The Leptin Receptor

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. 1995; PubMed Scopus Google Scholar, 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. S. A. 1995; PubMed Scopus Google Scholar, H. S. A. PubMed Scopus Google Scholar). These have led to the proposal that leptin as an the body of the of in the adipose tissue that in and be the leptin receptor. regulation of the leptin transcript and protein also been in to in R.C. Löllmann B. Hamann A. Napolitano-Rosen A. Kahn B.B. Lowell B.B. Flier J.S. J. 1995; PubMed Scopus Google Scholar, H. S. A. PubMed Scopus Google Scholar, R. M. A. J. B. J. Nature. 1995; PubMed Scopus Google Scholar, R.C. Hamann A. S. B. Lowell B.B. Flier J.S. Nat. Med. 1995; 1: PubMed Scopus Google in and in It is that an important for leptin is the to Lowell B. E. Flier J.S. Nature. PubMed Scopus Google Scholar). on leptin mRNA and protein have also been in to a variety of including and R. M. A. J. B. J. Nature. 1995; PubMed Scopus Google Scholar, A. J. J. J. PubMed Scopus Google Scholar, J. A. A. Friedman J. J. PubMed Scopus Google also been of leptin regulation in humans. The leptin mRNA is in by in the of body as well as in (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, A. J. Med. PubMed Scopus Google Scholar, J. J. 1995; PubMed Scopus Google Scholar, M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar, L. M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar). However, the of mRNA regulation in is that in at the protein human leptin is with in the rodent and (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, A. J. Med. PubMed Scopus Google Scholar). The protein is in with an of body and is body weight This regulation in mice and may that leptin is in as it is in although studies are to and important been a of human obesity be to mutations in the ob The ob been of human mutations have not been found J. J. 1995; PubMed Scopus Google Scholar, M. M. Barone M. B. M. Ravussin E. Flier J.S. M. S. Friedman J.M. PubMed Scopus Google Scholar, H. Y. M. H. S. J. M. H. M. PubMed Scopus Google Scholar). Although mutations mRNA levels of the with leptin mRNA levels have also not been described A. J. Med. PubMed Scopus Google Scholar, J. J. 1995; PubMed Scopus Google Scholar, M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar, L. M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar), that the of not be the of that the ob gene suggested of this with human obesity J. A. A. A. B. M. PubMed Scopus Google Scholar, Y. PubMed Scopus Google been by the that of leptin to in and weight Y. R. Science. 1995; PubMed Scopus Google Scholar, Maffei M. Lallone Freidman J.M. Science. 1995; PubMed Scopus Google Scholar, R. Science. 1995; PubMed Scopus Google Scholar, M. J.M. L. J. J. A. B. Zhang M. Nature. 1995; PubMed Scopus Google Scholar). Although the of leptin is in mice that are deficient in this protein be at in mice and mice with studies have that leptin may be an in that are not to leptin interest are studies that have the of These studies that leptin the or in and weight that leptin could on the Y. R. Science. 1995; PubMed Scopus Google Scholar, M. J.M. L. J. J. A. B. Zhang M. Nature. 1995; PubMed Scopus Google in leptin appears to be to not in also in Maffei M. Lallone Freidman J.M. Science. 1995; PubMed Scopus Google Scholar, R. Science. 1995; PubMed Scopus Google Scholar). Although the of are to be important may the of adipose tissue S. A. A. B. R. Nature. that leptin are not in human obesity in that leptin levels to be as the of body suggested that to or elevated levels of leptin may be important leptin in human obesity A. J. Med. PubMed Scopus Google Scholar). This of been by the of type many of exhibit elevated levels of These interest in the of the receptor for leptin and the of leptin signal also interest in the db/db a of leptin Y. R. Science. 1995; PubMed Scopus Google Scholar, Maffei M. Lallone Freidman J.M. Science. 1995; PubMed Scopus Google Scholar, R. Science. 1995; PubMed Scopus Google Scholar, M. J.M. L. J. J. A. B. Zhang M. Nature. 1995; PubMed Scopus Google Scholar) and elevated leptin levels 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. S. A. 1995; PubMed Scopus Google of the of the receptor for the leptin protein was through an expression cloning strategy M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar). of leptin were through a strategy or by leptin and These reagents were to identify a tissue a leptin M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar, R. Y. J. J. S. A. PubMed Scopus Google Scholar). and leptin was in the mouse this leptin a was and with this were with a protein. this were identified that a leptin receptor with an for leptin of about M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google of the identified in the expression cloning revealed a single receptor of the receptor M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar). This was consistent with a previous that the leptin protein be to a 1995; PubMed Scopus Google Scholar). The of were the receptor A. S. L. E. J. Med. PubMed Scopus Google Scholar), and the factor receptor J. J. PubMed Scopus Google Scholar). The of was about the was fairly that this protein not have However, and of the as a revealed that were multiple of in mice and including a with an of about M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar, H. Weng J. R.E. PubMed Scopus Google Scholar, G.H. Proenca R. J.M. Lee Friedman J.M. Nature. PubMed Scopus Google Scholar, J. A. Nat. Med. PubMed Scopus Google Scholar) The of the of of the and of are throughout their in the receptor at the most in with and H. Weng J. R.E. PubMed Scopus Google Scholar, G.H. Proenca R. J.M. Lee Friedman J.M. Nature. PubMed Scopus Google Scholar) have been of the of H. Weng J. R.E. PubMed Scopus Google Scholar, G.H. Proenca R. J.M. Lee Friedman J.M. Nature. PubMed Scopus Google Scholar, J. A. Nat. Med. PubMed Scopus Google Scholar) of the The most of is to the the the growing of transcript a of a also been described G.H. Proenca R. J.M. Lee Friedman J.M. Nature. PubMed Scopus Google Scholar). The and human are in of the and M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar, H. Weng J. R.E. PubMed Scopus Google mRNA expression of be with to the that are multiple receptor by distinct or in with the to expression in multiple at M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar, G.H. Proenca R. J.M. Lee Friedman J.M. Nature. PubMed Scopus Google Scholar, J. A. Nat. Med. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). the the mRNA levels are found in the and and levels of expression are in M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar). However, shown that the of by these are S. A. R. R.C. S. A. PubMed Scopus Google Scholar). and L. A. Tartaglia, unpublished observations. The mRNA species the is Although this be by or in mice and in in most it is expressed at very levels S. A. R. R.C. S. A. PubMed Scopus Google to this is in the the transcript is expressed at levels S. A. R. R.C. S. A. PubMed Scopus Google and be by in PubMed Scopus Google Scholar). of the transcript the most the the transcript been in the and PubMed Scopus Google Scholar), to be important in body weight by the the cloning of the leptin receptor an important was the gene it to the db as been by the parabiosis studies of decades of the gene its to a on mouse 4 M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar). This was the genetic to the db locus been by genetic of the gene the leptin receptor and db mice revealed that a in in this gene in db/db mice H. Weng J. R.E. PubMed Scopus Google Scholar, G.H. Proenca R. J.M. Lee Friedman J.M. Nature. PubMed Scopus Google Scholar). 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It is important to that although is of in the in their may that in and may been in mice leptin is Halaas M. Friedman J.M. Nat. 1966; 14: Scopus Google Scholar). It is also important to that are to signal that are distinct the as the protein and 1995; PubMed Scopus Google Scholar, S. 1994; PubMed Scopus Google Scholar), and it is that ability to control body weight may these as experiments in have shown that is also to to be by of the receptor H. M. Kim H. S. A. PubMed Scopus Google Scholar). for protein the mouse to the mutant in db/db of H. M. Kim H. S. A. PubMed Scopus Google to have a to the type H. M. Kim H. S. A. PubMed Scopus Google Scholar). with and the factor receptor as a However, are of type not by in H. M. Kim H. S. A. PubMed Scopus Google Scholar). is to with the of the receptor of a for is an important have been shown to with factor, and with a for signal as and 1995; PubMed Scopus Google Scholar, S. 1994; PubMed Scopus Google Scholar). However, was found to in not or H. M. Kim H. S. A. PubMed Scopus Google could with a it may through or as been shown for a of as and 1995; PubMed Scopus Google Scholar, S. 1994; PubMed Scopus Google Scholar). to these were the of the and the of as well as the receptor the of and the of R. H. J. PubMed Scopus Google Scholar). of these receptor were to and in the and were not that of the The that a could in to that of is for at This that not an and may be by or the ability of the leptin to a signal the that the leptin is of this is the for of shown that are at two distinct of R. H. J. PubMed Scopus Google Scholar). mutant receptor in the most are the ability to an However, this not the ability of to a receptor were the most was to H. M. Kim H. S. A. PubMed Scopus Google Scholar). this single the ability of to its ability to and and its ability to The of distinct the that multiple distinct may be by of the identified or as is most important for body weight regulation the of mutant the db mouse and for of the mutant are numerous important about the of in body weight of the in receptor is important to of this It is that leptin to a of the and that receptor in this of the leptin to the of and It is also that are with of and that receptor at these is important for leptin to the that signal are of Although an of signal is well it is to of these or as is most important in body weight The that is of and that leptin result in in gene expression The of by leptin in the and the of the they in body weight regulation many body weight nature of leptin is of to the of human It is that this as early in this as the of leptin the blood the to be Scopus Google Scholar) is that of have a in the in the of with is the that leptin is a result of the of the leptin to the of these and strategies to are the 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. 1995; PubMed Scopus Google Scholar, 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. S. A. 1995; PubMed Scopus Google Scholar, H. S. A. PubMed Scopus Google Scholar). These have led to the proposal that leptin as an the body of the of in the adipose tissue that in and be the leptin receptor. regulation of the leptin transcript and protein also been in to in R.C. Löllmann B. Hamann A. Napolitano-Rosen A. Kahn B.B. Lowell B.B. Flier J.S. J. 1995; PubMed Scopus Google Scholar, H. S. A. PubMed Scopus Google Scholar, R. M. A. J. B. J. Nature. 1995; PubMed Scopus Google Scholar, R.C. Hamann A. S. B. Lowell B.B. Flier J.S. Nat. Med. 1995; 1: PubMed Scopus Google in and in It is that an important for leptin is the to Lowell B. E. Flier J.S. Nature. PubMed Scopus Google Scholar). on leptin mRNA and protein have also been in to a variety of including and R. M. A. J. B. J. Nature. 1995; PubMed Scopus Google Scholar, A. J. J. J. PubMed Scopus Google Scholar, J. A. A. Friedman J. J. PubMed Scopus Google also been of leptin regulation in humans. The leptin mRNA is in by in the of body as well as in (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, A. J. Med. PubMed Scopus Google Scholar, J. J. 1995; PubMed Scopus Google Scholar, M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar, L. M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar). However, the of mRNA regulation in is that in at the protein human leptin is with in the rodent and (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, A. J. Med. PubMed Scopus Google Scholar). The protein is in with an of body and is body weight This regulation in mice and may that leptin is in as it is in although studies are to and important been a of human obesity be to mutations in the ob The ob been of human mutations have not been found J. J. 1995; PubMed Scopus Google Scholar, M. M. Barone M. B. M. Ravussin E. Flier J.S. M. S. Friedman J.M. PubMed Scopus Google Scholar, H. Y. M. H. S. J. M. H. M. PubMed Scopus Google Scholar). Although mutations mRNA levels of the with leptin mRNA levels have also not been described A. J. Med. PubMed Scopus Google Scholar, J. J. 1995; PubMed Scopus Google Scholar, M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar, L. M. Nat. Med. 1995; 1: PubMed Scopus Google Scholar), that the of not be the of that the ob gene suggested of this with human obesity J. A. A. A. B. M. PubMed Scopus Google Scholar, Y. PubMed Scopus Google been by the that of leptin to in and weight Y. R. Science. 1995; PubMed Scopus Google Scholar, Maffei M. Lallone Freidman J.M. Science. 1995; PubMed Scopus Google Scholar, R. Science. 1995; PubMed Scopus Google Scholar, M. J.M. L. J. J. A. B. Zhang M. Nature. 1995; PubMed Scopus Google Scholar). Although the of leptin is in mice that are deficient in this protein be at in mice and mice with studies have that leptin may be an in that are not to leptin interest are studies that have the of These studies that leptin the or in and weight that leptin could on the Y. R. Science. 1995; PubMed Scopus Google Scholar, M. J.M. L. J. J. A. B. Zhang M. Nature. 1995; PubMed Scopus Google in leptin appears to be to not in also in Maffei M. Lallone Freidman J.M. Science. 1995; PubMed Scopus Google Scholar, R. Science. 1995; PubMed Scopus Google Scholar). Although the of are to be important may the of adipose tissue S. A. A. B. R. Nature. that leptin are not in human obesity in that leptin levels to be as the of body suggested that to or elevated levels of leptin may be important leptin in human obesity A. J. Med. PubMed Scopus Google Scholar). This of been by the of type many of exhibit elevated levels of These interest in the of the receptor for leptin and the of leptin signal also interest in the db/db a of leptin Y. R. Science. 1995; PubMed Scopus Google Scholar, Maffei M. Lallone Freidman J.M. Science. 1995; PubMed Scopus Google Scholar, R. Science. 1995; PubMed Scopus Google Scholar, M. J.M. L. J. J. A. B. Zhang M. Nature. 1995; PubMed Scopus Google Scholar) and elevated leptin levels 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. S. A. 1995; PubMed Scopus Google of the of the receptor for the leptin protein was through an expression cloning strategy M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar). of leptin were through a strategy or by leptin and These reagents were to identify a tissue a leptin M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google Scholar, R. Y. J. J. S. A. PubMed Scopus Google Scholar). and leptin was in the mouse this leptin a was and with this were with a protein. this were identified that a leptin receptor with an for leptin of about M. Weng J. R. J. S. A. J.S. 1995; PubMed Scopus Google of the identified in the expression cloning revealed a single receptor of the receptor M. Weng J. R. J. S. A. J.S.