Animal Models of Obesity

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Animal Models of Obesity
The ob/ob mouse. The db/db mouse. The agouti
mouse.
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First, an interesting story about fat mice.
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Animal Models of Obesity

• first and second animal models of obesity were
  identified by an animal technician at Jackson
  Laboratories
• both types of obese mice were due to a
  spontaneous genetic mutation
• called obese mouse (ob/ob mouse) and the
  diabetic mouse (db/db mouse)

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Animal Models of Obesity

• first identified by Coleman at the Jackson Lab
  (Bar Harbor, Maine) in 1950s
• obese mice show a distinctive obese phenotype
• litter characteristics suggested that the
  mutation involved a single gene
• about ¼ of each litter developed obesity
• ob/ob mouse obese
• OB/OB mouse lean
• OB/ob mouse lean
• subsequently discovered that the mutation was
  on chromosome 6

1) The ob/ob Mouse

• involves the gene that encodes ob protein
  (leptin)

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• PHENOTYPE OF THE ob/ob MOUSE
• defect in thermogenesis by P3
• fat mass is increased by P14
• hyperphagia and obesity by P21 (increase in
  meal size)
• hypothermic as adults
• hyperglycemic
• mild increase in plasma insulin
• mild form of diabetes
• decreased metabolic rate
• decreased activity (?)

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Leptin Decreases Body Weight in Obese and Lean
Rats
Genetically Obese Mouse Vehicle
Genetically Obese Mouse Leptin
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Animal Models of Obesity
2) The db/db Mouse

• phenotype was also identified in the 1950s
• diabetic mice show a distinctive obese phenotype

• litter characteristics suggested that the
  mutation involved a single gene
• about ¼ of each litter developed obesity
• db/db mouse obese
• DB/DB mouse lean
• DB/db mouse lean
• subsequently discovered that the mutation was
  on chromosome 4
• involves the gene that encodes the long form of
  the leptin receptor (Ob-R)

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• PHENOTYPE OF THE db/db MOUSE
• diabetic mice show a distinctive phenotype
  (very similar to ob/ob mouse)
• fat mass is increased by P14
• hyperphagia and obesity by P21
• hypothermic as adults
• hyperglycemic
• hyperinsulinemic
• diabetic
• decreased metabolic rate

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Animal Models of Obesity

• 3) Agouti Mouse (AY/a)
• phenotype was identified in the 1960s
• these mice show a distinctive obese phenotype
• obesity is due to a mutation in the gene
  (agouti) that is expressed on chromosome 2 and
  encodes agouti protein
• dominant mutation results in ectopic expression
  of agouti protein

Wild type
Agouti
Interesting genetics heterozygote (Ay/a)
obese/yellow homozygote (Ay/Ay)
fatal homozygote (a/a) lean/black
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• PHENOTYPE OF THE AGOUTI MOUSE
• hyperphagia and obesity by 6-8 weeks (adult
  onset)
• obesity is mild to moderate enhanced by a high
  fat diet
• hyperinsulinemic
• increased linear growth long tails
• decreased metabolic rate
• normal thermoregulation
• activity levels have not been studied
• yellow coat color at birth
• unaffected litter mates have a black coat color

Agouti

• WHY A YELLOW COAT ???
• normally, agouti protein is expressed only in
  hair follicles and the testes
• over-expression of agouti protein peripherally
  produces yellow hair pigment - results in yellow
  coat color
• expression of agouti protein centrally
• produces the obese phenotype

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• obesity arises because agouti protein is an
  endogenous antagonist of MC4-R
• antagonism of MC4-R produces
• hyperphagia
• decreased metabolic rate
• insensitivity to leptin
• together, this produces an
• obese phenotype

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agouti
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