Elsevier

Molecular Metabolism

Volume 4, Issue 12, December 2015, Pages 961-970
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2015.09.014Get rights and content
Under a Creative Commons license
open access

Highlights

  • Glucagon stimulates PKA and inhibits CaMKKβ and AMPK in the arcuate nucleus (ARC).

  • Down-regulation of glucagon receptor in the ARC increases fasting-induced hyperphagia.

  • Glucagon is unable to decrease food intake in diet-induced obese (DIO) rats.

  • In DIO rats, glucagon fails to alter CaMKKβ and its downstream targets AMPK and pACC.

  • Down-regulation of CaMKKβ in the ARC restores glucagon sensitivity in obese rodents.

Abstract

Objective

Glucagon receptor antagonists and humanized glucagon antibodies are currently studied as promising therapies for obesity and type II diabetes. Among its variety of actions, glucagon reduces food intake, but the molecular mechanisms mediating this effect as well as glucagon resistance are totally unknown.

Methods

Glucagon and adenoviral vectors were administered in specific hypothalamic nuclei of lean and diet-induced obese rats. The expression of neuropeptides controlling food intake was performed by in situ hybridization. The regulation of factors of the glucagon signaling pathway was assessed by western blot.

Results

The central injection of glucagon decreased feeding through a hypothalamic pathway involving protein kinase A (PKA)/Ca2+-calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMP-activated protein kinase (AMPK)-dependent mechanism. More specifically, the central injection of glucagon increases PKA activity and reduces protein levels of CaMKKβ and its downstream target phosphorylated AMPK in the hypothalamic arcuate nucleus (ARC). Consistently, central glucagon significantly decreased AgRP expression. Inhibition of PKA and genetic activation of AMPK in the ARC blocked glucagon-induced anorexia in lean rats. Genetic down-regulation of glucagon receptors in the ARC stimulates fasting-induced hyperphagia. Although glucagon was unable to decrease food intake in DIO rats, glucagon sensitivity was restored after inactivation of CaMKKβ, specifically in the ARC. Thus, glucagon decreases food intake acutely via PKA/CaMKKβ/AMPK dependent pathways in the ARC, and CaMKKβ mediates its obesity-induced hypothalamic resistance.

Conclusions

This work reveals the molecular underpinnings by which glucagon controls feeding that may lead to a better understanding of disease states linked to anorexia and cachexia.

Keywords

Food intake
Glucagon
Hypothalamus
PKA
CamKKβ

Cited by (0)

5

Mar Quiñones and Omar Al-Massadi contributed equally to this work.