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Manipulation of dietary amino acids prevents and reverses obesity in mice through multiple mechanisms that modulate energy homeostasis

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posted on 10.08.2020 by Ada Admin, Chiara Ruocco, Maurizio Ragni, Fabio Rossi, Pierluigi Carullo, Veronica Ghini, Fabiana Piscitelli, Adele Cutignano, Emiliano Manzo, Rafael Maciel Ioris, Franck Bontems, Laura Tedesco, Carolina Greco, Annachiara Pino, Ilenia Severi, Dianxin Liu, Ryan P. Ceddia, Luisa Ponzoni, Leonardo Tenori, Lisa Rizzetto, Matthias Scholz, Kieran Tuohy, Francesco Bifari, Vincenzo Di Marzo, Claudio Luchinat, Michele O. Carruba, Saverio Cinti, Ilaria Decimo, Gianluigi Condorelli, Roberto Coppari, Sheila Collins, Alessandra Valerio, Enzo Nisoli
Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance, as such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can i) promote the brown fat thermogenic program and fatty acid oxidation, ii) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, iii) change the gut microbiota composition, and iv) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy lifespan. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

Funding

This work was supported by Fondazione Umberto Veronesi to C.R., University of Milan to F.R. (Research Fellowship grant 1280/2016), Professional Dietetics (Milan, Italy) to E.N. (support to laboratory), Cariplo Foundation to E.N. and to A.V. (grant 2016-1006), and Louis-Jeantet Foundation grant to R.C.

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