Energy Metabolism & Diseases of Modern Civilization: Part III: Therapeutic Options
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Transcript of Energy Metabolism & Diseases of Modern Civilization: Part III: Therapeutic Options
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Energy Metabolism & Diseases of Modern Civilization:
Part III: Therapeutic Options
Johannes Klein, University of Lübeck, Germany
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Adipocyte Biology
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Adipocyte-Based Therapies
Alteration of Insulin/EC/GIP Signalling
Obesity, Insulin Resistance
Premature Mortality
Lipog
enes
is
3-Adrenoceptor Agonists/TZD/CNTF
Conversion of WAT to BAT
Obesity
Insulin Resistance
Ther
mogen
esis
Leptin/Adiponectin/Visfatin Analoga11-HSD-1 Inhibitors
PAI-1/RAS/Adipotensin BlockersRBP4 Urinary Excretion Enhancer
Insulin Resistance, Dyslipidemia, Obesity
Amenorrhea, Hypertension,
Atherosclerosis
Hormon
e Sec
retio
n
Klein 2006Trends in Endocrinology and Metabolism
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Farooqi et al., N Engl J Med, 1999
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Oral, E. A. et al. N Engl J Med 2002;346:570-578
Mean ({+/-}SE) Plasma Glucose Levels in Response to an Insulin-Tolerance Test (Panel A) and an Oral Glucose-Tolerance Test (Panel B) in Nine Patients at Base Line and after Four Months of
Leptin-Replacement Therapy
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Oral, E. A. et al. N Engl J Med 2002;346:570-578
Clinical Course of Patient 1, as Assessed by Changes in Mean Triglyceride Levels, Glycosylated Hemoglobin Values, and Serum Leptin Values
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Welt, C. K. et al. N Engl J Med 2004;351:987-997
Follicular, Ovarian, and Endometrial Ultrasonographic Measurements at the Beginning and End of the One-Month Baseline Period and at Their Maximum during r-metHuLeptin Treatment
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Welt, C. K. et al. N Engl J Med 2004;351:987-997
Representative Patterns of LH Pulsatile Characteristics at Baseline and after Two Weeks of r-metHuLeptin Therapy in Eight Subjects
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Survival
Individual Protection Against Environment:
Fit for Fight & Flight:
Immune System
Preservation of Species:
Reproduction:
Endocrine System
Energy storage & release:Energy management
Klein, Discovery Medicine 2006
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Fit for Fight & Flight
Reproduction
Energy storage & release
Adipose Tissue
ImmuneFunction
Endocrine Function
Energy Management
Klein, Discovery Medicine 2006
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Mögliche Ursachen einer Dysregulation des EnergiestoffwechselsI) „Afferenz“ gestört:
- veränderte Regulation der Energieaufnahme/-verwertung
II) „Efferenz“ gestört:
- Effektormechanismen der Energieabgabe gestört
Mögliche Ursachen:- genetisch: Leptin-Mangel, Melanokortin-Rezeptor-Mutationen (MC4), Ghrelin?- Umwelt:
- Medikamente: Cortison, Cannabis- Lifestyle bei kumulativem Effekt von „Meßfehlern“ (Insuffizienz des Systems, Regelschwankungen zu korrigieren)
Mögliche Ursachen:- genetisch: 3-Adrenozeptor-, UCP-1-Mutationen- Umwelt:
- Medikamente: beta-Blocker- Lifestyle bei inadäquater „Sympathikus-Adaptation“
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Adipositas: Therapieansätze
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• Diät: Low Calorie Diet, Very Low Calorie Diet, Lower-Fat Diets
• Bewegung
• Verhaltenstherapie
• Bariatrische Chirurgie (u. a. gastric banding, Y-Roux-Anastomose, Gastroplastie)
• Pharmakotherapie
•„priming“ in utero?
Adipositas: Therapieansätze
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Equation of Energy Homeostasis
Food Influx = Energy Efflux
FatFat
EnvironmentGenes
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Mögliche Ursachen einer Dysregulation des EnergiestoffwechselsI) „Afferenz“ gestört:
- veränderte Energieaufnahme/-verwertung
II) „Efferenz“ gestört:
- Effektormechanismen der Energieabgabe gestört
Mögliche Ursachen:- genetisch: Leptin-Mangel, Melanokortin-Rezeptor-Mutationen (MC4), Ghrelin?- Umwelt:
- Medikamente: Cortison, Cannabis- Lifestyle bei kumulativem Effekt von „Meßfehlern“ (Insuffizienz des Systems, Regelschwankungen zu korrigieren)
Mögliche Ursachen:- genetisch: 3-Adrenozeptor-, UCP-1-Mutationen- Umwelt:
- Medikamente: beta-Blocker- Lifestyle bei inadäquater „Sympathikus-Adaptation“
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Medikamentöse AdipositastherapieI Afferenz:
Orlistat (Resorptionshemmer)Phentermin
II Efferenz:3-Adrenozeptor-Agonisten
Schilddrüsenhormon T3
III Afferenz u. Efferenz:SibutraminCannabis-Rezeptor-AntagonistLeptinCiliary Neurotrophic Factor (CNTF)Inkretine?
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The slim obesity market
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An appetizing choice to the slim market?
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Johannes KleinDepartment of Internal Medicine I
UNIVERSITY HOSPITAL
Schleswig-Holstein, Lübeck
Das Endocannabinoid-System: Von der Unterkühlung der Maus zum Hot Topic beim Menschen
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Johannes KleinDepartment of Internal Medicine I
UNIVERSITY HOSPITAL
Schleswig-Holstein, Lübeck
Molekulare Angriffspunkte und Wirkmechanismen Der Endocannabinoide
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Das Endocannabinoid-System
1990 – Klonierung des CB1-Rezeptors
1964 – Chemische Identifizierung von THC
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Johannes KleinDepartment of Internal Medicine I
UNIVERSITY HOSPITAL
Schleswig-Holstein, Lübeck
Vorkommen von “Endocannabinoid”-Rezeptoren
• Gebiete im Gehirn, die für Regelung des Energie- haushaltes bedeutsam sind (z. B. Appetit)
• Nervensystem d. Darmes
• Fettzellen • Leberzellen
CB1
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Cannabinoid-Rezeptoren, Endocannabinoide
E
LL
M
472
1
1
360
1990: CB1-Rezeptor1993: CB2-Rezeptor
CB1
CB2
7-Transmembran-Rezeptoren
NOH
O
H
Anandamid
1992
2-Arachidonoyl-Glycerin
1995O
OH
O OH
Lipide
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Eigenschaften der Endocannabinoide:Biochemie
• werden schnell wieder abgebaut (durch Enzyme)
• werden « bei Bedarf » (nach Stimulation) synthetisiert (werden nicht in Vesikeln aufbewahrt !)(daneben auch konstitutive Produktion möglich)
• sind Lipide (Arachidonsäure-Abkömmlinge, ähnlich Prostaglandinen)
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Gi/o
CB1
Cannabinoide
Aktivierung von CB1-Rezeptoren
► Verminderung der Erregbarkeit der Neuronen
Adenylat-cyclase
↓ cAMP
-
Ca2+-
↓ Kalziumkanäle
K++↑ Kaliumkanäle
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0
20
40
60
80
100
120
Basal 100nM 1µM
UC
P1 P
rote
in(%
of B
asal
)
**
**
CB Agonist
Terminal Differentiation
Control
B
4
0 (h
)
100
60
(% of Basal)
mRNA Levels
A
Perwitz N, Klein J, Horm Metab Res, 2006
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Cb1-Receptor agonists induce hypothermia in rodents and primates
Rawls et al. 2002, Compton et al. 1992, Fan et al. 1994, Spina et al. 1998, Fox et al. 2001
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Das Endocannabinoid-System ist ein vielseitiges Signalsystem im Körper
aktiviert um ...
zu ruhenReduktion der Bewegungsaktivität
zu habituieren Modulation der Gedächtnisverarbeitung
zu schützenReduktion der neuronalen Aktivität
zu entspannen Reduktion von Schmerz. Reduktion der Körpertemperatur
zu essenInduktion des Essens, Aufbau von Fetten, Verstärkung des Belohnungsverhaltens
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Das Endocannabinoid-System
1990
1992
1993
– Klonierung des CB1-Rezeptors
– Erstes Endocannabinoid: Anandamid
– Klonierung des CB2-Rezeptors
1964 – Chemische Identifizierung von THC
1999 – Erste Charakterisierung von Mäusen ohne CB1
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Science, 1999
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CB1-Rezeptor-KO-Mausmodell
Zimmer et al., Proc. Natl. Acad. Sci 1999
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Johannes KleinDepartment of Internal Medicine I
UNIVERSITY HOSPITAL
Schleswig-Holstein, Lübeck
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Increased mortality in CB1 receptor knockout mice
Zimmer et al., Proc. Natl. Acad. Sci 1999
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Das Endocannabinoid-System
1990
1992
1993
1994
– Klonierung des CB1-Rezeptors
– Erstes Endocannabinoid: Anandamid
– Klonierung des CB2-Rezeptors
– Erster CB1-Rezeptor-Blocker: Rimonabant
1964 – Chemische Identifizierung von THC
1999 – Erste Charakterisierung von Mäusen ohne CB1
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Johannes KleinDepartment of Internal Medicine I
UNIVERSITY HOSPITAL
Schleswig-Holstein, Lübeck
Rimonabant: Cb1-Rez.-Hemmer
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Cb1-Receptor agonists induce hypothermia in rodents and primates
Rawls et al. 2002, Compton et al. 1992, Fan et al. 1994, Spina et al. 1998, Fox et al. 2001
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Rimonabant (µg) -- ----30
5030
Rimonabant blockiert diesen Effekt
Anandamid-Injektion in den Hypothalamus schon gesättigter Ratten induziert “Fress-Sucht”
Kum
ulat
ive
Futte
rauf
nahm
e
(g
/100
g K
örpe
rgew
icht
)
0,0
1,51,20,9
0,6
0,3
2,11,8
Endocannabinoide und Futteraufnahme
Jamshidi et al, Br J Pharm 2001;134:1151-4
-- 50Anandamid (ng)
*
CB1-Blockade verhindert Überfüttern
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Version 1.215 June 2005
Sites of CB1 receptor and effects of CB1 blockade
Site of Action Mechanism(s) Addresses
Hypothalamus / Nucleus accumbens
Food intakeBody weightIntra abdominal adiposity
Adipose tissue Adiponectin Lipogenesis
DyslipidemiaInsulin resistance
Muscle Glucose uptake Insulin resistance
Liver Lipogenesis Dyslipidemia
Insulin resistance
GI tract Satiety signalsBody weightIntra abdominal adiposity
DiMarzo 2001; Ravinet Trillou et al 2003; Cota et al 2003;Pagotto et al 2005; Van Gaal et al 2005; Liu et al 2005; Osei-Hyiaman et al 2005
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Das Endocannabinoid-System
1990
1992
1993
1994
– Klonierung des CB1-Rezeptors
– Erstes Endocannabinoid: Anandamid
– Klonierung des CB2-Rezeptors
– Erster CB1-Rezeptor-Blocker: Rimonabant
1964 – Chemische Identifizierung von THC
2001 – Endocannabinoide als Neurotransmitter
1999 – Erste Charakterisierung von Mäusen ohne CB1
2005 – Rimonabant: Phase III-Ergebnisse
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RIO-Programm: Studiendesign
Rimonabant 20 mg
Rimonabant 5 mg
Plazebo
Plazebo
Woche 104Woche 52EinschlussRandomisierung
Woche 0EinschlussRandomisierung
Woche - 4Woche - 6
Leichte Diät, Kalorienbedarf reduziert um 600 kcal/Tag
ScreeningPlazebo
Run-in Phaseeinfachblind
Behandlungsdauer: 1 oder 2 Jahre doppelblind
Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27
Plazebo
Rimonabant 5 mg
Rimonabant 20 mg
Wiederholte Randomisierung: RIO-North America
Rimonabant 20 mg
Rimonabant 5 mg
Plazebo
Plazebo
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Consistent Weight Change
Pooled data from:L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727, JP. Després, Int J. Obes. Relat Metab Disod 2004, 28 (Suppl1) pS28; T5:O2-005
RIO~EuropePlaceboR 20 mg
RIO~LipidsPlaceboR 20 mg
RIO~NAPlaceboR 20 mg
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 LOCF
Wei
ght c
hang
e (k
g)
Weeks
-8.6 kg*
-3.6 kg*
* For RIO EU, completers
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X. Pi-Sunyer, Circulation 2005:111(13);1727.
RIO~NA: Prevention of Weight Regain by Chronic Therapy
Weight (kg) Change from Baseline over 2 Years (Mean +/- SEM)
-7.4 kg ± 0.4
-2.3 kg ± 0.5
-3.2 kg ± 0.4
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 LOCF-10
-8
-6
-4
-2
0
0 8 16 24 32 40 48 56 64 72 80 88 96 104 LOCF
Weeks
Wei
ght c
hang
e (K
g)
Placebo
Rimonabant 20 mg Rimonabant 20 mg/PLB
ITT, LOCF
Version 1.215 June 2005
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RIO~Program: Placebo-substracted change for metabolic syndrome
parameters
SBP (mmHg)
Waist circumference (cm)
Triglycerides (%)
HDL-cholesterol (%)ITT, LOCF
Mean (+ SEM)
-13.2 -15.1 -12.4 -16.4
-20
-15
-10
-5
0
5
10
** *
*
%
*p<0.001
-20
-15
-10
-5
0
5
10
7.2 8.9 8.1 8.4
** * *
*p<0.001
%
-6
-5
-4
-3
-2
-1
0
*
*p<0.001
cm-3.6
*
-4.2
*
-4.7
*
-3.30
-1
-2
-3
-4
-5
-6
-3
-2,5
-2
-1,5
-1
-0,5
0
0,5
P<0.05P<0.05NSNS
-0.2 -1.2 -1.7 -2.3mmHg
0-0.5
-1-1.5
-2-2.5
-3
0.5
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Johannes KleinDepartment of Internal Medicine I
UNIVERSITY HOSPITAL
Schleswig-Holstein, Lübeck
Nebenwirkungen von Rimonabant
Beschwerde (%)Placebo Rimonabant 5
mgRimonabant 20
mgn=348 n=358 n=339
Übelkeit 5.7 6.1 12.1
Schwindel 4.9 3.1 9.1
Gelenkschmerzen 8.0 9.8 8.8
Durchfall 6.6 6.1 7.4
Rückenschmerzen 6.9 6.1 7.1
Erbrechen 2.3 3.9 5.9
Hypoglykämie 1.7 1.4 5.3
Müdigkeit 3.7 5.3 5.3
Angst 2.6 1.1 5.0
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Das Endocannabinoid-System
1990
1992
1993
1994
– Klonierung des CB1-Rezeptors
– Erstes Endocannabinoid: Anandamid
– Klonierung des CB2-Rezeptors
– Erster CB1-Rezeptor-Blocker: Rimonabant
1964 – Chemische Identifizierung von THC
2001 – Endocannabinoide als Neurotransmitter
1999 – Erste Charakterisierung von Mäusen ohne CB1
2005 – Rimonabant: Phase III-Ergebnisse
2006 – Rimonabant: Markteinführung in Europa
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Johannes KleinDepartment of Internal Medicine I
UNIVERSITY HOSPITAL
Schleswig-Holstein, Lübeck
Cb1-Antagonists (Rimonabant and Successors):
Smoking Cessation
Cb2-Agonists:Osteoporosis
Anandamide Breakdown Inhibitors (FAAH Inhibitors)EpilepsyParkinson‘s DiseaseAlzheimer‘s DiseaseNociceptive PainStress-induced pain:Anxiety, posttraumatic stress disorderLearning – ExtinctionInflammatory Conditions: Multiple Sclerosis, IBD?Tumor cell proliferation
Potential Indications of Modulators of the Endocannabinoid System
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http://www.medscape.com/viewarticle/497960
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• Grundkomponenten der Energiehomöostase-Gleichung
• Brennwerte, Diät-Zusammensetzung von Hauptnährstoffen
• Regelelemente der Energiehomöostase
• Fettzellfunktionen
• Differenzielle Ansätze zur Therapie von „diabesity“
• Biologie des Endocannabinoidsystems
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