Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2015) 37 GP09.08 | DOI: 10.1530/endoabs.37.GP.09.08

ECE2015 Guided Posters Nuclear receptors and signalling (8 abstracts)

Study of a possible interaction between reactive oxygen species and the mTORC1 pathway in the regulation of energy balance

Magalie Haissaguerre 1, , Samantha Clark 1, , Antoine Tabarin 1, & Daniela Cota 1,

1INSERM U862, Neurocentre Magendie, Bordeaux, France; 2University of Bordeaux, Bordeaux, France; 3Endocrinology Department, Haut Leveque Hospital, University Hospital of Bordeaux, Pessac, France.

Obesity and its consequent metabolic disorders are severe health problems. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is an important hypothalamic integrator of the actions of nutrients and hormones on food intake (FI). Nutrient availability also affects the formation of reactive oxygen species (ROS) in the hypothalamus and regulates neuronal activity. In the present study, we hypothesise that modulation of mTORC1 activity mediates ROS effects on FI. To this purpose, C57Bl6J mice or WT and KO mice deficient for the mTORC1 downstream target S6K1 were treated with an i.c.v. injection of the ROS producer H2O2 or the ROS scavenger honokiol, alone or in combination with the mTOR inhibitor rapamycin or the mTOR activator leptin and changes in FI and body weight were assessed. Western blots were performed to study hypothalamic mTORC1 activity. ROS levels were analysed in POMC neurons using dihydroethidium combined with immunofluorescence. I.c.v. administration of H2O2 induced phosphorylation of S6K1 within the hypothalamus, increased expression of c-fos, a marker of neuronal activity, in the arcuate nucleus and increased ROS signal in POMC neurons. These effects were associated with a significant decrease in food intake over 24 h. Conversely, i.c.v. administration of honokiol increased FI. The behavioural effects of H2O2 and honokiol were not seen in S6K1 KO mice. Pharmacological experiments using i.c.v. coadministration of H2O2 and rapamycin in C57Bl6J mice showed that rapamycin (at a dose not acting on FI) was able to blunt the anorexigenic effect of H2O2. Similarly, i.c.v. honokiol administration combined with an i.p. leptin injection decreased the anorexigenic effect of leptin, suggesting that leptin requires ROS formation to reduce FI. Our preliminary results confirm that ROS modulators require a functional mTORC1 pathway to regulate FI. Studies are ongoing to better define this relationship at the molecular and neuroanatomical level.

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