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Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function
Open accessAbstract
The adipose-derived hormone, leptin, acts via its receptor (LRb) to convey the status of body energy stores to the brain, decreasing feeding and potentiating neuroendocrine energy expenditure. The failure of high levels of leptin in most obese individuals to promote weight loss defines a state of diminished responsiveness to increased leptin, termed leptin resistance. Leptin stimulates the phosphorylation of several tyrosine residues on LRb to mediate leptin action. We homologously replaced LRb in mice with a receptor with a mutation in one of these sites (Tyr985) in order to examine its role in leptin action and signal attenuation in vivo. Mice homozygous for this mutation are neuroendocrinologically normal, but females demonstrate decreased feeding, decreased expression of orexigenic neuropeptides, protection from high-fat diet-induced obesity, and increased leptin sensitivity in a sex-biased manner. Thus, leptin activates autoinhibitory signals via LRb Tyr985 to attenuate the anti-adiposity effects of leptin, especially in females, potentially contributing to leptin insensitivity in obesity.
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“These results support data from cultured cells (22) suggesting that Tyr985 attenuates leptin action in vivo, presumably by serving as the SOCS-3 binding site (24).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [24]
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“mutation of Tyr985 in these (l/l) mice resulted in a lean phenotype characterized by reduced food intake and adiposity, and increased leptin sensitivity (24).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [24]
In the citing paper
“mutation of LRb Tyr985 prevents SOCS-3 action on the leptin receptor and thereby results in mice which display increased leptin sensitivity, are lean and are resistant to DIO (24).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [24]
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Cites
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“Although the effects of Tyr985 and other sensitizers of leptin signaling are most easily and commonly studied by examining the regulation of STAT3 signaling, the increased suppression of AgRP and NPY mRNA expression in the l/l animals also suggests the importance of Tyr985 in attenuating STAT3-independent signals, sin…”
BackgroundMethodInfluentialSelf-citationTwo defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity
El-Haschimi, K., Pierroz, D. D., Hileman, S. M., Bjørbæk, C., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9842 · Cited by 887
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Adipose tissue as an endocrine organ
Galić, S., Oakhill, J. S., & Steinberg, G. R. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.08.018 · Cited by 1,654
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Friedman, J. M. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0095-y · Cited by 661
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Metadata
- Authors
- Björnholm, M., Münzberg, H., Leshan, R. L., Villanueva, E. C., Bates, S. H., Louis, G. W., Jones, J. C., Ishida-Takahashi, R., Bjørbaek, C., & Myers, M. G.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Myers, Martin G.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-05-01
- Volume
- 117
- Issue
- 5
- Pages
- 1354-1360
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1838925
- OpenAlex
- W2109717216
- Cited by
- 183
- References
- 48
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 3 · 2021: 3 · 2020: 11 · 2019: 7 · 2018: 8 · 2017: 13 · 2016: 3 · 2015: 8 · 2014: 17 · 2013: 16 · 2012: 17
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Svenska Sällskapet för Medicinsk Forskning
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56731, R37DK056731, DK 57768, R01DK057768, R01DK056731)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- leptin, leptin receptor, leptin resistance, obesity, high-fat diet-induced obesity, feeding behavior, orexigenic peptides, sex differences, neuroendocrine regulation, energy homeostasis
- MeSH terms
- Animals, Endocrine System, Female, Male, Mice, Inbred C57BL, Obesity, Receptors, Cell Surface, Sensitivity and Specificity, Sex Factors, Thinness, Tyrosine, Signal Transduction, Amino Acid Substitution, Leptin, Mice, Receptors, Leptin
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