1. Bioactive compounds of Brazilian Regional fruits for treatment of metabolic diseases William Festuccia Institute of Biomedical Sciences University of São Paulo, Brazil william.festuccia@usp.br

2. Nutrient sensor mTOR as modulator of adiposity and inflammation Bioactive compounds of Brazilian and Quebec Regional fruits for treatment of metabolic diseases Presentation Outline

3. Disclosure I have no actual or potential conflict of interest in relation to this presentation.

4. First Law of Thermodynamics Energy can be transformed, changed from one form to another, but cannot be created or destroyed

5. Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosissteatohepatitiscirrhosis Coronary heart disease Diabetes Diabetes Dyslipidemia Dyslipidemia Hypertension Hypertension Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Skin Gall bladder disease Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Phlebitis venous stasis Gout Diseases associated with Obesity Idiopathic intracranial hypertension Stroke Cataracts Severe pancreatitis

6. Brain Adipose tissue Muscle Liver Pancreas Obesity: over-supply of nutrients Fatty acids Amino acids Glucose

7. mTORC1 mTORC2 mTOR: mechanistic target of rapamycin is the catalytic core of 2 protein complexes

8. AMINO ACIDS GLUCOSE FATTY ACIDS GROWTH FACTORS Protein Synthesis Lipid Synthesis Anaplerosis Cell Size Proliferation Growth Obesity fat cell size & number ? mTORC1

9. Leucine activates mTORC1 by inducing its translocation to the lysosomes

10. mTORC1 and 2 are activated by growth factors

11. Adipose tissue mTORC1 is overactivated in obesity

12. Is mTOR involved in the regulation of adiposity?

13. Rapamycin inhibits mTORC1 and 2 in adipose tissue

14. Chronic mTOR inhibition reduces adiposity RETRO MASS (% BW) DNA CONTENT ADIPOCYTE DIAMETER

15. Rapamycin reduces lipid incorporation and LPL activity and expression in adipose tissue

16. Rapamycin reduces mRNA levels of genes regulated by PPARgamma FAT/CD36 LIPIN 1 PEPCK FATP1 Vehicle Rapamycin

17. Rapamycin reduces PPARgamma mRNA levels and DNA binding activity PPARgamma 1 PPARgamma 2 DNA binding activity (% of control) Vehicle Rapamycin

18. mTORC1 modulates adiposity by affecting the nuclear receptor PPARgamma mTORC1 PPARγ RXR + ?

19. Obesity: chronic low-grade adipose tissue inflammation

20. Obesity induces macrophage polarization

21. TNFα, LPS TLR4 AKT/PKB X Cre-Lox System

22. Characterization of the macrophage mTORC2 deficiency mice model

23. mTORC2 deficiency abolishes Akt activation by Toll like receptor ligands in BMDM

24. mTORC2 deficiency potentiates macrophage polarization to M1 pro-inflammatory profile

25. Myeloid cell mTORC2 deficiency decreases mice survival upon acute LPS challenge

26. Conclusion mTORC2 display anti-inflammatory actions on macrophages Future Directions mTORC2 gain of function experiments mechanism underlying mTORC2 anti- inflammatory actions

27. Screening of Quebec and Brazilian fruits aiming to identify bioactive molecules to prevent and treat obesity and type 2 diabetes Quebec Institute of Cardiology School of Pharmacy Dr Franco M Lajolo Dr André Marette

28. 90% of T2D cases are preventable by lifestyle modifications such as consuming a diet rich in fruits and vegetables. Willett WC, Science, 2002 Lindström J et al., Lancet, 2006 World Health Organization Consumption of fruits is inversely correlated with T2D prevalence Low fruit and vegetable intake is among the top 10 selected risk factors for global mortality A minimum of 400g of fruit and vegetables per day for the prevention of chronic diseases FRUITS AND VEGETABLES vs TYPE 2 DIABETES

29. PHENOLIC COMPOUNDS: POLYPHENOLS Naringenina Resveratrol Elagic acid

30. Acknowledgments Institute of Biomedical Sciences, USP Juliana Magdalon Vivian Paschoal Thiago Belchior Patricia Chimin Alex Shimura School of Pharmacy - USP Franco Lajolo Maria Inés Genovese Marcela Roquim Helena Barros Quebec Institute of Cardiology – Laval University André Marette Yves Deshaies Fernando Forato Anhê Genevieve Pilon Mat Laplante Pierre-Gilles Blanchard Institute of Nutraceutical and Functional Food – Laval University Yves Desjardins

31. Thank you!!!