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Cited by 1,086Regulation of Appetite and ObesityCytokine Signaling Pathways and InteractionsAdipokines, Inflammation, and Metabolic Diseases

Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.

Vaisse, Christian, Halaas, Jeffrey L, Horvath, Curt M., Darnell, James E., Stoffel, Markus, Friedman, Jeffrey M.·1996·Nature Genetics
DOI 10.1038/ng0996-95
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Abstract

Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass through effects on satiety and energy metabolism. Leptin's precise sites of action are not known. The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues including the hypothalamus. Ob-R is a member of the gp130 family of cytokine receptors which are known to stimulate gene transcription via activation of cytosolic STAT proteins. In order to identify the sites of leptin action in vivo, we assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor where they are phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus where they bind DNA and activate transcription. The activation of STAT proteins in response to leptin was assayed in a variety of mouse tissues known to express Ob-R. Leptin injection activated Stat3 but no other STAT protein in the hypothalamus of ob/ob and wild-type mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. Activation of Stat3 by leptin was dose dependent and first observed after 15 minutes and maximal at 30 minutes. Our data indicate the hypothalamus is a direct target of leptin action and that this activation is critically dependent on the gp-130-like leptin receptor isoform missing in C57BLKS/J db/db mice. This is the first in vivo demonstration of leptin signal transduction.

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Crossref · 10.1038/ng0996-95

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  • Signaling by this class of receptors is generally time limited as a consequence of secondary activation of SOCS proteins and specific tyrosine phosphatases.

    “Signaling by this class of receptors is generally time limited as a consequence of the secondary activation of SOCS (suppressor of cytokine signaling) proteins, which inhibit the JAK kinase, and of specific tyrosine phosphatases, which shut off cytokine signaling after the signal transduction pathway is initially activated.”

    From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [45]

  • The leptin receptor signals via the JAK-Stat pathway, which depends in part on phosphorylation of tyrosine residues of specific protein substrates, including Stat3.

    “The leptin receptor signals via the Janus kinase-signal transducers and activators of transcription (JAK-Stat) pathway, which depends in part on phosphorylation of tyrosine residues of specific protein substrates, including Stat3 (45).”

    From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [45]

  • Leptin activates signal transduction in specific neural populations in the hypothalamus and other brain regions.

    “Leptin activates signal transduction in specific neural populations in the hypothalamus and other brain regions (45).”

    From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [45]

  • Phosphorylation of Tyr1138 recruits STAT3, which is phosphorylated by Jak2, dimerizes, translocates to the nucleus, and functions as a transcription factor.

    “phosphorylation of Tyr1138 recruits signal transduction and activator of transcription-3 (STAT3), which is then itself phosphorylated on tyrosine residues by Jak2 allowing it to dimerize and translocate to the nucleus where it functions as a transcription factor (6, 23, 186).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [186]

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Authors
Vaisse, C., Halaas, J. L., Horvath, C. M., Darnell, J. E., Stoffel, M., & Friedman, J. M.
Affiliations
  • Rockefeller University (US)
  • Howard Hughes Medical Institute (US)
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
1996-09
Volume
14
Issue
1
Pages
95-97
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng0996-95
OpenAlex
W2056383195
Cited by
1,086
References
20
Citations by year
2026: 8 · 2025: 12 · 2024: 20 · 2023: 16 · 2022: 15 · 2021: 28 · 2020: 33 · 2019: 39 · 2018: 20 · 2017: 27 · 2016: 36 · 2015: 18 · 2014: 48 · 2013: 38 · 2012: 42
FWCI
16.79
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK-41096, R01DK041096)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
leptin, STAT3, hypothalamus, leptin receptor, ob/ob mice, db/db mice, STAT activation, receptor isoforms, energy metabolism, satiety
MeSH terms
Animals, Base Sequence, Carrier Proteins, DNA-Binding Proteins, Hypothalamus, Mice, Obese, Molecular Sequence Data, Proteins, Receptors, Cell Surface, Time Factors, Signal Transduction, Trans-Activators, DNA Primers, Leptin, STAT3 Transcription Factor, Mice, Receptors, Leptin

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