Understanding Obesity Genes and Environment in the Determination of Body Weight Prof. Rudy Leibel

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1 Understanding Obesity Genes and Environment in the Determination of Body Weight R. Leibel Division of Molecular Genetics and Naomi Berrie Diabetes Center Columbia University 1 Why Is Body Weight (Fat Mass) Regulated? UP Reproduction Environmental vicissitudes DOWN Predator evasion WA GES OF EVOLUTION Defense against loss of fat mass >> gain 2 Adiposity(u) f(q) f(w) Past Present 3 The screen versions of these slides have full details of copyright and acknowledgements 1

2 Ligand Receptor Both A 0 A 1 A 2 B 0 B 1 B 2 A1 + B 1 mild phenotype severe phenotype gene environment 4 Barsh and Schwartz, Nature Rev Genetics, 3:589, 2002 X VMN: profound obesity X LHA: anorexia, weight loss 5 Hormone secreted from fat in proportion to mass = cell size x number LEPTIN 6 The screen versions of these slides have full details of copyright and acknowledgements 2

3 Barsh and Schwartz Monogenic Forms of Obesity Human rare Leptin rare Leptin receptor rare rare PC1 4-6% of severe human obesity POMC α-msh MC4R Food Intake ob/ob db/db KO Cpe ASP A y KO Energy Expenditure fat/fat Rodent 8 Barsh and Schwartz The screen versions of these slides have full details of copyright and acknowledgements 3

4 Multiple Biological Effects of Leptin in Humans Food intake Onset of puberty Energy intake (KJ)/ kg lean mass LH (IU/L) months months Before Wt = 42 kg at 3 yrs After Wt = 31 kg at 7 yrs Farooqi et al., JCI. 2002;110:1093 and Farooqi et al., Nature 2001;414:34 10 LEPTIN RECEPTOR P roband H D416 D HD416 HEIGHT WEIGHT Barsh and Schwartz The screen versions of these slides have full details of copyright and acknowledgements 4

5 POMC 35 Girl s weight 30 Boy s weight 82 P P97 P90 P75 P50 P25 P10 p P90 P75 P50 P25 P10 p Age (months) Age (years) Patient A 14 MC4R Mutations Result in a Dominantly Inherited Obesity Syndrome Increased linear growth 9 yr old proband 16 yr old wild type brother Hyperphagia Mean adlibitum energy intake (KJ/kg lean mass) *** wild-type controls Age (yrs) Increased bone mineral density BMD g/cm Farooqi et al., NEJM 2003,348: Age (years) 15 The screen versions of these slides have full details of copyright and acknowledgements 5

6 Mutations in MC4R Represent the Commonest Monogenic Human Obesity Syndrome Farooqi et al., NEJM 2003,348: Barsh et al., Nature 404:644, The screen versions of these slides have full details of copyright and acknowledgements 6

7 Dizygotic twins 19 Monozygotic twins 20 Mexican American African American C PE H anis CPE4 CPE8 obese lean Loyola ENK1 ENK2 obese lean -604G/A Ghr elin G1939A Arg51Gln Leu72Met PPAR1 PPA R PPAR1A ga mma PPAR6 En kephalinb ENK4-1 ENK4-2 ENK4-3 NPY1 NPY NPY3 OXR1-1 OXR1-2 Or exin OXR3-1 r eceptor OXR3-1b OXR3-2 OXR5 OXR7 21 The screen versions of these slides have full details of copyright and acknowledgements 7

8 Caucasian C PE L EPR M C 3 R M C 4 R PPA R ga mma CPE4 CPE3 Gln223Arg Lys656Asn Val81Ile MC4R3 PPAR1 PPAR1A PPAR6 I owa Adult Child obese lean obese lean 22 BMI as a Function of Age, Sex, and rs Genotype INSIG2 2q CC GG+GC Age Category (years) CC GG+GC Age Category (years) CC GG+GC A. Herbert et al., Science 312, (2006) Age Category (years) LEPR CART MSH MC4R LEPTIN 24 The screen versions of these slides have full details of copyright and acknowledgements 8

9 PER C ENT BODY FAT Adjusted for A ge (39 ( days) 22 PER C ENT BODY FAT /+ (n = 56) db/+ (n = 51) ob/+ (n = 9) db/+ob/+ (n = 5) GENOTYPE 25 Leptin Threshold Effects Signal Threshold Impedance: LEPR, CPE, POMC, AGRP, MC4R, etc. 26 Bioenergetics of Reduced Body Weight Calories per Day Needed to Maintain Weight * * Thin Average Heavy Obese Fat-Free Mass (kg) 27 The screen versions of these slides have full details of copyright and acknowledgements 9

10 Biological Response (Energy Intake) NPY AGRP MCH OREXIN MC4R POMC CRF CART Concentration of Leptin 28 Is Threshold Changeable? Leptin Concentration VMH lesion Chronic weight increase Neuronal loss of aging Puberty initial LH lesion Anorexia nervosa Cachectic illness Fat Mass 29 Simerly et al., Science The screen versions of these slides have full details of copyright and acknowledgements 10

11 CNTF Reduces Body Weights Long Term and Ind uces Cell Proliferation in the Hypothalamus M. V. Kokoeva et al., Science 310, (2005) Published by AAAS 31 Investigators Columbia University University of Pennsylvania Krista Vandenborne Rockefeller University Jules Hirsch Mike Rosenbaum Wendy Chung Stuart Weisberg Dan University Bloomfield of Laval Streamson Chua Mount Sinai Tony Hosp Ferrante Rochelle Jean-Amie Goldsmith Simoneau Yiying ZhangCharles Manisha Mobbs Desai Sanobar Denis Joanisse Parkar Wahida Karmally Naoki Matsuoka Loan Phan Dan McCann Media Weill Medical Berghout College Sharon Wardlaw Dwight Lou Aronne Matthews Solveig Halldorsdottir Judy Korner EmersonWhittington NYORC Amgen Inc. Steve Alex DePaoli Heymsfield Liyong Deng Trish Lanzano Xavier Pi-Sunyer Carol Boozer Harry Kisilieff 32 THANKS Extreme and/or familial obesity Obesity with short stature or developmental delay 33 The screen versions of these slides have full details of copyright and acknowledgements 11

12 34 The screen versions of these slides have full details of copyright and acknowledgements 12