Hypothalamic inhibition of acetyl-CoA carboxylase stimulates hepatic counter-regulatory response independent of AMPK activation in rats.

Gustavo A Santos,Leticia Ignacio-Souza,Daniele C Vitorino,Licio A Velloso,Daniela S Razolli,Rodrigo Ferreira De Moura,Adriana S Torsoni,Erika A F R Roman,Marcio A Torsoni,Vinícius D Pereira,Reury Fp Bacurau

doi:10.1371/journal.pone.0062669

Abstract

BackgroundHypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability.Methodology/Principal FindingsIn this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation.Conclusion/SignificanceHypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.

Highlights

The hypothalamus actively participates in energy expenditure, satiety signals and counter-regulatory response [1,2,3]
To evaluate whether the acetyl-CoA carboxylase (ACC)-antisense oligonucleotide (ASO) treatment affected the neuronal populations in the arcuate nucleus (ARC), paraventricular nucleus (PVH) and lateral hypothalamus (LH) differently, we performed immunoflorescence staining of hypothalamus samples from control and ACC-ASO rats
As expected, it decreased in the ARC, PVH and LH after administration of ACC-ASO (Fig. 1D)

Summary

Introduction

The hypothalamus actively participates in energy expenditure, satiety signals and counter-regulatory response [1,2,3]. AMP-activated protein kinase (AMPK) can integrate signaling circuits between peripheral tissues and the hypothalamus to regulate food intake and whole-body energy expenditure [3,4]. This important cell energy sensor can activate the catabolic pathways that produce ATP when energy availability is low. Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Since all models employed seem to involve malonylCoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability

Methods

Results

Conclusion