Development of anti-aP2 therapeutics against diabetes and ... · Development of anti-aP2...
Transcript of Development of anti-aP2 therapeutics against diabetes and ... · Development of anti-aP2...
Dr. Mehmet Furkan Burak
ACP Annual Scientific Meeting, MA 2016
Development of anti-aP2 therapeutics against diabetes and fatty liver disease
Financial Disclosure
I don’t have any conflict of interest
Rosen, Cell 2014
70 Trillion $
Obesity recognized as a disease
Spiegelman, Nature 2006
aP2
Adipocyte Fatty Acid Binding Protein (FABP4-aP2)
Furuhashi, Nature Rev 2008
Genetic deficiency of aP2 is protective in many diseases
aP2
aP2-/-aP2dele on
aP2 & Diabetes
aP2
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Blood
Gluco
se (mg/
dl)
Maeda2005CellMetabolism
aP2 & Atherosclerosis
aP2
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Ath
ero
sclero
sis
+/+ -/-
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Boord2004Circula on
aP2 & Fatty Liver Disease
aP2
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Hepato
steato
sis
aP2 ?
Serum aP2 levels increased with obesity Serum aP2 increases with BMI and obesity
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Serum aP2 in genetic obesity in
mouse and man
Serum aP2 and BMI
Cao & Hotamisligil, unpublished
Data suggest mouse may be a good model for human
Serum aP2 increases with BMI and obesity
Hotamisligil Confidential
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Fast
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Promoter polymorphism results in decreased adipose aP2 expression n: 7899
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PI-IgG aP2 antibody
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PI-IgG aP2 antibody PI-IgG aP2 antibody
PI-lgG aP2 antibody
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Figure 6
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Lipolysis
β-adrenergic stimulation
MVB
Other
Organs ?
Glucose Production
aP2
aP2
Treatment & tests HFD – become obese 6 21 25
Birth
Week 0
HFD
Vehicle or anti-aP2 monoclonal antibody 33mg/kg, 2x/week
subQ injections
Study Design
- Weekly Fasting Blood glucose
Fed Body Weight
- Week 2 Glucose tolerance test
- Week 3 Insulin tolerance test
- Week 4-5 Clamp – SAC
- Histological and molecular tests
from week 4-5 tissues.
Give me the same!
Sorry! You are
in control group
The monoclonal anti-aP2 antibody CA33 improved glucose metabolism
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Insulin(n
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HA3
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Glucose(mg/dl)
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Burak et al. Science TM 2015
The monoclonal anti-aP2 antibody CA33 improved glucose metabolism
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Week 0 Week 1 Week 3 Week 5
PBS CA33
Glu
cose
(m
g/d
l) *
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6 hr fasting
Burak et al. Science TM 2015
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PBS
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Glucose(mg/dl)
Timea erglucose(min)
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Insulin(ng/ml)
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CA33 effect is specific to aP2 and robust in different obesity models
Burak et al. Science TM 2015
PEPCK Pck1
G6pc
SAC
clamp Steady state basal acclimatization
Tissue collection
-5 0 5 45 10 15...
2 hr 2.5 hr 45 min
Clamp Settings
+++ Insulin + Glucose H-glucose C-glucose 3
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CA33 decreased liver glucose production and increased peripheral insulin sensitivity
Burak et al. Science TM 2015
1 cm 1 cm
PBS CA33
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Liver Weight(g)
Liver % Bodyweight
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CA33
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CA33 treatment improved lipid metabolism
and reversed hepatosteatosis in obese mice
Burak et al. Science TM 2015
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Cholesterol(mg/dl)
VehicleCA33
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mRNA/36B4
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Scd1 Fasn Acc1
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Scd1 Fasn Acc1
Vehicle CA33C D
CA33 treatment improved lipid metabolism
and reversed hepatosteatosis in obese mice
Burak et al. Science TM 2015
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igh
ts (
g)
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CA33 prevented HFD induced weight gain and decreased BW
weeks
CA33 decreased fat mass
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Fatmass(g)
Leanmass(g)
Vehicle CA33
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ycompo
sion
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LiverWeight %Bodyweight
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LiverWeight
%BodyWeight
Weight
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DCA
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Burak et al. Science TM 2015
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CA33 accelerated oxidative metabolism and decreased fat mass
Burak et al. Science TM 2015
- aP2 secretion increased with fasting.
- Serum aP2 levels increased with human obesity and contributes to hyperglycemia.
- Secreted aP2 can be effectively targeted by a monoclonal antibody to ameliorate diabetes and reduce fat mass and hepatic steatosis.
- CA33, as a potential preclinical molecule that lowered fasting blood glucose, improved glucose metabolism, increased systemic insulin sensitivity and reduced liver steatosis.
- These metabolic outcomes were; -reproducible in two independent models of obesity, genetic and dietary, -specific to aP2, -linked to the regulation of hepatic glucose output and peripheral glucose utilization.
- CA33 also decreased fat mass and increased oxidative capacity without any effect on physical
activity and food intake.
Summary
Acknowledgement
DP2 transition aP2
8 November 2013 Dr. Gökhan Hotamisligil
Dr.Valerie Stone
Dr.Patrick Gordan Dr.Barbara Blair