P347 The influence of metformin treatment on signaling systems, AMP-activated kinase and mitochondrial dynamics in the hypothalamus of agouti-mice (Ay/a)

Abstract

Objectives The effects of metformin (MF) on peripheral metabolism, insulin sensitivity and CNS can be realized through hypothalamic mechanisms. The aim of this work was to study the influence of MF treatment on signaling systems, AMP-activated kinase (AMPK) and mitochondrial dynamics in hypothalamic neurons of agouti-mice (Ay/a) with melanocortin type obesity. Methods Obese agouti-mice were treated with MF during 9 days (200 mg/kg/day), and expression and phosphorylation of AMPK and the signal and mitochondrial proteins were analyzed by Western blotting and RT-PCR. The C57Bl/6J micewere taken as a control. Results In the hypothalamus of agouti-mice, MF treatment restored expression of pro-opiomelanocortin, increased D2-dopamine signaling and the ratio of D2/D1-signaling pathways, activated the leptin signaling, as illustrated by the increase of Ser473-phosphorylation of Akt-kinase, and normalized the expression of Mfn1 and Drp1 proteins responsible for mitochondria biogenesis, but it had a little effect on AMPK activity. Discussion MF-induced improvement of hypothalamic regulation and functions inagouti-mice is associated with the decreased body weight, the improved glucose tolerance and insulin sensitivity, which indicates a close relationship between MF effect on CNS and its peripheral effects. Conclusions Long-term MF treatment restored the dopamine and leptin signaling, the ratio of anorexigenic and orexigenic factors and mitochondrial dynamics in the hypothalamus of agouti-mice with melanocortin obesity. Significance The obtained data indicates that the hypothalamus is the most important target for MF, and central effects of MF can make a significant contribution to its therapeutic potential in obesity. This work was supported by RSF (16-15-10388).