The Genetics of Body Weight Regulation. Ethical Considerations . - PDF document

The Genetics of Body Weight Regulation. Ethical Considerations . Columbia University 19 May 2006 R. Leibel Division of Molecular Genetics Naomi Berrie Diabetes Center Columbia University • Are there “blameworthy” medical phenotypes? • Is obesity an example? If so, who is to blame? • Complex traits: medical phenotypes at the interface of genes and environment 1

1986 Hormone secreted from fat in proportion to mass = cell size x number LEPTIN 2

“The will is by its nature so free that it can never be constrained" (Passions of the Soul, I, art.41). R. Descartes 3

Onset of puberty Food intake Multiple biological effects of leptin Energy intake (KJ)/kg lean mass 16 LH (IU/L) 300 in humans 14 250 12 200 24 months 10 8 150 6 100 4 50 12 months 2 0 0 2000 2200 2400 0200 0400 0600 0800 Before After Wt = 42 kg at 3 yrs Wt = 31 kg at 7 yrs Farooqi et al. JCI. 2002;110:1093 and Farooqi et al. Nature 2001;414:34 BRAIN Adiposity Environment Thermodynamics BODY 4

Prader Willi Syndrome X LHA: anorexia, weight loss X VMN: profound obesity Barsh and Schwartz, Nature Rev Genetics, 3:589, 2002 5

Barsh and Schwartz 2002 POMC 6

Barsh and Schwartz 2002 Patient A 7

MC4R Mutations Result In A Dominantly Inherited Obesity Syndrome INCREASED LINEAR GROWTH HYPERPHAGIA 9 YR OLD PROBAND 16 YR OLD WILD-TYPE BROTHER Mean adlibitum energy intake (KJ/ kg lean mass) 250 *** 200 150 100 50 0 0-5 6-10 11-15 wild-type controls Age (yrs) INCREASED BONE MINERAL DENSITY Farooqi et al, NEJM 2003,348:1085-10 Barsh et al. Nature 404:644, 2000 8

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Hanis Loyola obese lean obsese lean CPE4 ENK1 CPE CPE8 ENK2 -604 G/A EnkephalinB ENK4-1 G1939A ENK4-2 Ghrelin Arg51Gln ENK4-3 Leu72Met NPY1 NPY PPAR1 NPY3 PPAR PPAR1A OXR1-1 gamma PPAR6 OXR1-2 OXR3-1 Orexin Mexican American OXR3-1b Receptor OXR3-2 OXR5 OXR7 African American IOWA Adult Child obese control obese control CPE4 CPE CPE8 Gln223Arg LEPR Lys656Asn -769 -762 MC3R -201 Val81Ile MC4R MC4R3 PPAR1 PPAR gamma PPAR1A PPAR6 Caucasian 11

Ligand Receptor Both A 0 A 1 A 2 B 0 B 1 B 2 A 1 + B 1 mild phenotype severe phenotype gene environment 12

THANKS RL232@columbia.edu Extreme and/or familial obesity Obesity with short stature or developmental delay 13

O L O L THANKS 14

I. The vegetative brain (hypothalamus) participates in energy homeostasis X LHA: anorexia, weight loss X VMN: profound obesity Barsh and Schwartz, Nature Rev Genetics, 3:589, 2002 15

IV. Free Will and Body Weight 16

Cartesian Issues Relating to Control of Body Energy Stores • Explicit signals emanating from the soma communicate with the brain •Endocrine (leptin, insulin, ghrelin, pyy, cck) •Neural (vagus) • The brain uses biochemical pathways parallel to those in the soma gauge systemic fuel status (AMP kinase; fatty acids; glucose) • The brain contains a physical analog of peripheral fuel storage cell(s) (“homunculus”) X LHA: anorexia, weight loss X VMN: profound obesity Barsh and Schwartz, Nature Rev Genetics, 3:589, 2002 17

Barsh and Schwartz 2002 Barsh and Schwartz 2002 18

Schwartz nature 2002 Human LEPR Mutation LEPR Mutation Human Human LEPR Mutation E xtracellula xtracellula r Cytoplasmic Cytoplasmic E r TM TM C Domain C Domain C Domain C Domain Box 1 Box 2 Box 1 Box 2 N N C C Splice Site Splice Site for for huB219.1 huB219.1 huB219.2 huB219.2 huB219.3 huB219.3 Normal Leptin Leptin Normal Mutated Leptin Mutated Leptin receptor receptor receptor receptor Isoforms Isoforms Isoforms Isoforms Ob-Ra Ob-Rb Ob-Ra Ob-Rc Ob-Rb Ob-Rc Ob-Rd Ob-Rd 19

180 170 H EIG H T 160 150 140 LEPTIN RECEPTOR 130 120 Proband 110 100 HD416 90 W EIG H T 80 70 60 50 40 30 20 10 0 Barsh and Schwartz 2002 20