Hypothalamic CaMKK? mediates glucagon anorectic effect and its diet-induced resistance.

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)/Ca(2+)-calmodulin-dependent protein kinase kinase ? (CaMKK?)/AMP-activated protein kinase (AMPK)-dependent mechanism. More specifically, the central injection of glucagon increases PKA activity and reduces protein levels of CaMKK? 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 CaMKK?, specifically in the ARC. Thus, glucagon decreases food intake acutely via PKA/CaMKK?/AMPK dependent pathways in the ARC, and CaMKK? 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.

SUBMITTER: Quinones M 

PROVIDER: S-EPMC4731730 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature