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H2020 European Research Council, Grant/Award Number: ERC-2014-AdG/669622; Fundación Científica Asociación Española Contra el Cáncer, Grant/Award Number: PROYE18061FERN; Ministerio de Ciencia e Innovación, Grant/Award Number: SAF2013-48256-R; the Asturias Regionla Government (PCTI) co-funding 2018- 2022/FEDER (IDI/2018/146), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527)...

A number of natural plant products have a long-standing history in both traditional and modern medical applications. Some secondary metabolites induce autophagy and mediate autophagy-dependent healthspan- and lifespan-extending effects in suitable mouse models. Here, we identified isobacachalcone (ISO) as a non-toxic inducer of autophagic flux that acts on human and mouse cells in vitro, as well as mouse organs in vivo. Mechanistically, ISO inhibits AKT as well as, downstream of AKT, the mechanistic target of rapamycin complex 1 (mTORC1), coupled to the activation of the pro-autophagic transcription factors EB (TFEB) and E3 (TFE3). Cells equipped with a constitutively active AKT mutant failed to activate autophagy. ISO also stimulated the AKT-repressible activation of all three arms of the unfolded stress response (UPR), including the PERK-dependent phosphorylation of eukaryotic initiation factor 2α (eIF2α). Knockout of TFEB and/or TFE3 blunted the UPR, while knockout of PERK or replacement of eIF2α by a non-phosphorylable mutant reduced TFEB/TFE3 activation and autophagy induced by ISO. This points to crosstalk between the UPR and autophagy. Of note, the administration of ISO to mice improved the efficacy of immunogenic anticancer chemotherapy. This effect relied on an improved T lymphocyte-dependent anticancer immune response and was lost upon constitutive AKT activation in, or deletion of the essential autophagy gene Atg5 from, the malignant cells. In conclusion, ISO is a bioavailable autophagy inducer that warrants further preclinical characterization.

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.