Transcript Coronary heart disease

Bioactive compounds of Brazilian Regional
fruits for treatment of metabolic diseases
William Festuccia
Institute of Biomedical Sciences
University of São Paulo, Brazil
[email protected]
Presentation Outline
• Nutrient sensor mTOR as modulator of adiposity
and inflammation
• Bioactive compounds of Brazilian and Quebec
Regional fruits for treatment of metabolic
diseases
Disclosure
• I have no actual or potential conflict of interest in
relation to this presentation.
First Law of Thermodynamics
Energy can be transformed, changed from one form to another,
but cannot be created or destroyed
Diseases associated with Obesity
Pulmonary disease
abnormal function
obstructive sleep apnea
hypoventilation syndrome
Nonalcoholic fatty liver
disease
Idiopathic intracranial
hypertension
Stroke
Cataracts
steatosis
steatohepatitis
cirrhosis
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
Gall bladder disease
Severe pancreatitis
Gynecologic abnormalities
Cancer
abnormal menses
infertility
polycystic ovarian syndrome
breast, uterus, cervix
colon, esophagus, pancreas
kidney, prostate
Osteoarthritis
Skin
Gout
Phlebitis
venous stasis
Obesity: over-supply of nutrients
Brain
Adipose tissue
Pancreas
Fatty acids
Amino acids
Glucose
Muscle
Liver
mTOR: mechanistic target of rapamycin is the
catalytic core of 2 protein complexes
mTORC1
mTORC2
GROWTH
FACTORS
AMINO ACIDS
GLUCOSE
FATTY ACIDS
mTORC1
Protein Synthesis
Lipid Synthesis
Anaplerosis
Cell Size
Proliferation
Growth
?
Obesity
fat cell size & number
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 mRNA levels of genes regulated
by PPARgamma
Vehicle
FATP1
FAT/CD36
Rapamycin
PEPCK
LIPIN 1
Rapamycin reduces PPARgamma mRNA levels and DNA
binding activity
Rapamycin
Vehicle
PPARgamma
1
PPARgamma
2
DNA binding activity
(% of control)
mTORC1 modulates adiposity by affecting the
nuclear receptor PPARgamma
mTORC1
+
?
RXR
PPARγ
Obesity: chronic low-grade adipose tissue
inflammation
Obesity induces macrophage polarization
TNFα, LPS
TLR4
X
Cre-Lox
System
AKT/PKB
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
inflammatory actions
anti-
Screening of Quebec and Brazilian fruits aiming to identify
bioactive molecules to prevent and treat obesity and type
2 diabetes
School of
Pharmacy
Dr Franco M Lajolo
Quebec
Institute of
Cardiology
Dr André Marette
FRUITS AND VEGETABLES vs TYPE 2 DIABETES
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
PHENOLIC COMPOUNDS: POLYPHENOLS
Resveratrol
Naringenina
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!!!