## 4 Conclusions  
In this study, for the first time, we carried out an optimization of the MAE factors of temperature, % EtOH and time for the total compounds (phenolic compounds and elenolic acids) obtained by HPLC-MS. The optimum MAE conditions for the highest recovery of total compounds from olive leaves were 123 \({}^{\circ}\)C, 100% EtOH and 23 min. An optimization of MAE conditions was also carried out to obtain the maximum content of compounds from olive leaves that have shown the capacity to activate AMPK, whereby the optimum MAE conditions were 111 \({}^{\circ}\)C, 42% ethanol/water (_y/v_) and extraction time of 23 min. Thus, these optimum conditions for temperature and % EtOH were different compared to those for total compounds. For that reason, a multi-response analysis by desirability was carried out to obtain optimum MAE conditions for both responses. The optimum conditions were 111 \({}^{\circ}\)C, 100% EtOH and 23 min to obtain 74.39 mg g\({}^{-1}\) d.w. of total compounds and 9.00 mg g\({}^{-1}\) d.w. of total AMPK bioactive compounds. Optimum desirability was 0.97, thus, these responses are close to their individual optimum values. Therefore, these optimum MAE conditions can be applied to obtain an olive leaf extract enriched in total compounds and in compounds with the capacity to activate AMPK; thus, this could be used as a treatment in diseases such as obesity.  
The following are available online at [[http://www.mdpi.com/2076-3417/10/13/4620/s1](http://www.mdpi.com/2076-3417/10/13/4620/s1)]([http://www.mdpi.com/2076-3417/10/13/4620/s1](http://www.mdpi.com/2076-3417/10/13/4620/s1)), Table S1: Phenolic and other compounds identified in MAE olive leaf extracts by HPLC-ESI-TOF-MS, Table S2: Calibration curves of standards., Table S3: Compounds quantified in MAE olive leaf extracts by HPLC-ESI-TOF-MS (mg g\({}^{-1}\) d.w.).  
Figure 4: Response surface plots showing combined effects of process variables for desirability in total compounds and total AMPK bioactive compounds: Temperature (\({}^{\circ}\)C)-% EtOH (**a**), Temperature (\({}^{\circ}\)C)–time (min) (**b**) and % EtOH–time (min) (**c**).  
**Author Contributions:** Conceptualization, A.M.G.-C., D.A.-R. and [PERSON]-[PERSON]; methodology, [PERSON] and [PERSON]-[PERSON]; software, B.M.-G. and [PERSON]-[PERSON]; validation, D.A.-R. and S.P.-M.; formal analysis, [PERSON]-[PERSON]; investigation, [PERSON]-[PERSON]; data curation, B.M.-G. and [PERSON]-[PERSON]; writing--original draft preparation, B.M.-G.; writing--review and editing, A.M.G.-C., [PERSON]-M. and D.A.-R.; supervision, [PERSON]-C., D.A.-R. and [PERSON]-C. All authors have read and agreed to the published version of the manuscript.  
**Funding:** This research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (project AGL2015-67995-C3-2), by the Ministry of Science, Innovation and Universities (RTI2018-096724-B-C22), by the Ministry of Economy, Knowledge, Business and University of the Junta de Andalucia (B-AGR-466-UGR18).  
**Acknowledgments:** The author [PERSON] is grateful to the National Youth Guarantee System for the grant for young research personnel. Also, the authors are grateful to the University of Granada for a \"Contrato Puente\" postdoctoral contract (S.P.-M.).  
**Conflicts of Interest:** The authors declare no conflict of interest.