In the last years, autophagy has been revealed as an essential pathway for multiple biological processes and physiological functions. As a catabolic route, autophagy regulation by nutrient availability has been evolutionarily conserved from yeast to mammals. On one hand, autophagy induction by starvation is associated with a significant loss in body weight in mice. Here, we demonstrate that both genetic and pharmacological inhibition of the autophagy process compromise weight loss induced by starvation. Moreover, autophagic potential also impacts on weight gain induced by distinct hypercaloric regimens. Atg4b-deficient mice, which show limited autophagic competence, exhibit a major increase in body weight in response to distinct obesity-associated metabolic challenges. This response is characterized by the presence of larger adipocytes in visceral fat tissue, increased hepatic steatosis, as well as reduced glucose tolerance and attenuated insulin responses. Similarly, autophagy-deficient mice are more vulnerable to experimentally induced type-I diabetes, showing an increased susceptibility to acute streptozotocin administration. Notably, pharmacological stimulation of autophagy in wild-type mice by spermidine reduced both weight gain and obesity-associated alterations upon hypercaloric regimens. Altogether, these results indicate that systemic autophagic activity influences the resilience of the organism to weight gain induced by high-calorie diets, as well as to the obesity-associated features of both type-1 and type-2 diabetes.

Departament of Cellular and Molecular Biology Centro de Investigaciones Biológicas CSIC Madrid Spain

Departamento de Biología Fundamental Universidad de Oviedo Oviedo Spain

Departamento de Bioquímica y Biología Molecular Instituto Universitario de Oncología Universidad de Oviedo Oviedo Spain

Equipe 11 labellisée par la Ligue Nationale Contre le Cancer INSERM U1138 Centre de Recherche des Cordeliers Paris France

Instituto de Investigación Sanitaria del Principado de Asturias Oviedo Spain

Metabolomics and Molecular Cell Biology Platforms Gustave Roussy Villejuif France

Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France

Sotio a c Prague Czech Republic

Université Paris Descartes Sorbonne Paris Cité Paris France

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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1