20 YEARS OF LEPTIN: Human disorders of leptin action
Abstract
The discovery of leptin has provided a robust framework upon which our current understanding of the mechanisms involved in energy homeostasis has been built. In this review, we describe how the identification of humans with mutations in the genes encoding leptin and the leptin receptor and the characterisation of the associated clinical phenotypes have provided insights into the role of leptin-responsive pathways in the regulation of eating behaviour, intermediary metabolism and the onset of puberty. Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain.
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Leptin treatment is effective in obesity caused by leptin and leptin receptor genetic polymorphisms, which are rare (<5% of obese individuals).
“While leptin treatment is effective in obesity that is caused by leptin and leptin receptor genetic polymorphisms, these are rare (<5% of obese individuals) [95].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [95]
Human studies showed that patients with obesity were leptin-resistant and had higher levels of leptin.
“However, on the contrary, human study showed that patients with obesity were leptin-resistant and had higher levels of leptin [82].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [82]
The most recent meta-analyses reported that, for at least 12 months of treatment, placebo-subtracted weight loss ranged from 2.9% to 6.8%: phentermine/topiramate 6.8% (3 trials), liraglutide 5.4% (4 trials), naltrexone/bupropion 4.0% (5 trials), and orlistat 2.9% (17 trials).
“Data from the most recent meta-analyses showed that the overall placebo-subtracted weight reduction (%) with the use of anti-obesity drugs for at least 12 months ranged from 2.9 to 6.8%: phentermine/topiramate (3 trials, 6.8%) liraglutide (4 trials, 5.4%), naltrexone/bupropion (5 trials, 4.0%), and orlistat (17 trials, 2.9%) [11, 54, 81–84] (Table 2).”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [82]
The attainment of appropriate leptin concentrations is indispensable for the maturation of the hypothalamic-pituitary-gonadal axis, normal pubertal progression, and maintenance of fertility.
“As has been shown for bodyweight, the attainment of appropriate leptin concentrations is indispensable for the maturation of the hypothalamic-pituitary-gonadal axis, normal pubertal progression, and maintenance of fertility.96”
From Pubertal development and regulation (2016) · cites this paper as [96]
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- Authors
- Farooqi, I. S., & O'Rahilly, S.
- Affiliations
- University of Cambridge (GB)
- ORCID
- Farooqi, I Sadaf
- Venue
- Journal of Endocrinology
- Publisher
- Bioscientifica
- Published
- 2014-10
- Volume
- 223
- Issue
- 1
- Pages
- T63-T70
- ISSN
- 0022-0795 (ISSN-L)
- 1479-6805
- OpenAlex
- W2324976104
- Cited by
- 280
- References
- 49
- Citations by year
- 2026: 4 · 2025: 16 · 2024: 12 · 2023: 27 · 2022: 24 · 2021: 32 · 2020: 24 · 2019: 34 · 2018: 29 · 2017: 22 · 2016: 29 · 2015: 23 · 2014: 4
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (100574)
- National Institute for Health and Care Research (NF-SI-0513-10109, NF-SI-0507-10380)
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- NIHR Cambridge Biomedical Research Centre
- 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, leptin receptor, leptin deficiency, obesity, energy homeostasis, eating behaviour, intermediary metabolism, puberty onset, leptin signaling, genetic mutations
- MeSH terms
- Animals, Brain, Energy Metabolism, Humans, Models, Genetic, Mutation, Obesity, Signal Transduction, Leptin, Receptors, Leptin
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