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Bioactive compounds of Brazilian Regional fruits for treatment of metabolic diseases
William FestucciaInstitute of Biomedical SciencesUniversity of São Paulo, Brazil
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• Nutrient sensor mTOR as modulator of adiposity and inflammation
• Bioactive compounds of Brazilian and Quebec Regional fruits for treatment of metabolic diseases
Presentation Outline
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Disclosure
• I have no actual or potential conflict of interest in relation to this presentation.
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First Law of ThermodynamicsEnergy can be transformed, changed from one form to another,
but cannot be created or destroyed
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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
StrokeStrokeCataractsCataracts
Severe pancreatitisSevere pancreatitis
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Brain
Adipose tissueMuscle
LiverPancreas
Obesity: over-supply of nutrients
Fatty acidsAmino acids
Glucose
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mTORC1 mTORC2
mTOR: mechanistic target of rapamycin is the catalytic core of 2 protein complexes
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AMINO ACIDSGLUCOSEFATTY ACIDS
GROWTH FACTORS
Protein SynthesisLipid Synthesis
Anaplerosis
Cell Size Proliferation
GrowthObesity
fat cell size & number
?
mTORC1
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Leucine activates mTORC1 by inducing its translocation to the lysosomes
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mTORC1 and 2 are activated by growth factors
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Adipose tissue mTORC1 is overactivated in obesity
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Is mTOR involved in the regulation of adiposity?
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Rapamycin inhibits mTORC1 and 2 in adipose tissue
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Chronic mTOR inhibition reduces adiposity
RETRO MASS (% BW)
DNA CONTENT ADIPOCYTE DIAMETER
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Rapamycin reduces lipid incorporation and LPL activity and expression in adipose tissue
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Rapamycin reduces mRNA levels of genes regulated by PPARgamma
FAT/CD36 LIPIN 1PEPCKFATP1
Vehicle Rapamycin
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Rapamycin reduces PPARgamma mRNA levels and DNA binding activity
PPARgamma 1
PPARgamma 2
DNA binding activity (% of control)
Vehicle Rapamycin
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mTORC1 modulates adiposity by affecting the nuclear receptor PPARgamma
mTORC1
PPARγRXR
+ ?
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Obesity: chronic low-grade adipose tissue inflammation
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Obesity induces macrophage polarization
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TNFα, LPS
TLR4
AKT/PKBXCre-Lox System
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Characterization of the macrophage mTORC2 deficiency mice model
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mTORC2 deficiency abolishes Akt activation by Toll like receptor ligands in BMDM
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mTORC2 deficiency potentiates macrophage polarization to M1 pro-inflammatory profile
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Myeloid cell mTORC2 deficiency decreases mice survival upon acute LPS challenge
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Conclusion
• mTORC2 display anti-inflammatory actions on macrophages
Future Directions• mTORC2 gain of function experiments• mechanism underlying mTORC2 anti-
inflammatory actions
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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
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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
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PHENOLIC COMPOUNDS: PHENOLIC COMPOUNDS: POLYPHENOLSPOLYPHENOLS
Naringenina
Resveratrol
Elagic acid
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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
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Thank you!!!