholar) used amino of the intracellular The most obvious of OB-R forms is to the long intracellular domain form the likely from the growing of short intracellular domain forms (Fig. 1). transcript a form of OB-R a has also been described G.H. Proenca R. Montez J.M. Carroll K.M. Darishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar). The murine and human receptors are in amino of both the extracellular and intracellular domains (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar, 34Chen H. Charlat O. Tartaglia L.A. Woolf E.A. Weng X. Ellis S.J. Lakey N.D. Culpepper J. Moore K.J. Breitbart R.E. Duyk G.M. Tepper R.I. Morgenstern J.P. Cell. 1996; 84: 491-495Abstract Full Text Full Text PDF PubMed Scopus (1918) Google Scholar).The mRNA expression of OB-R be with due to the that there are multiple receptor forms encoded by distinct or in analysis with generated from the extracellular domain to OB-R expression in multiple at (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar, 35Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar, 36Cioffi J.A. Shafer A.W. Zupancic T.J. Smith-Gbur J. Mikhail A. Platika D. Snodgrass H.R. Nat. Med. 1996; 2: 585-589Crossref PubMed Scopus (626) Google Scholar, Campfield L.A. Burn P. J. Clin. Invest. 1996; PubMed Scopus Google Scholar). the mouse, the highest OB-R mRNA levels are found in the choroid and and levels of expression are detected in (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar). However, analysis has shown that the of detected by these are short intracellular domain forms N. S. A. Stoffel R. R.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar). Deng and L. A. Tartaglia, unpublished observations. The mRNA species the long intracellular domain is much less Although this form can be detected by or in both mice and humans in in most it is expressed at very levels N. S. A. Stoffel R. R.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google to this is in the (Fig. the transcript is expressed at much higher levels N. S. A. Stoffel R. R.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google and can be detected by in J.G. N. Williams P. FEBS Lett. 1996; PubMed Scopus Google Scholar). fact, of the so only more long form transcript than the most short form the the long form transcript has been detected in the and J.G. N. Williams P. FEBS Lett. 1996; PubMed Scopus Google Scholar), thought to be important in body weight Leptin Receptor by the the cloning of the leptin receptor an important question was whether the gene it to the db as been predicted by the parabiosis studies of decades of the gene OB-R its to a on mouse 4 (28Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3204) Google Scholar). This was within the genetic to the db locus been by genetic of the gene the leptin receptor from normal and db mice revealed that a in fact, in this gene in db/db mice (34Chen H. Charlat O. Tartaglia L.A. Woolf E.A. Weng X. Ellis S.J. Lakey N.D. Culpepper J. Moore K.J. Breitbart R.E. Duyk G.M. Tepper R.I. Morgenstern J.P. 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The is a single within an the extreme and region of the short intracellular domain form of OB-R This results in the of a an that into the transcript the long intracellular domain form of OB-R (Fig. This is of the 6 and of the region of the primary short form and is the long and short intracellular domains a result of this the long form transcript in db/db mice would a protein in the of the intracellular domain has been and is identical to the short form The that the in db/db mice is in the OB-R gene for the of this receptor in body weight the of the ob/ob and db/db phenotypes that leptin can control over body weight of OB-R are as or and are by to that are and to a wild type mouse splicing can result in that either short line or long line intracellular db/db mice, these splicing can the long intracellular domain are by a partial by the db This results in a the long intracellular The is by an and are not to has also been shown that an OB-R is