Induction of leptin resistance by activation of cAMP-Epac signaling

Research output: Contribution to journalArticle

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Abstract

Leptin regulates energy balance and glucose homeostasis. Shortly after leptin was identified, it was established that obesity is commonly associated with leptin resistance, though the molecular mechanisms remain to be identified. To explore potential mechanisms of leptin resistance, we employed organotypic brain slices to identify candidate signaling pathways that negatively regulate leptin sensitivity. We found that elevation of adenosine 3′, 5′-monophosphate (cAMP) levels impairs multiple signaling cascades activated by leptin within the hypothalamus. Notably, this effect is independent of protein kinase A activation. In contrast, activation of Epac, a cAMP-regulated guanine nucleotide exchange factor for the small G protein Rap1, was sufficient to impair leptin signaling with concomitant induction of SOCS-3 expression. Epac activation also blunted leptin-induced depolarization of hypothalamic POMC neurons. Finally, central infusion of an Epac activator blunted the anorexigenic actions of leptin. Thus, activation of hypothalamic cAMP-Epac pathway is sufficient to induce multiple indices of leptin resistance.

Original languageEnglish (US)
Pages (from-to)331-339
Number of pages9
JournalCell Metabolism
Volume13
Issue number3
DOIs
StatePublished - Mar 2 2011

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Leptin
Guanine Nucleotide Exchange Factors
Pro-Opiomelanocortin
Monomeric GTP-Binding Proteins
Cyclic AMP-Dependent Protein Kinases
Adenosine
Hypothalamus
Homeostasis
Obesity
Neurons
Glucose
Brain

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Induction of leptin resistance by activation of cAMP-Epac signaling. / Fukuda, Makoto; Williams, Kevin W.; Gautron, Laurent; Elmquist, Joel K.

In: Cell Metabolism, Vol. 13, No. 3, 02.03.2011, p. 331-339.

Research output: Contribution to journalArticle

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