A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction
Abstract
The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions 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 [22]
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 [22]
Unlike mice, human subjects with mutations in the leptin or leptin receptor gene appear to have normal adrenal function.
“but unlike mice, human subjects with mutations in the leptin or leptin receptor gene appear to have normal adrenal function.”
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 [22]
Leptin-resistant subjects with a mutation in the leptin receptor had evidence of hypothalamic hypothyroidism with low T4, normal basal TSH, and sustained TSH response to TRH.
“leptin-resistant subjects with a mutation in the leptin receptor had evidence of hypothalamic hypothyroidism with low T4, normal basal TSH, and sustained TSH response to TRH (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 [22]
Leptin-resistant subjects have a mild but significant growth delay during early childhood in addition to decreased GH secretion and low IGF-1 and IGFBP-3 levels.
“whereas leptin-resistant subjects have a mild but significant growth delay during early childhood in addition to decreased GH secretion and low IGF-1 and IGFBP-3 levels (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 [22]
Reproductive dysfunction occurs in humans with leptin deficiency or resistance due to mutations in the leptin gene or the leptin receptor gene.
“In addition, reproductive dysfunction occurs in humans with leptin deficiency or resistance due to mutations in the leptin gene or the leptin receptor gene, respectively.”
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 [22]
Evaluation of the HPA axis in leptin-resistant subjects did not reveal any abnormalities.
“Similarly, evaluation of the HPA axis in the leptin-resistant subjects did not reveal any abnormalities (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 [22]
Subjects with mutations of the leptin gene or the leptin receptor gene present with normal adrenal function.
“In contrast to findings in rodents, subjects with mutations of the leptin gene or the leptin receptor gene present with normal adrenal function (16,18).”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [18]
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 [57]
Individuals with homozygous mutations in LEPR presented with early-onset morbid obesity and reduced growth hormone and thyrotropin secretion.
“In addition to the reproductive phenotype, individuals with homozygous mutations in LEPR presented with early-onset morbid obesity and reduced growth hormone and thyrotropin secretion.100”
From Pubertal development and regulation (2016) · cites this paper as [100]
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 [100]
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- Authors
- Clément, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J.-M., Basdevant, A., Bougnères, P., Lebouc, Y., Froguel, P., & Guy-Grand, B.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Hôpital Armand-Trousseau (FR)
- Hôtel-Dieu de Paris (FR)
- Corresponding author
- Froguel, Philippe
- ORCID
- Venue
- Nature
- Published
- 1998-03
- Volume
- 392
- Issue
- 6674
- Pages
- 398-401
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1639930240
- Cited by
- 2,346
- References
- 30
- Citations by year
- 2026: 17 · 2025: 45 · 2024: 38 · 2023: 65 · 2022: 50 · 2021: 66 · 2020: 47 · 2019: 56 · 2018: 62 · 2017: 73 · 2016: 75 · 2015: 82 · 2014: 75 · 2013: 84 · 2012: 79
- FWCI
- 50.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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 receptor, leptin, obesity, pituitary dysfunction, truncated receptor, homozygous mutation, growth hormone deficiency, thyrotropin deficiency, hypogonadotropic hypogonadism, pubertal development, energy homeostasis
- MeSH terms
- Adult, Body Height, Body Weight, Carrier Proteins, Family Health, Female, Genotype, Homozygote, Humans, Male, Mutation, Obesity, Pituitary Diseases, Receptors, Cell Surface, RNA, Messenger, Polymorphism, Single-Stranded Conformational, Human Growth Hormone, Receptors, Leptin
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