Genetics of Obesity

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Genetics of Obesity
Kathy Mountjoy Molecular Medicine Physiology,
University of Auckland New Zealand
Mountjoy, Kyiv 2003
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Energy Homeostasis
BODY WEIGHT
Increase Decrease
ENERGY INTAKE Ingestion of Protein Fat Carb
ohydrate
ENERGY EXPENDITURE Physical Activity Diet
induced Thermogenesis Basal Metabolic Rate
Body weight maintained through complex mechanisms
ensuring a constant supply of energy for cellular
functions.
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World Wide Obesity Epidemic

• In the last decade, the incidence of obesity has
  increased by 1/3.
• 154 million people worldwide suffer from obesity
• 300,000 people die of obesity-related diseases in
  the USA every year.
• In NZ, 55 Maori men and 42 Maori women over 40
  years are obese.
• Children and adolescents are not immune to the
  obesity epidemic.
• Obesity is a serious life threatening DISEASE and
  a major risk factor for type II diabetes, heart
  attack, stroke, and some types of cancer,
  including breast and colon cancers.
• Today, there are no safe and well tolerated drugs
  available to induce long-term weight loss.

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Interaction of Genes and Environment
GENES
ENVIRONMENT
Spontaneous mutation rate 0.5 /million
years Over 10,000 years 0.005 change
Over 10,000 years Major changes in diet and
lifestyle
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50 Years on since the discovery of DNA
Genes are not just units of heredity. They are
exquisite mechanisms for translating experience
into action. Because of the way their promoters
switch on and off in response to external
instruction, genes are very far from being fixed
in their actions. They are devices for
extracting information from the environment,
every minute, every second, the pattern of genes
being expressed changes. Genes are the
mechanisms of experience. Matt Ridley
2003 Nature via Nurture
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Current Epidemic of Obesity

• Net result of over-consumption of food, increased
  energy efficiency and reduced physical activity.

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Monogenic Rodent Models of Obesity
Mutation Genotype
Gene Obese ob/ob mice
leptin Diabetes/Fatty db/db
mice, fa/fa rats leptin receptor Agouti
Ay/a, AVY/a Agouti protein Fat
fat/fat CpE Tubby
tub/tub Tubby
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Lipostatic Theory - 1953Suggested a circulating
factor acts on the brain to inhibit food intake
and adiposity.
Mountjoy, Kyiv Presentation 2003
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Impact of Mouse Genetics on understanding
appetite and body weight regulation

• Ob/ob mouse - spontaneous mutation that caused
  obesity
• Leptin(ob/ob) gene cloned in 1994

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Dominant Agouti Yellow obese mouse and non-agouti
lean black mouse

• Ectopic production of agouti protein
• antagonises a-MSH -
• in skin to give a yellow coat colour
• in brain at the MC4R to give obesity

AVY/a
a/a
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MSH Induced Pigmentation in AVY/a Mice
NDP-MSH treated
Untreated

• a-MSH induced pigmentation is most marked in Ay
  mice and not observed in e /e mice (Geshwind,
  1966)

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Agouti Banding
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Mouse Genetics
Understanding the genetics of the Dominant Agouti
Yellow Obese mouse was fundamental to our
understanding of the roles for melanocortin peptid
es and melanocortin receptors in pigmentation and
obesity.
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Pro-opiomelanocortin (POMC)
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Ablation of POMC gene results in Obesity

• mutations in human POMC
• with recessive pattern of
• inheritance
• - red hair
• - hyperphagia
• - obesity
• mouse POMC knockout
• - obesity
• - impaired pigmentation

H Krude et al, Nature Genetics 19 155, 1998
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Mutations in POMC
BG Challis et al Human Molecular Genetics 11
1997, 2002
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Phenotypes of MC4-R and MC3-R Knockout Mice
MC4-R -/- obese, hyperphagic, hyperglycemic, hy
perinsulinemic, increased body length MC3-R
-/- increased fat mass, reduced lean
mass, increased feed efficiency,
reduced activity MC3-R -/- MC4-R
-/- significantly heavier than MC4-R -/-
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Morbid obesity associated with human MC4-R
mutations

• gt4 morbidly obese children have a mutation
  in
• one MC4-R allele
• most common known monogenic cause of human
  obesity
• Phenotype
• - hyperphagia starts at 8
  months
• - tendency toward tall statue
• - hyperinsulinemia
• - increased bone mineral density

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No evidence for human MC3-R mutations underlying
obesity or Type 2 diabetes

• two polymorphisms in human MC3-R coding
  identified
• Val81Ile and
  Lys6Thr
• neither associated with Type 2 diabetes in
• - French Caucasians (J Clin Endoc Metab 86,
  2895, 2001)
• - Maori Kindred with obesity and Type 2 diabetes
• (Wong et al, Diabetes Research
  Clinical Practice,
• 58 61-71, 2002)

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Parallels between monogenic rodent models of
obesity and human obesity
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The Melanocortin System plays a pivotal role in
energy homeostasis.
Knockout Mice POMC KO mice - obese MC3-R KO
mice - obese MC4-R KO mice - obese Human
Mutations POMC mutations (recessive) - 0bese MC4-
R mutations - 5 morbidly obese children
have point mutations in one allele
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Central Melanocortin System
RD Cone TEM 10, 211, 1999
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Long term regulation of body weight and adiposity
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Hypothalamic Modulation of Food Intake
Orexigenic
Anorexigenic

• NPY
• MCH
• Orexins
• AGRP
• Opioids
• Galanin
• ? Food intake
• ? Parasympathetic tone (? insulin)
• ? Sympathetic tone (?expenditure)
• ? Fat intake

CART CRH POMC ? a-MSH/MC4R Insulin GIP-1 Serotoni
n ? Food intake ? Parasympathetic tone (?
insulin) ? Sympathetic tone (? expenditure) ?
Fat oxidation
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Integration of Feeding-related signals from
adipose tissue, the gut, and the brain
SC Woods et al Science 280 1378, 1998
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Short term regulation of feeding

• Taste perception
• Meal size
• Satiety or increased appetite - regulated by
  nutrient, neural and peptide signals arising from
  gut and pancreas
• Signals emanating from GI system and energy
  stores are received and integrated by diverse
  neuronal circuits in the hypothalamus and
  brainstem.

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Gut Peptides - Satiety Signals
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Regulation of satiety by insulin, glucose

• Increased glucose levels following food intake
• Increased b cell production of insulin
• Arcuate nucleus - hypothalamus - glucose and
  insulin sensing neurons that inhibit food intake

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Regulation of satiety by GI factors

• Stimulation of gut peptide secretion by
  chemicals/nutrients and mechanical stretching
• Meal size
• Satiety - mainly regulated by nutrient, neural
  and peptide signals arising from gut
• Signals emanating from GI system and energy
  stores are received and integrated by diverse
  neuronal circuits in the hypothalamus and
  brainstem.

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Many gut peptides decrease food intake and
require intact brainstem for satiety effect

• Cholecystokinin (CCK)
• Enterostatin
• Bombesin
• Gastric inhibitory peptide (GIP)
• Neuromedin B

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One gut peptide, PYY3-36 regulates satiety
through hypothalamic neurons

• PYY3-36 is stimulated in GI tract following food
  intake
• PYY3-36 signals NPY-Y2 receptors in arcuate
  nucleus to inhibit food intake

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Ghrelin is a gut peptide that stimulates appetite
- mediated through hypothalamus

• Ghrelin is stimulated in GI tract during periods
  of fasting
• Ghrelin signals GHS receptors in arcuate nucleus
  to stimulate food intake

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Genome Scans Focusing on Human Obesity
Chr 2 Mexican Americans, French
POMC African Americans, Caucasians Chr
3 Caucasians, Native Americans, African
Americans, South Pacific Islanders Chr
5 Western European Origin African Americans Chr
8 Mexican Americans, Caucasians b3 Adrenergic
receptor Chr 10 Caucasians, South Pacific
Islanders Chr 17 Caucasians, Mexican
Americans Chr 20 Native Americans, Caucasians
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Conclusion

• Obesity represents a complex biological
  phenomenon.
• Consistent pattern of QTLs across several
  different populations of ethnic groups suggest
  that there are a small number of obesity-related
  genes with common effects across populations.
• Future anti-obesity drugs targeted to
  neuro-humoral pathways identified from mouse
  genetic studies.

Mountjoy, Kyiv 2003