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

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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

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

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“The will is by its nature so free that it can never be constrained"

(Passions of the Soul, I, art.41).

• R. Descartes

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50 100 150 200 250 300 Energy intake (KJ)/kg lean mass 2 4 6 8 10 12 14 16 12 months 24 months 2000 2200 2400 0200 0400 0600 0800 LH (IU/L)

Onset of puberty Food intake

Multiple biological effects of leptin in humans

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 BODY

Environment

Adiposity

Thermodynamics

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Prader Willi Syndrome

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

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Barsh and Schwartz 2002

POMC

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Barsh and Schwartz 2002

Patient A

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MC4R Mutations Result In A Dominantly Inherited Obesity Syndrome

50 100 150 200 250 0-5 6-10 11-15 wild-type controls *** Age (yrs) Mean adlibitum energy intake (KJ/ kg lean mass)

INCREASED LINEAR GROWTH 9 YR OLD PROBAND 16 YR OLD WILD-TYPE BROTHER HYPERPHAGIA INCREASED BONE MINERAL DENSITY Farooqi et al, NEJM 2003,348:1085-10

Barsh et al. Nature 404:644, 2000

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10

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PPAR6 PPAR1A PPAR1

PPAR gamma

Leu72Met Arg51Gln G1939A

• 604 G/A

Ghrelin

CPE8 CPE4

CPE

lean

• bese

Hanis OXR7 OXR5 OXR3-2 OXR3-1b OXR3-1 OXR1-2 OXR1-1

Orexin Receptor

NPY3 NPY1

NPY

ENK4-3 ENK4-2 ENK4-1 ENK2 ENK1

EnkephalinB

lean

• bsese

Loyola

Mexican American African American

PPAR6 PPAR1A PPAR1

PPAR gamma

MC4R3

MC4R

Val81Ile

• 201
• 762
• 769

MC3R Lys656Asn

Gln223Arg LEPR

CPE8 CPE4

CPE

control

• bese

control

• bese

Child Adult IOWA

Caucasian

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Ligand Receptor Both A0 A1 A2 B0 B1 B2 A1 + B1 mild severe gene environment phenotype phenotype

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THANKS

RL232@columbia.edu

Extreme and/or familial obesity Obesity with short stature or developmental delay

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O L O L

THANKS

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I.

The vegetative brain (hypothalamus) participates in energy homeostasis

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

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IV.

Free Will and Body Weight

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Cartesian Issues Relating to Control

• f 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”)

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

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Barsh and Schwartz 2002 Barsh and Schwartz 2002

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Schwartz nature 2002

Human LEPR Mutation Human Human LEPR Mutation LEPR Mutation

TM TM E Extracellula

xtracellular

r

Cytoplasmic Cytoplasmic

C C Domain Domain C C Domain Domain Box 1 Box 1 Box 2 Box 2

N N C C

Splice Splice Site Site for for huB219.1 huB219.1 huB219.2 huB219.2 huB219.3 huB219.3 Ob-Rb Ob-Ra Ob-Rc Ob-Rd

Normal Normal Leptin

Leptin

receptor receptor Isoforms Isoforms

Ob-Rb Ob-Ra Ob-Rc Ob-Rd

Mutated Mutated Leptin Leptin receptor receptor Isoforms Isoforms

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10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180

H EIG H T W EIG H T

Proband HD416

LEPTIN RECEPTOR

Barsh and Schwartz 2002