Transcript Document

Therapeutic Modulation of
Adipose Tissue Mass and Function
Johannes Klein, MD PhD
Professor of Endocrinology, Dept. of Internal Medicine, University of Lübeck
Major Current Tenets:
• Fat is bad, and that‘s it.
• Fat is fat, and that‘s it.
Let me have men about me that are fat;
Sleek-headed men, and such as sleep o' nights:
Yond Cassius has a lean and hungry look;
He thinks too much: such men are dangerous.
Shakespear, Julius Caesar, 1599
What is beauty?
Venus from Willendorf?
(~ 25.000 B.C.)
What‘s the evidence for fat tissue
being „a good force“?
Individual Protection
Against Environment:
Preservation of Species:
Fit for Fight & Flight:
Reproduction:
Immune System
Endocrine System
Survival
Energy storage & release:
Energy management
Klein, Discovery Medicine 2006
Adipose tissue als „Critical link Organ“
Fit for Fight & Flight
Immune
Function
Reproduction
Endocrine
Function
Adipose Tissue
Energy Management
Energy storage & release
Klein, Discovery Medicine 2006
FIG. 2. Weight change in intervention (n = 198) and control groups (n = 175)
Park, H. A. et al. J Clin Endocrinol Metab 2007;92:3809-3815
Copyright ©2007 The Endocrine Society
Hypoplasia/
Hypotrophy:
Lipodystrophy
Diabetes
Dyslipidaemia
Fat Cell Mass
Eufunction
Longevity
Fertility
Glucose/Energy Homeostasis
Intact Immune System
Cardioprotection
Hyperplasia/
Hypertrophy:
Obesity
Diabetes
Dyslipidaemia
Cardiovascular Morbidity
Hypertonus
Cancer
Dysfunction:
Adiposopathy
Major Current Tenets:
• So, perhaps fat is not so bad, after all.
• Fat is Fat, and that‘s it.
Insulin-mediated glucose disposal
(mg/kg lean body mass/min)
Intraabdominal Fat Mass Correlates With Insulin Resistance
15
r= -0.59
10
5
0
0
2
4
Intra-abdominal adipose tissue volume (L)
Banerji et al 1999
6
Waist Circumference Independently Associated With CHD
(even if corrected for BMI)
3.0
Relative risk
2.5
2.31
p for trend = 0.007
2.44
2.06
2.0
1.5
1.27
1.0
0.5
0.0
<69.8
69.8-<74.2
74.2-<79.2
79.2-<86.3
Quintiles of waist circumference (cm)
Rexrode et al 1998
86.3-<139.7
Depot-specific lipolysis, insulin sensitivity,
and endocrine function in fat cells
Kovsan, Klein, Rudich et al., Am J Physiol Endocrinol Metab 2008
Autologous adipose stem cells used to treat traumatic skull defects
Lendeckel et al. J Craniomaxillofac Surg 2004
Major Current Tenets:
• So, perhaps fat is not so bad, after all.
• All fat is NOT created equal. Fat at the wrong place
at the wrong time is pathogenic.
Fat Cell Functions
Insulin Sensitivity
Insulin Signaltransduction
Protection against obesity
Increased longevity
Diabetes
Blood Glucose
Molecules
Insulin
Membrane
Cytoplasm
P
IRS
Glut4
Signalling Cascade
Glucose uptake
Lipid accumulation
Insulin Receptor Substrate-1 is Essential for Fat Accumulation
Fasshauer and Klein et al., Mol Cell Biol 2001
Incretin Interaction with Adipocyte Function
x
GIP Receptor
Knock-out
Adipocyte Lines
• Visceral
• Subcutaneous
• Brown
Inhibition of gastric inhibitory polypeptide
signaling prevents obesity
Miyawaki K et al. Nature Medicine 2002
Does GIP signaling
directly impact on
differentiation/lipogenesis?
Microscopy
WT
GIPR-KO
Day 0
Day 3
Day 6
Fat Cell Functions
Insulin Sensitivity
Thermogenesis
Reduction of Brown Fat Glucose Uptake in PET Scans in Adults
Cold-Exposed
Ambient Temperature
Garcia CA et al. Mol Imaging Biol 2005
Molecular Targets for the Induction of Thermogenesis
Klein
Anorexigenic Compounds/Hormones Targeting These Factors
• Metformin
• CNTF
• Endocannabinoid System
• Leptin
Fat Cell Functions
Insulin Sensitivity
Thermogenesis
Hormone Secretion
Leptin Therapy of Lipodystrophic Diabetes
Oral, E. A. et al. N Engl J Med 2002;346:570-578
Leptin Therapy of Amenorrhea
Welt, C. K. et al. N Engl J Med 2004;351:987-997
Klein et al. 2006
Targeting Adipose Function Harbours
Therapeutic Potential for Multi-System Disease
Current Clinical and Investigational Approaches Focus on:
I
Exploitation of Endocrine Function
II Stimulation of Energy Dissipation/Thermogenesis
III Modulation of Energy Storage/Lipid Accumulation
Unresolved Issues
Potential Solution
Angiogenic Markers
Tissue and Depot Selectivity
Adiposopathy
Exploitation of Physical-Chemical Traits
Including Specific Cell Surface Markers
Combined Modulation of Different Adipose
Functions: e. g. Coupling of Lipogenesis
Inhibition to Lipid Oxidation
Acknowledgements
The Klein Group
Collaborators
Universidad Complutense, Madrid, Spain
M Benito
BBDC, University of Toronto, Toronto, Canada
DJ Drucker
Leipzig University, Leipzig, Germany
M Fasshauer
PBRC, Baton Rouge, USA
TW Gettys
JDC, Harvard University, Boston, USA
CR Kahn, BB Lowell
HH Klein, Bochum University, Germany
HH Klein
Obesity Research Center, Cincinnati, USA
MH Tschöp
Appendix
I
Leptin Therapies
II
Fat Cell Targeting
III
Fat Cell Size, Adipogenesis, Cell Model
IV
Fat as Multi-System Target
Leptin Therapy of Obesity
Farooqi et al., N Engl J Med, 1999
Leptin Therapy of Lipatrophic Diabetes
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
Oral, E. A. et al. N Engl J Med 2002;346:570-578
Leptin Therapy of Amenorrhea
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
Welt, C. K. et al. N Engl J Med 2004;351:987-997
Targeting of the White Fat Vascular Marker Prohibitin
with Apoptosis-Inducting Peptides
Kolonin MG et al. Nature Medicine 2004
Glucocorticoids Change Fat Cell Morphology
Control
Glucocorticoids
Adipogenesis
Adipocyte Cell Model
Preadipocytes
Different Mouse Models
Microscopy
Adipocytes
Fat Stain
Retroviral Immortalization
Microscopy
Fat Stain
Differentiation
(10 days)
4 weeks
Characteristic Functions
7
6
5
4
3
2
1
mRNA
Basal
Hormone Secretion
Thermogenesis
Protein
Leptin Secretion
(µg/l/day)
Glucose Uptake
(x Basal)
Insulin Sensitivity
10nM
1nM
100nM
Insulin
Klein, J Biol Chem 1999
Klein, J Biol Chem 2000
Klein, Mol Cell Biol 2001
Iwen, J Endocrinol 2008
UCP-1 Expression
Klein, Mol Endocrinol 2000
Ott, J Endocrinol 2002
Ott, Mol Cell Endocrinol 2005
Perwitz, Horm Metab Res 2006
Days of Differentiation
Kraus, J Endocrinol 2002
Klein, Bioessays 2002
Klein, J Endocrinol 2005
Mäuser, Eur J Pharmacol 2007
Fat as Multi-System Target
Kraus and Klein, Adipocytes 2005