Human Leptin Deficiency Caused by a Missense Mutation: Multiple Endocrine Defects, Decreased Sympathetic Tone, and Immune System Dysfunction Indicate New Targets for Leptin Action, Greater Central than Peripheral Resistance to the Effects of Leptin, and Spontaneous Correction of Leptin-Mediated Defects
Abstract
We have previously demonstrated that genetically based leptin deficiency due to a missense leptin gene mutation in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism. We have now performed detailed assessments of endocrine, sympathetic, and immune function. We have also identified a new adult female homozygous patient in this extended family who is severely obese and amenorrheic. In this family all wild-type and heterozgous individuals have normal body weight. Seven obese members of this family, whom we presume to have been leptin deficient, died during childhood. There are several findings that indicate potentially novel targets for leptin action in humans. Four homozygous patients (1 adult male, 2 adult females, and 1 child) have sympathetic system dysfunction, whereas all heterozygous subjects have normal sympathetic system function. Despite sympathetic system dysfunction and postural hypotension, 1 of 3 homozygous adult patients has impaired renin-aldosterone function. The patients also exhibit alterations in GH and PTH-calcium function, and 1 of them has decreased bone mineral density. Despite their obesity, these patients do not have risk factors for cardiovascular disease, such as hypertension, impairments in lipid metabolism, or hyperleptinemia [corrected]. These data support the hypothesis that the obese may have central, but not peripheral, resistance to the effects of leptin and that hyperleptinemia [corrected] may mediate the cardiovascular morbidity of the obese who are not leptin deficient. Furthermore, these data indicate that there may be several new targets for leptin action in human physiology. Such new targets may lead to novel pharmacological strategies for the use of leptin agonists and antagonists in the treatment of human disease. All 19 normal weight individuals in this family are alive, whereas 7 of 11 obese individuals died in childhood after infections. The odds ratio for mortality in the context of this obesity phenotype is 25.4, indicating that this mutation severely impairs key biological functions during childhood, negatively impacting on survival. We found that only the obese child in this family had thyroid function abnormalities. The oldest homozygous female patient started to menstruate, albeit with a luteal phase defect, 7 months ago, after a delay of over 20 yr, whereas the younger adult subjects are still hypogonadic. Thus, we conclude that due to their long life span, humans who survive the negative effects of leptin deficiency during childhood can, in contrast to ob/ob mice, over decades compensate some of the effects of leptin deficiency on immunity and endocrine function through mechanisms that remain to be elucidated.
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Leptin 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 [4]
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 [4]
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 [4]
Leptin-deficient subjects have decreased GH response to insulin-induced hypoglycemia and exercise tests but normal heights.
“Leptin-deficient subjects have decreased GH response to insulin-induced hypoglycemia and exercise tests but normal heights (4)”
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 [4]
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 [4]
Leptin-deficient subjects had elevated basal cortisol and ACTH levels but normal urinary free cortisol and response to dexamethasone suppression.
“Leptin-deficient subjects had elevated basal cortisol and ACTH levels but normal urinary free cortisol and response to dexamethasone suppression (4).”
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 [4]
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 [4]
Children with congenital leptin deficiency are prone to early death as a result of severe infections during childhood because of defects in T cell number and function.
“Children with congenital leptin deficiency are prone to early death as a result of severe infections during childhood because of defects in T cell number and function (28).”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [28]
Leptin-deficient subjects respond dramatically to leptin administered in replacement doses, which induces markedly decreased appetite and food intake and results in a significant reduction in body weight.
“These leptindeficient subjects respond in a dramatic fashion to leptin administered in replacement doses, which induces markedly decreased appetite and food intake and which in turn result in a significant reduction in body weight (28)(29)(30).”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [28]
Children with congenital leptin deficiency given leptin have appropriately timed pubertal development.
“These children, when given leptin, have an appropriately timed pubertal development (28,29).”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [28]
Genetically based leptin deficiency due to a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism.
“We have previously demonstrated that genetically based leptin deficiency due to a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism (7, 10).”
From Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults (2004) · cites this paper as [10]
At baseline, patient A had clinical features of hypogonadism, with testosterone and free testosterone below the normal range for his age.
“At baseline, before leptin replacement, patient A had clinical features of hypogonadism, as previously reported (10). His baseline measurements of testosterone and free testosterone were below the normal range for his age (10).”
From Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults (2004) · cites this paper as [10]
Patients B and C had at baseline regular menstrual periods characterized by a luteal phase defect with low midluteal phase progesterone levels.
“Patients B and C had at baseline regular menstrual periods characterized by a luteal phase defect with low midluteal phase progesterone levels (10).”
From Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults (2004) · cites this paper as [10]
In a study of four patients with leptin deficiency due to gene mutations, three had normal blood pressure and one had high blood pressure.
“A study that included four patients with leptin deficiency due to gene mutations found that despite severe obesity, three of these patients had normal BP and only one had high BP, possibly owing to unexplained high levels of adrenocorticotropic hormone, which can increase plasma cortisol levels as well as BP134.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [134]
Leptin-deficient individuals displayed evidence of autonomic dysfunction, including postural hypotension, reduced blood pressure responses to cold pressor stimuli, and diminished RAAS responses to upright posture.
“Moreover, these leptin-deficient individuals displayed evidence of autonomic dysfunction, including postural hypotension, reduced BP responses to cold pressor stimuli and diminished RAAS responses to upright posture.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [134]
Leptin-deficient humans generally are not hypertensive and do not have increased SNS activity.
“Although BP and SNS activity have been assessed in only a few leptin-deficient humans, they generally are not hypertensive and do not have increased SNS activity.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [115]
Humans with leptin deficiency are generally not hypertensive and do not have increased sympathetic activity despite severe obesity, hyperinsulinemia, insulin resistance and most other characteristics of the metabolic syndrome.
“Although leptin’s effects on SNS activity and BP in humans have not been extensively studied, humans with leptin deficiency are generally not hypertensive and do not have increased sympathetic activity despite severe obesity, hyperinsulinemia, insulin resistance and most other characteristics of the metabolic syndrome [49].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [49]
Three adults and one child with severe obesity and complete leptin deficiency had sympathetic hypofunction manifest by orthostatic hypotension and an attenuated cold pressor test.
“Ozata et al92 reported that three adults and one child with severe obesity and complete leptin deficiency had sympathetic hypofunction manifest by orthostatic hypotension and an attenuated cold pressor test.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [92]
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- Authors
- Ozata, M., Ozdemir, I. C., & Licinio, J.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1999-10
- Volume
- 84
- Issue
- 10
- Pages
- 3686-3695
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2059063316
- Cited by
- 739
- References
- 48
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 12 · 2023: 18 · 2022: 14 · 2021: 35 · 2020: 14 · 2019: 17 · 2018: 22 · 2017: 27 · 2016: 31 · 2015: 25 · 2014: 41 · 2013: 42 · 2012: 39
- FWCI
- 11.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin deficiency, missense mutations, consanguinity, morbid obesity, hypogonadism, amenorrhea, sympathetic dysfunction, orthostatic hypotension, growth hormone, parathyroid hormone, bone mineral density, leptin resistance, hyperleptinemia, cardiovascular risk, immune dysfunction, luteal phase defect, thyroid function abnormalities, consanguineous pedigree, child mortality, Turkish families
- MeSH terms
- Adult, Aged, Child, Endocrine System Diseases, Female, Humans, Immune System, Male, Middle Aged, Pedigree, Sympathetic Nervous System, Vascular Resistance, Mutation, Missense, Leptin
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