Congenital leptin deficiency is associated with severe early-onset obesity in humans
Abstract
The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.
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The nature of the neuroendocrine defects in leptin-deficient rodents and in leptin-deficient or leptin-resistant humans differ in some important respects, suggesting that the role of leptin in mediating the neuroendocrine response to starvation may be different in humans versus rodents.
“The nature of the neuroendocrine defects in leptin-deficient rodents and in leptin-deficient or leptin-resistant humans differ in some important respects, however, suggesting that the role of leptin in mediating the neuroendocrine response to starvation may be different in humans versus rodents (2-4, 8, 22).”
From The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men (2003) · cites this paper as [2]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredLeptin is an adipocyte-derived hormone whose absence in mice and humans causes abnormal energy homeostasis and profound obesity that is ameliorated by leptin treatment.
“Leptin is an adipocyte-derived hormone whose absence in mice (1) and humans (2-4) causes abnormal energy homeostasis and profound obesity that is ameliorated by leptin treatment (5, 6).”
From The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men (2003) · cites this paper as [2]
In humans, as in mice, congenital absence of leptin or functional leptin deficiency due to inactivating mutations of the leptin receptor causes severe obesity accompanied by neuroendocrine abnormalities.
“In humans, as in mice, congenital absence of leptin or functional leptin deficiency due to inactivating mutations of the leptin receptor causes severe obesity accompanied by neuroendocrine abnormalities (2-4, 22).”
From The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men (2003) · cites this paper as [2]
Single-gene Mendelian defects account for about 8% (or perhaps more) of cases of morbid human obesity.
“The importance of the aforementioned neural circuits for human obesity has been established in a series of genetic studies in which it has been shown that single-gene Mendelian defects account for '8% (or perhaps more) of cases of morbid human obesity (55)(56)(57)(58)(59)(60)(61)(62)(63).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [56]
Homozygous mutations in genes encoding leptin (LEP) or leptin receptor (LEPR) cause hypogonadotropic hypogonadism in human beings.
“The finding that homozygous mutations in genes encoding leptin (LEP) or leptin receptor (LEPR) cause hypogonadotropic hypogonadism in human beings emphasises the role of leptin in reproduction.98–100”
From Pubertal development and regulation (2016) · cites this paper as [99]
Genetic mutations in the leptin pathway can be a cause of human obesity.
“Mutations in the leptin pathway can be a cause of human obesity (5–7).”
From Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults (2004) · cites this paper as [6]
Absolute leptin deficiency causes obesity.
“While absolute leptin deficiency causes obesity (118, 212)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [118]
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- Authors
- 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., Cheetham#, C. H., Earley#, A. R., Barnett, A. H., Prins, J. B., & O'Rahilly, S.
- Affiliations
- University of Cambridge (GB)
- Guy's Hospital (GB)
- Churchill Hospital (GB)
- Heartlands Hospital (GB)
- ORCID
- Venue
- Nature
- Published
- 1997-06-26
- Volume
- 387
- Issue
- 6636
- Pages
- 903-908
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1512875938
- Cited by
- 2,936
- References
- 21
- Citations by year
- 2026: 33 · 2025: 52 · 2024: 47 · 2023: 69 · 2022: 56 · 2021: 80 · 2020: 71 · 2019: 73 · 2018: 73 · 2017: 87 · 2016: 84 · 2015: 96 · 2014: 125 · 2013: 110 · 2012: 108
- FWCI
- 48.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- 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 deficiency, early-onset obesity, frameshift mutation, consanguinity, energy balance, appetite, energy expenditure
- MeSH terms
- Adult, Animals, Body Composition, Child, Child, Preschool, Consanguinity, Female, Cricetinae, Homozygote, Humans, Male, Metabolism, Inborn Errors, Mice, Obese, Molecular Sequence Data, Obesity, Pedigree, Proteins, Transfection, Frameshift Mutation, CHO Cells, Sequence Analysis, DNA, Age of Onset, Polymorphism, Single-Stranded Conformational, Leptin, Mice
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