Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin

Münzberg, Heike; Huo, Lihong; Nillni, Eduardo A.; Hollenberg, Anthony N.; Bjørbæk, Christian

doi:10.1210/en.2002-221037

Cited by 328Regulation of Appetite and ObesityCytokine Signaling Pathways and InteractionsHypothalamic control of reproductive hormones

Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin

Münzberg, Heike, Huo, Lihong, Nillni, Eduardo A., Hollenberg, Anthony N., Bjørbæk, Christian·2003·Endocrinology

DOI 10.1210/en.2002-221037

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Abstract

Leptin acts on the brain to regulate body weight and neuroendocrine function. Proopiomelanocortin (POMC) neurons in the hypothalamus are important targets of leptin. These cells express the leptin receptor ObRb, and leptin can regulate POMC mRNA levels, but the cellular mechanisms by which this occurs is unknown. Here we show evidence that leptin stimulates pomc gene transcription via activation of intracellular signal transducer and activator of transcription 3 (STAT3) proteins. In pomc-promoter assays using transfected cells, leptin induces pomc promoter activity. Expression of dominant negative STAT3 strongly suppresses this effect. Furthermore, maximal activation requires the presence of the STAT3-binding site, tyrosine 1138, of ObRb. Mutational analysis identifies a 30-bp promoter element that is required for regulation by leptin. In rats, robust leptin-dependent induction of STAT3 phosphorylation is demonstrated in hypothalamic POMC neurons using double immunohistochemistry. In total, approximately 37% of POMC cells are positive for phospho-STAT3 after leptin treatment. Furthermore, leptin-responsive POMC neurons are concentrated in the rostral region of the hypothalamus. Combined, our data show that a subpopulation of POMC neurons is leptin-responsive and suggest that stimulation of hypothalamic pomc gene expression in these cells requires STAT3 activation. We speculate that STAT3 is critical for leptin-dependent effects on energy homeostasis that are mediated by the central melanocortin system.

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HA-ObRb/Pomc-Cre/Leprdb/db mice had modestly increased hypothalamic POMC mRNA.
“HA-ObRb/Pomc-Cre/Leprdb/db mice had modestly increased hypothalamic POMC mRNA (Figure 6A) consistent with a role of leptin signaling to stimulate Pomc gene expression (Munzberg et al., 2003; Thornton et al., 1997).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Munzberg et al., 2003

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Leptin targets in the mouse brain
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Critical role of STAT3 in leptin's metabolic actions
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PI3K integrates the action of insulin and leptin on hypothalamic neurons
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Central Leptin Acutely Reverses Diet-Induced Hepatic Insulin Resistance
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Synaptic plasticity in neuronal circuits regulating energy balance
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Leptin Signaling in the Nucleus Tractus Solitarii Increases Sympathetic Nerve Activity to the Kidney
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Suppression of Leptin Receptor Messenger Ribonucleic Acid and Leptin Responsiveness in the Ventromedial Nucleus of the Hypothalamus during Pregnancy in the Rat
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Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats
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The estrogen receptor α colocalizes with proopiomelanocortin in hypothalamic neurons and binds to a conserved motif present in the neuron-specific enhancer nPE2
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LRb signals act within a distributed network of leptin‐responsive neurones to mediate leptin action
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The central melanocortin system and the regulation of energy balance
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Independent and Additive Effects of Central POMC and Leptin Pathways on Murine Obesity
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Leptin and leptin receptor: Analysis of a structure to function relationship in interaction and evolution from humans to fish
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Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fak) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB)
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Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures
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Authors: Münzberg, H., Huo, L., Nillni, E. A., Hollenberg, A. N., & Bjørbæk, C.
Affiliations: Beth Israel Deaconess Medical Center (US)
Brown University (US)
Corresponding author: Bjørbæk, Christian
ORCID: Huo, Lihong
Hollenberg, Anthony N.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2003-05-01
Volume: 144
Issue: 5
Pages: 2121-2131
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2002-221037
OpenAlex: W2071839617
Cited by: 328
References: 74
Citations by year: 2026: 4 · 2025: 7 · 2024: 12 · 2023: 7 · 2022: 8 · 2021: 13 · 2020: 7 · 2019: 9 · 2018: 14 · 2017: 12 · 2016: 12 · 2015: 18 · 2014: 20 · 2013: 29 · 2012: 15
FWCI: 4.99
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (5 P30 DK-36836, R01DK060673, R01 DK60673, P30DK036836)
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 › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords: leptin, STAT3, proopiomelanocortin, transcriptional regulation, STAT3 phosphorylation, melanocortin system, energy homeostasis, dominant-negative STAT3
MeSH terms: Animals, Binding Sites, Brain, DNA-Binding Proteins, Gene Expression Regulation, Humans, Hypothalamus, Hypothalamus, Middle, Male, Neurons, Peptide Fragments, Phosphorylation, Pro-Opiomelanocortin, Promoter Regions, Genetic, Receptors, Cell Surface, Recombinant Proteins, Transcription, Genetic, Trans-Activators, Rats, Sprague-Dawley, Leptin, STAT3 Transcription Factor, Mice, Rats, Receptors, Leptin

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Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin

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