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Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities.
José M Bravo-San Pedro,Valentina Sica
José M Bravo-San Pedro,Valentina Sica,Isabelle Martins,Jonathan Pol,Friedemann Loos,Maria Chiara Maiuri,Sylvère Durand,Noélie Bossut,Fanny Aprahamian,Gerasimos Anagnostopoulos,Mireia Niso-Santano,Fernando Aranda,Ignacio Ramírez-Pardo,Justine Lallement,Jessica Denom,Erwan Boedec,Philip Gorwood,Nicolas Ramoz,Karine Clément,Véronique Pelloux,Alili Rohia,François Pattou,Violeta Raverdy,Robert Caiazzo,Raphaël GP Denis,Patricia Boya,Lorenzo Galluzzi,Frank Madeo,Stéphanie Migrenne-Li,Céline Cruciani-Guglielmacci,Nektarios Tavernarakis,Carlos López-Otín,Christophe Magnan,Guido Kroemer