Abnormal regulation of the leptin gene in the pathogenesis of obesity.
Open accessAbstract
A subset of obese humans has relatively low plasma levels of leptin. This finding has suggested that in some cases abnormal regulation of the leptin gene in adipose tissue is etiologic in the pathogenesis of the obese state. The possibility that a relative decrease in leptin production can lead to obesity was tested by mating animals carrying a weakly expressed adipocyte specific aP2-human leptin transgene to C57BL/6J ob/ob mice (which do not express leptin). The transgene does not contain the regulatory elements of the leptin gene and is analogous to a circumstance in which the cis elements and/or trans factors regulating leptin RNA production are abnormal. The ob/ob mice carrying the transgene had a plasma leptin level of 1. 78 ng/ml, which is approximately one-half that found in normal, nontransgenic mice (3.72 ng/ml, P < 0.01). The ob/ob animals expressing the leptin transgene were markedly obese though not as obese as ob/ob mice without the transgene. The infertility as well as several of the endocrine abnormalities generally evident in ob/ob mice were normalized in the ob/ob transgenic mice. However, the ob/ob transgenic mice had an abnormal response when placed at an ambient temperature of 4 degreesC, suggesting that different thresholds exist for the different biologic effects of leptin. Leptin treatment of the ob/ob transgenic mice resulted in marked weight loss with efficacy similar to that seen after treatment of wild-type mice. In aggregate these data suggest that dysregulation of leptin gene can result in obesity with relatively normal levels of leptin and that this form of obesity is responsive to leptin treatment.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The possibility that leptin is efficacious in obese humans with low leptin concentrations has not been directly tested in humans.
“Although leptin has been shown to have potent weight-reducing effects in obese animals with low leptin concentrations, this possibility has not been directly tested in humans (43).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [43]
Leptin has potent weight-reducing effects in obese animals with low leptin concentrations.
“Although leptin has been shown to have potent weight-reducing effects in obese animals with low leptin concentrations, this possibility has not been directly tested in humans (43).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [43]
Leptin could potentially be efficacious in obese patients with low plasma leptin concentrations.
“The demonstration that leptin can have therapeutic effects in some patients with low leptin concentrations in other settings (see above) suggests that leptin could potentially be efficacious in those obese patients with low plasma leptin concentrations (43).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [43]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
This paper’s reference list could not be split into single entries.
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419 · see citing works
Self-citationSerum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans
Considine, 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., et al. (1996) · New England Journal of Medicine · doi:10.1056/nejm199602013340503 · Cited by 6,326 · see citing works
Weight-Reducing Effects of the Plasma Protein Encoded by the <i>obese</i> Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451 · see citing works
Self-citationEffects of the <i>obese</i> Gene Product on Body Weight Regulation in <i>ob</i> / <i>ob</i> Mice
Pelleymounter, M. A., Cullen, M. J., Baker, M. B., Hecht, R., Winters, D., Boone, T., & Collins, F. (1995) · Science · doi:10.1126/science.7624776 · Cited by 4,017 · see citing works
A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis
Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., & Spiegelman, B. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81410-5 · Cited by 3,864 · see citing works
Maffei, M., Halaas, J., Ravussin, E., Pratley, R. E., Lee, G. H., Zhang, Y., Fei, H., Kim, S., Lallone, R., Ranganathan, S., et al. (1995) · Nature Medicine · doi:10.1038/nm1195-1155 · Cited by 3,725 · see citing works
Self-citationStimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor
Tontonoz, P., Hu, E., & Spiegelman, B. M. (1994) · Cell · doi:10.1016/0092-8674(94)90006-x · Cited by 3,533 · see citing works
Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R., & Burn, P. (1995) · Science · doi:10.1126/science.7624778 · Cited by 3,243 · see citing works
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., et al. (1997) · Nature · doi:10.1038/43185 · Cited by 2,936 · see citing works
Abnormal splicing of the leptin receptor in diabetic mice
Lee, G.-H., Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., & Friedman, J. M. (1996) · Nature · doi:10.1038/379632a0 · Cited by 2,327 · see citing works
Self-citationChanges in Energy Expenditure Resulting from Altered Body Weight
Leibel, R. L., Rosenbaum, M., & Hirsch, J. (1995) · New England Journal of Medicine · doi:10.1056/nejm199503093321001 · Cited by 2,012 · see citing works
The role of neuropeptide Y in the antiobesity action of the obese gene product
Stephens, T. W., Basinski, M., Bristow, P. K., Bue-Valleskey, J. M., Burgett, S. G., Craft, L., Hale, J., Hoffmann, J., Hsiung, H. M., Kriauciunas, A., et al. (1995) · Nature · doi:10.1038/377530a0 · Cited by 1,498 · see citing works
The role of depot fat in the hypothalamic control of food intake in the rat
Gc, K. (1953) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1953.0009 · Cited by 1,432 · see citing works
Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice
Coleman, D. L. (1978) · Diabetologia · doi:10.1007/bf00429772 · Cited by 1,307 · see citing works
A leptin missense mutation associated with hypogonadism and morbid obesity
Strobel, A., Issad, T., Camoin, L., Ozata, M., & Strosberg, A. D. (1998) · Nature Genetics · doi:10.1038/ng0398-213 · Cited by 1,158 · see citing works
OBESE, A NEW MUTATION IN THE HOUSE MOUSE*
INGALLS, A. M., DICKIE, M. M., & SNELL, G. D. (1950) · Journal of Heredity · doi:10.1093/oxfordjournals.jhered.a106073 · Cited by 1,090 · see citing works
Physiological response to long-term peripheral and central leptin infusion in lean and obese mice.
Halaas, J. L., Boozer, C., Blair-West, J., Fidahusein, N., Denton, D. A., & Friedman, J. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.16.8878 · Cited by 1,033 · see citing works
Self-citationMethods for the determination of adipose cell size in man and animals
Hirsch, J., & Gallian, E. (1968) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)43151-7 · Cited by 894 · see citing works
Diet-induced obese mice develop peripheral, but not central, resistance to leptin.
van Heek, M., Compton, D. S., France, C. F., Tedesco, R. P., Fawzi, A. B., Graziano, M. P., Sybertz, E. J., Strader, C. D., & Davis, H. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119171 · Cited by 752 · see citing works
Overexpression of the obese (ob) gene in adipose tissue of human obese subjects
Lönnqvist, F., Arner, P., Nordfors, L., & Schalling, M. (1995) · Nature Medicine · doi:10.1038/nm0995-950 · Cited by 708 · see citing works
Increased obese mRNA expression in omental fat cells from massively obese humans
Hamilton, B. S., Paglia, D., Kwan, A. Y. M., & Deitel, M. (1995) · Nature Medicine · doi:10.1038/nm0995-953 · Cited by 526 · see citing works
Role of leptin in fat regulation
Collins, S., Kuhn, C. M., Petro, A. E., Swick, A. G., Chrunyk, B. A., & Surwit, R. S. (1996) · Nature · doi:10.1038/380677a0 · Cited by 520 · see citing works
Recombinant ob protein reduces feeding and body weight in the ob/ob mouse.
Weigle, D. S., Bukowski, T. R., Foster, D. C., Holderman, S. D., Kramer, J. M., Lasser, G. W., Lofton–Day, C., Prunkard, D. E., Raymond, C. K., & Kuijper, J. L. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118254 · Cited by 420 · see citing works
Decreased food intake does not completely account for adiposity reduction after ob protein infusion.
Levin, N. W., Nelson, C., Gurney, A., VANDLEN, R. L., & de Sauvage, F. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.4.1726 · Cited by 372 · see citing works
Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity.
Considine, R. V., Considine, E. L., Williams, C. J., Nyce, M. R., Magosin, S., BAUER, T. L., Rosato, E., Colberg, J. E., & Caro, J. F. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118007 · Cited by 353 · see citing works
Cellularity of adipose depots in six strains of genetically obese mice
Johnson, P. R., & Hirsch, J. (1972) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39428-1 · Cited by 278 · see citing works
A fat-specific enhancer is the primary determinant of gene expression for adipocyte P2 in vivo.
Ross, S. R., Graves, R. A., Greenstein, A., Platt, K. A., Shyu, H.-L., Mellovitz, B., & Spiegelman, B. M. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.24.9590 · Cited by 212 · see citing works
Obesity, Leptin, and the Brain
Rohner‐Jeanrenaud, F., & Jeanrenaud, B. (1996) · New England Journal of Medicine · doi:10.1056/nejm199602013340511 · Cited by 173 · see citing works
Appetite and the regulation of body composition
Weigle, D. S. (1994) · The FASEB Journal · doi:10.1096/fasebj.8.3.8143936 · Cited by 155 · see citing works
Identification of a potent adipocyte-specific enhancer: involvement of an NF-1-like factor.Preprint
Graves, R. A., Tontonoz, P., Ross, S. R., & Spiegelman, B. M. (1991) · Genes & Development · doi:10.1101/gad.5.3.428 · Cited by 132 · see citing works
REGULATORY INFLUENCES OF ADIPOSE TISSUE ON FOOD INTAKE AND BODY WEIGHT*
Liebelt, R. A., Ichinoe, S., & Nicholson, N. (1965) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1965.tb34820.x · Cited by 76 · see citing works
LANE, P. W., & Dickie, M. M. (1954) · Journal of Heredity · doi:10.1093/oxfordjournals.jhered.a106439 · Cited by 47 · see citing works
Chung, W. K., Chua, S. C., Lee, G., et al. (1997) · Obesity Research · doi:10.1002/j.1550-8528.1997.tb00291.x · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Leptin and the regulation of body weight in mammals
Friedman, J. M., & Halaas, J. L. (1998) · Nature · doi:10.1038/27376 · Cited by 5,405 · see citing works
Self-citationShort-chain fatty acids in control of body weight and insulin sensitivity
Canfora, E. E., Jocken, J. W., & Blaak, E. E. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.128 · Cited by 2,298 · see citing works
Ahima, R. S., & Flier, J. S. (2000) · Annual Review of Physiology · doi:10.1146/annurev.physiol.62.1.413 · Cited by 1,428 · see citing works
Leptin and the endocrine control of energy balance
Friedman, J. M. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0095-y · Cited by 661 · see citing works
Self-citationParks, B. W., Nam, E., Org, E., Kostem, E., Norheim, F., Hui, S. T., Pan, C., Civelek, M., Rau, C. D., Bennett, B. J., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.007 · Cited by 544 · see citing works
Leptin at 14 y of age: an ongoing story
Friedman, J. M. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26788b · Cited by 272 · see citing works
Self-citationLeptin and the Hypothalamic-Pituitary Regulation of the Gonadotropin-Gonadal Axis
Chan, J. L., & Mantzoros, C. S. (2001) · Pituitary · doi:10.1023/a:1012947113197 · Cited by 124 · see citing works
Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity
Dallner, O. S., Marinis, J. M., Lu, Y.-H., Birsoy, K., Werner, E., Fayzikhodjaeva, G., Dill, B. D., Molina, H., Moscati, A., Kutalik, Z., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0370-1 · Cited by 106 · see citing works
Self-citationM<scp>ETABOLIC</scp> L<scp>ESSONS FROM</scp> G<scp>ENETICALLY</scp> L<scp>EAN</scp> M<scp>ICE</scp>
Reitman, M. L. (2002) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.22.010402.102849 · Cited by 75 · see citing works
- Authors
- Ioffe, E., Moon, B., Connolly, E., & Friedman, J. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-09-29
- Volume
- 95
- Issue
- 20
- Pages
- 11852-11857
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC21729
- OpenAlex
- W2078769875
- Cited by
- 117
- References
- 33
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 1 · 2020: 1 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 1 · 2015: 6 · 2014: 6 · 2013: 4 · 2012: 2
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- leptin, obesity, ob/ob mice, adipose tissue, leptin deficiency, weight loss, infertility, endocrine disorders, leptin resistance
- MeSH terms
- Animals, Base Sequence, Cell Count, Eating, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Mice, Obese, Mice, Transgenic, Obesity, Phenotype, Proteins, Weight Loss, Polymerase Chain Reaction, Adipocytes, DNA Primers, Leptin, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
