Download - Manuel Serrano-Lo último en obesidad
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Pharmacological control
of energy expenditure and obesity
with PI3K inhibitors
in mice and monkeys
Spanish National Cancer Research Center (CNIO)
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Reducing the IIS pathway:
Akt
PI3K
insulin/IGF1
--
Foxo mTORC1
S6K
IRS
Raptor
Lts8
Pten
The insulin/IGF1 signaling (IIS) pathway in healthspan and lifespan
anabolism
CR
RAPA
# increases longevity
• in mice, flies, worms
• in humans (FOXO3 alleles
are linked to longevity)
# improves glucose homeost.
• upon aging or high fat
# increases energy expenditure
• lower nutritional storage
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EDITORIAL
September 13, 2012
Humans with PTEN germline mutations are obese
Genetic evidence in humans also links PTEN with the control of obesity
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Rationale
anabolism ins. res.metab. synd.
longevityobesityIIS PI3Kovernutrition
PI3Ki
• CNIO-PI3Ki (a, d)
• GDC-0941 (a, b, g, d)
• BYL-719 (a)
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• obese mice after 8 months of HFD
• 13-25% body weight gain
-5 -4 0 1 2 3 4 5 6 7 8 9 11 1210 13
CNIO-PI3Ki 10 mg/kg
15 mg/kgCNIO-PI3Ki
GDC-0941 10 mg/kg
GDC-0941 75 mg/kg
vehicle
-3 -2 -1
70
80
90
100
110
0 2 4 6 8 10
time (days)
body
weig
ht
change (
%)
body weight change
** * * * *** ** * * * ** ** ***
*** ** * * * *
0
50
100
150
200
glu
cose (
mg/d
l)
body weight change
at day 10
60
70
80
90
100
110
body
weig
ht
change (
%)
*
***
*
std.
diet
glycemia at day 13
0
average food intake
g/d
ay/
mouse
1
2
3
4
Weight loss after 2 weeks of PI3Ki treatment
Ortega-Molina et al., Cell Metab. 2015
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Decreased adiposity after 2 weeks of PI3Ki treatment
vehicle
day -7 day 7 day 14
CNIO-
PI3Ki
15mg/kg
adiposity by DXA
14.2%6.5%
CNIO-PI3Ki GDC-0941
0
10
20
30
40
vehicle 10mg/kg 15mg/kg 10mg/kg 75mg/kg
fat (%
)
0
10
20
30
40
fat (%
)
**
0.06
SD
SD0
5
10
15
20
25
30
35
lea
n (
g)
0
5
10
15
20
25
30
35
lea
n (
g)
lean mass
CNIO-PI3Ki GDC-0941
vehicle 10mg/kg 15mg/kg 10mg/kg 75mg/kg
D -7
D 7
D 14
fat mass
Ortega-Molina et al., Cell Metab. 2015
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vehicleCNIO-PI3Ki 10
mg/kg
GDC-0941
10mg/kg GDC-0941 75
mg/kg
liver
CNIO-PI3Ki 15
mg/kg
heart/lung
Reduced liver steatosis and pericardial fat after 2 weeks of PI3Ki treatment
Ortega-Molina et al., Cell Metab. 2015
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Mechanisms of action of PI3Ki
H&E Ucp1
vehicle
PI3Ki
BAT
0
2
4
6
8
10
fold
change
** **
*
* *
Ortega-Molina et al., Cell Metab. 2012
brown
*
- - -
fold
change
forsk: + + +
100
150
200
250
****
**
Ucp1
pre-brown
- - -+ + +
PI3Kicontrol
20
***
** **
pre-brown brown
3T3-L1 Cebpβ
3T3-L1 Cebpβ
40
30
10
0
50
25
0
Pgc1a
**
PI3Kicontrol
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Mechanisms of action of PI3Ki
April 2015
Figure adapted from:
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Long-term PI3Ki treatment reduces high fat diet-induced obesity
body weight during PI3Ki treatment
(drinking water)
20
30
40
50
60
0 10 20 30 40 50 60 70
time (days)
bo
dy w
eig
ht (g
) HFD: vehicle
HFD: CNIO-PI3Ki
SD: vehicle
SD: CNIO-PI3Ki
24%
Ortega-Molina et al., Cell Metab. 2015
# Body weight reduction is not continuous, but reaches an equilibrium
# Body weight reduction is only observed under overnutrition
Note: Dosing is 0.1 mg/ml in the drinking water, producing an average of ~60 ng/ml serum concentration, which is ~40x lower that the concentration achieved by gavage of 15 mg/kg.
HFD: high fat dietSD: standard diet
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Long-term treatment with CNIO-PI3Ki protects from steatosis and reduces lipid stores
F4
/80
H&
E
1
0
x
SD-vehicle SD-CNIO-PI3Ki HFD-vehicle HFD-CNIO-PI3KiH
&E
Oil
Red
O
live
reW
AT
Ortega-Molina et al., Cell Metab. 2015
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Mechanisms of action of PI3Ki
Ortega-Molina et al., Cell Metab. 2015
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Long-term PI3Ki treatment reverts high fat diet-induced obesity
0 20 40 60 140 160 180 200
80
100
120
140
time (days)
body
weig
ht
change (
%)
vehicle
CNIO-PI3Ki
no treatment
no treatment
obese mice under continuous HFD
Ortega-Molina et al., Cell Metab. 2015
# No evidence for the emergence of resistance
# No evidence for irreversible metabolic changes
# No evidence for toxicities
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Long-term PI3Ki treatment reverts high fat diet-induced obesity
vehicle
CNIO-Pi3Ki
Ob/Ob mice
Ortega-Molina et al., Cell Metab. 2015
# PI3Ki is effective under overnutrition conditions
(even if the diet is “balanced”)
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Long-term PI3Ki treatment reverts high fat diet-induced obesity
Ortega-Molina et al., Cell Metab. 2015
# Overnutrition (even in the absence of pre-existent obesity) is
sufficient for the activity of PI3Ki
# Lab-to-lab reproducibility
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Other properties of CNIO-PI3Ki
Ortega-Molina et al., Cell Metab. 2015
• The drug does not cross the blood-brain barrier
• No alterations on the arcuate nucleus of the hypothalamus
(expression of orexigenic and anorexigenic neuropeptides)
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Preliminary dosing study in Rhesus monkeys at the NIA-NIH (Rafael de Cabo)
Ortega-Molina et al., Cell Metab. 2015
The highest dose tested of 2.1 mg/kg i.v. was considered safe.
Note. the following assay using obese macaques was done with the same dose
but per os and this gave a serum concentration of drug at 2h of ~30 ng/ml.
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Assay in Rhesus monkeys at the NIA-NIH (Rafael de Cabo)
Ortega-Molina et al., Cell Metab. 2015
Note: Dosing is 2 mg/kg p.o. which produced a peak at 2h of ~30 ng/ml serum concentration.
This is ~80x lower than the peak achieved in mice with 15 mg/kg p.o. or ~2x lower than the continuous concentration achieved in mice with 0.1 mg/ml in the drinking water.
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Summary of the data in macaques
Ortega-Molina et al., Cell Metab. 2015
Treatment of obese macaques with low and chronic doses of CNIO-PI3Ki results in:
• Reduction of adiposity
• A tendency to correct fasting glycemia
• No evidence of toxicities, morbidities, or discomfort
The dose used in the macaques is extremely low, in the order of ~80x lower than
the one used in mice under similar administration conditions.
• Mice: 15 mg/kg p.o., which results in a serum peak of drug at 2h of ~2 µg/ml
• Macaques: 2 mg/kg p.o., which results in a serum peak of drug at 2h of ~30 ng/ml
Based on the preliminary escalation assay, we anticipate that the dose could be
increased at least by 10x.
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Tumor Suppression Group
Assays with monkeys:
Rafael de Cabo, NIA-NIH, Baltimore
NIH Animal Center, Poolesville
Experimental Therapeutics
Joaquin Pastor
Sonia MartinezAna Ortega-Molina (now at MSKCC, NY)
Elena Lopez-Guadamillas
Analysis of the hypothalamus:
Miguel Lopez
CIMUS, Santiago de Compostela
Spanish National Cancer Research Centre (CNIO)