Intracerebroventricular Administration of Metformin Inhibits Ghrelin-Induced Hypothalamic AMP-Kinase Signalling and Food Intake

Abstract

Background/Aims: The antihyperglycaemic drug metformin reduces food consumption through mechanisms that are not fully elucidated. The present study investigated the effects of intracerebroventricular administration of metformin on food intake and hypothalamic appetite-regulating signalling pathways induced by the orexigenic peptide ghrelin. Methods: Rats were injected intracerebroventricularly with ghrelin (5 µg), metformin (50, 100 or 200 µg), 5-amino-imidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 25 µg) and L-leucine (1 µg) in different combinations. Food intake was monitored during the next 4 h. Hypothalamic activation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), regulatory-associated protein of mTOR (Raptor), mammalian target of rapamycin (mTOR) and p70 S6 kinase 1 (S6K) after 1 h of treatment was analysed by immunoblotting. Results: Metformin suppressed the increase in food consumption induced by intracerebroventricular ghrelin in a dose-dependent manner. Ghrelin increased phosphorylation of hypothalamic AMPK and its targets ACC and Raptor, which was associated with the reduced phosphorylation of mTOR. The mTOR substrate, S6K, was activated by intracerebroventricular ghrelin despite the inhibition of mTOR. Metformin treatment blocked ghrelin-induced activation of hypothalamic AMPK/ACC/Raptor and restored mTOR activity without affecting S6K phosphorylation. Metformin also reduced food consumption induced by the AMPK activator AICAR while the ghrelin-triggered food intake was inhibited by the mTOR activator L-leucine. Conclusion: Metformin could reduce food intake by preventing ghrelin-induced AMPK signalling and mTOR inhibition in the hypotalamus.

Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase

“…Despite the endeavors of previous researchers, indications of the involvement of the hypothalamus in metformin-induced weight loss, as well as the details of the underlying mechanism have been conflicting (16,19,27). Moreover, acute administration of metformin into the lateral cerebral ventricle had no effect on food intake in rats (29). However, since it is possible that metformin can affect the hypothalamus by crossing the blood-brain barrier (17,19,21), it was more reasonable to investigate metformin's effects on hypothalamic regulation of food intake by administering it into the third ventricle (1,12).…”

“…Hypothalamic AMPK activity contributes to the regulation of food intake, i.e., activation of AMPK in the hypothalamus increases food intake in vivo and increases NPY in vitro (5,20). In line with a rational hypothesis, the involvement of hypothalamic AMPK in the anorectic action of metformin has been intensively studied (5,19,29). In cell cultures using primary rat hypothalamic neurons, metformin was shown to suppress an increase in AMPK induced by low glucose, supporting the role of hypothalamic AMPK in metformininduced anorexia (5).…”

“…However, peripheral administration of metformin does not affect hypothalamic AMPK activity in obese rats despite reducing food intake (19). In addition, administration of metformin into the lateral cerebral ventricle does not change hypothalamic AMPK phosphorylation in rats (29). Therefore, it is unclear whether administration of metformin reduces food intake via hypothalamic AMPK (5,19).…”

“…Some reports have shown that metformin treatment affects the hypothalamic neuropeptide Y (NPY) system in obese rats and mice, although the effect of metformin on neuropeptide systems requires further investigation (19,27). A direct effect of metformin on hypothalamic AMPK was not observed in studies of food intake, despite the strong evidence for AMPK-mediated improvement of glucose regulation induced by metformin (16,19,29,35). In addition to the association between the hypothalamus and metformin-induced anorexia, we have shown that peripheral administration of metformin may reduce food intake via neuronal activation in the hindbrain regions that mediate satiety signals from peripheral tissues (15).…”

Metformin: A Hopeful Promise in Aging Research

“…In addition to its glucoregulatory action, metformin has gained attention for its pleiotropic effects and activity in a variety of tissues, such as muscles, adipose tissue, ovary, endothelium, and brain (Diamanti-Kandarakis et al 2010;Foretz et al 2014). Food intake (Adeyemo et al 2014;Pernicova and Korbonits 2014) and body weight (Glueck et al 2001) are decreased as a result of a direct action of metformin on the hypothalamic centers regulating satiety and feeding (Stevanovic et al 2012); it may also influence metabolic and cellular processes associated with the development of chronic conditions of aging, including inflammation, fatty liver, oxidative damage, protein glycation, cellular senescence, diminished autophagy, apoptosis, and development of several types of cancer (Isoda et al 2006;Kita et al 2012;Hirsch et al 2013;Woo et al 2014). A number of recent studies support the role of metformin in improving health span and life span in different animal models (Anisimov et al 2011;Martin-Montalvo et al 2013;Anisimov 2014;De Haes et al 2014).…”