Therapeutic Modulation of Adipose Tissue Mass and Function

Therapeutic Modulation of Adipose Tissue Mass and Function Johannes Klein, MD Ph. D 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 p for trend = 0. 007 2. 0 1. 5 2. 06 2. 31 2. 44 1. 27 1. 0 0. 5 0. 0 <69. 8 -<74. 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 Glut 4 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, 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-met. Hu. Leptin 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 Protein Leptin Secretion (µg/l/day) 3 l-b C l sa Ba 1 n. M 3 m. RNA l-b C t. ro op l sa Basal Is 7 6 5 4 3 2 1 Hormone Secretion Thermogenesis Ba Glucose Uptake (x Basal) Insulin Sensitivity 10 n. M 100 n. M 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