Food Intake Adaptation to Dietary Fat Involves PSA-Dependent Rewiring of the Arcuate Melanocortin System in Mice

Authors
Alexandre Benani, Cécile Hryhorczuk, Alexandra Gouazé, Xavier Fioramonti, Xavier Brenachot, Christophe Guissard, Alice Krezymon, Thibaut Duparc, André Colom, Emmanuelle Nédélec, Caroline Rigault, Aleth Lemoine, Jean Gascuel, Rita Gerardy-Schahn, Philippe Valet, Claude Knauf, Anne Lorsignol, and Luc Pénicaud

Lab
Université de Bourgogne, Dijon, France / INSERM, Toulouse, France / Hannover Medical School, Hannover, Germany

Journal
The Journal of Neuroscience

Abstract
Hormones such as leptin and ghrelin can rapidly rewire hypothalamic feeding circuits when injected into rodent brains. These experimental manipulations suggest that the hypothalamus might reorganize continually in adulthood to integrate the metabolic status of the whole body. In this study, we examined whether hypothalamic plasticity occurs in naive animals according to their nutritional conditions. For this purpose, we fed mice with a short-term high-fat diet (HFD) and assessed brain remodeling through its molecular and functional signature. We found that HFD for 3 d rewired the hypothalamic arcuate nucleus, increasing the anorexigenic tone due to activated pro-opiomelanocortin (POMC) neurons. We identified the polysialic acid molecule (PSA) as a mediator of the diet-induced rewiring of arcuate POMC. Moreover, local pharmacological inhibition and genetic disruption of the PSA signaling limits the behavioral and metabolic adaptation to HFD, as treated mice failed to normalize energy intake and showed increased body weight gain after the HFD challenge. Altogether, these findings reveal the existence of physiological hypothalamic rewiring involved in the homeostatic response to dietary fat. Furthermore, defects in the hypothalamic plasticity-driven adaptive response to HFD are obesogenic and could be involved in the development of metabolic diseases.

BIOSEB Instruments Used:
OXYLET, Indirect Calorimeter (OXYLET)