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Hypothalamic CaMKKβ mediates glucagon anorectic effect and its diet-induced resistance

Mar Quiñones1, Omar Al-Massadi1, Rosalía Gallego2

  • 1Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.

Molecular Metabolism
|February 25, 2016
PubMed
Abstract

Insights

Glucagon reduces feeding via a hypothalamic pathway involving protein kinase A (PKA), CaMKKβ, and AMPK. This mechanism is impaired in obesity, but CaMKKβ inhibition restores glucagon sensitivity.

Area of Science:

  • Neuroendocrinology
  • Molecular mechanisms of appetite regulation

Background:

  • Glucagon receptor antagonists and antibodies are investigated for obesity and type II diabetes.
  • The molecular basis of glucagon's effect on food intake and associated resistance is largely unknown.

Purpose of the Study:

  • To elucidate the molecular pathways through which central glucagon influences feeding behavior.
  • To investigate the role of hypothalamic signaling in glucagon resistance observed in obesity.

Main Methods:

  • Administration of glucagon and adenoviral vectors into specific hypothalamic nuclei of lean and diet-induced obese rats.
  • Assessment of neuropeptide expression via in situ hybridization and glucagon signaling pathway factors by western blot.

Main Results:

  • Central glucagon reduced feeding via a PKA/CaMKKβ/AMPK pathway in the arcuate nucleus (ARC), decreasing AgRP expression.
  • Inhibition of PKA or activation of AMPK in the ARC blocked glucagon-induced anorexia.
  • Obesity-induced glucagon resistance was linked to CaMKKβ, as its inactivation in the ARC restored glucagon sensitivity.

Conclusions:

  • This study reveals the molecular underpinnings of glucagon's control over feeding.
  • Understanding these pathways may inform therapeutic strategies for anorexia, cachexia, obesity, and type II diabetes.
Keywords:
CamKKβFood intakeGlucagonHypothalamusPKA

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