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Cited by 22Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Ghrelin induces leptin resistance by activation of suppressor of cytokine signaling 3 expression in male rats: implications in satiety regulation

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Heldsinger, Andrea, Grabauskas, Gintautas, Wu, Xiaoyin, Zhou, ShiYi, Lu, Yuanxu, Song, Il, Owyang, Chung·2014·Endocrinology
DOI 10.1210/en.2013-2095PMC PMC4164930
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Abstract

The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) –bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior.

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  • Ghrelin acts in opposition to leptin to downregulate feeding behavior via vagal afferent pathways by inducing cAMP-mediated increase in SOCS3 expression, which negatively affects leptin-induced pY-STAT3 and blocks neuronal firing in nodose ganglia neurons.

    “The orexigenic hormone ghrelin acts in opposition to leptin to downregulate feeding behavior via the vagal afferent pathways by inducing exchange protein activated by cAMP–mediated increase in SOCS3 expression, which negatively affects leptin-induced pY-STAT3 and blocks neuronal firing in nodose ganglia neurons”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Heldsinger et al., 2014

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Authors
Heldsinger, A., Grabauskas, G., Wu, X., Zhou, S., Lu, Y., Song, I., & Owyang, C.
Affiliations
  • University of Michigan (US)
  • Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48019
Corresponding author
Owyang, Chung
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2014-10-01
Volume
155
Issue
10
Pages
3956-3969
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2013-2095
PMC
PMC4164930
OpenAlex
W1980572174
Cited by
22
References
61
Citations by year
2025: 2 · 2024: 2 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 1 · 2015: 1
FWCI
0.65
Type
journal article
Language
en
Open access
Locations
  • Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Michigan (48109, P30 DK34933)
  • College of Pharmacy, University of Michigan
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933, P30 DK 34933, R01DK048419, R01-DK-48419, DK34933, R01DK058913)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
ghrelin, leptin resistance, SOCS3, Epac, STAT3 phosphorylation, nodose ganglion, vagal afferent neurons, leptin receptor, growth hormone secretagogue receptor, satiety regulation, feeding behavior, fasting, dietary intake, neuronal firing
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Animals, Appetite Regulation, Cells, Cultured, Feeding Behavior, Male, Satiation, Transcriptional Activation, Up-Regulation, Rats, Sprague-Dawley, Leptin, Suppressor of Cytokine Signaling Proteins, Rats, Ghrelin

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