Bioactive compounds of Brazilian Regional fruits for treatment of metabolic diseases

William FestucciaInstitute of Biomedical SciencesUniversity of São Paulo, Brazil

william.festuccia@usp.br

• Nutrient sensor mTOR as modulator of adiposity and inflammation

• Bioactive compounds of Brazilian and Quebec Regional fruits for treatment of metabolic diseases

Presentation Outline

Disclosure

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

First Law of ThermodynamicsEnergy can be transformed, changed from one form to another,

but cannot be created or destroyed

Pulmonary diseasePulmonary diseaseabnormal functionabnormal functionobstructive sleep apneaobstructive sleep apneahypoventilation syndromehypoventilation syndrome

Nonalcoholic fatty liver Nonalcoholic fatty liver diseasediseasesteatosissteatosissteatohepatitissteatohepatitiscirrhosiscirrhosis

Coronary heart diseaseCoronary heart disease

DiabetesDiabetes

DyslipidemiaDyslipidemia

HypertensionHypertension

Gynecologic abnormalitiesGynecologic abnormalitiesabnormal mensesabnormal mensesinfertilityinfertilitypolycystic ovarian syndromepolycystic ovarian syndrome

OsteoarthritisOsteoarthritis

SkinSkin

Gall bladder diseaseGall bladder disease

CancerCancerbreast, uterus, cervixbreast, uterus, cervixcolon, esophagus, pancreascolon, esophagus, pancreaskidney, prostatekidney, prostate

PhlebitisPhlebitisvenous stasisvenous stasis

GoutGout

Diseases associated with ObesityIdiopathic intracranial Idiopathic intracranial hypertensionhypertension

StrokeStroke

CataractsCataracts

Severe pancreatitisSevere pancreatitis

Brain

Adipose tissueMuscle

LiverPancreas

Obesity: over-supply of nutrients

Fatty acidsAmino acids

Glucose

mTORC1 mTORC2

mTOR: mechanistic target of rapamycin is the catalytic core of 2 protein complexes

AMINO ACIDSGLUCOSEFATTY ACIDS

GROWTH FACTORS

Protein SynthesisLipid Synthesis

Anaplerosis

Cell Size Proliferation

GrowthObesity

fat cell size & number

?

mTORC1

Leucine activates mTORC1 by inducing its translocation to the lysosomes

mTORC1 and 2 are activated by growth factors

Adipose tissue mTORC1 is overactivated in obesity

Is mTOR involved in the regulation of adiposity?

Rapamycin inhibits mTORC1 and 2 in adipose tissue

Chronic mTOR inhibition reduces adiposity

RETRO MASS (% BW)

DNA CONTENT ADIPOCYTE DIAMETER

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

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

Rapamycin reduces mRNA levels of genes regulated by PPARgamma

FAT/CD36 LIPIN 1PEPCKFATP1

Vehicle Rapamycin

Rapamycin reduces PPARgamma mRNA levels and DNA binding activity

PPARgamma 1

PPARgamma 2

DNA binding activity (% of control)

Vehicle Rapamycin

mTORC1 modulates adiposity by affecting the nuclear receptor PPARgamma

mTORC1

PPARγRXR

+ ?

Obesity: chronic low-grade adipose tissue inflammation

Obesity induces macrophage polarization

TNFα, LPS

TLR4

AKT/PKBXCre-Lox System

Characterization of the macrophage mTORC2 deficiency mice model

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

mTORC2 deficiency potentiates macrophage polarization to M1 pro-inflammatory profile

Myeloid cell mTORC2 deficiency decreases mice survival upon acute LPS challenge

Conclusion

• mTORC2 display anti-inflammatory actions on macrophages

Future Directions• mTORC2 gain of function experiments• mechanism underlying mTORC2 anti-

inflammatory actions

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

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

PHENOLIC COMPOUNDS: PHENOLIC COMPOUNDS: POLYPHENOLSPOLYPHENOLS

Naringenina

Resveratrol

Elagic acid

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

Thank you!!!