1. Eating Himself to Death:
NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE
Eating Himself to Death:
Leptin Signaling Gone Wrong by
Michèle I. Shuster
Department of Biology
New Mexico State University
Las Cruces, NM
Licensed image ©aleutie|Fotolia,

2. video

3. CQ#1: Which of the following could cause a mouse to be obese?
Inability to produce leptin.
Leptin is produced, but mutated so that it doesn’t work.
Too much leptin is produced.
Leptin receptor is altered and can’t bind leptin.
More than one answer above is correct. [be prepared to discuss and justify]

4. CQ#2: If no leptin, then…
Obese
Normal weight
Under weight

5. CQ#3: If leptin is made, but can’t bind its receptor, then …
Obese
Normal weight
Under weight

6. CQ#4: If leptin is made, but can’t bind its receptor, then leptin levels will be …
High
Low
[be prepared to explain]

7. CQ#5: If leptin is overexpressed, then …
Obese
Normal weight
Under weight

8. CQ#6: If leptin receptors are altered and can’t bind leptin, then…
Obese
Normal weight
Under weight

9. CQ#7: If leptin receptors are altered and can’t bind leptin, then leptin levels will be …
High
Low

10. The case…
From New England Journal of Medicine, Martin Wabitsch, Jan-Bernd Funcke, Belinda Lennerz, et al, Biologically Inactive Leptin and Early-Onset Extreme Obesity, 372, 48, Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

11. Bouncing Baby Boy! Born at 40 wks of gestation (normal)
Normal birth weight
3680 grams (about 8 lbs)
Began to gain weight rapidly

12. Eating Behavior As an infant As a toddler
Cried (hard!) if not breast fed every hour during the day and once every night.
As a toddler
More interested in food than friends/play.
Family had to hide food.
Family had to be very strict about diet.

13. Eating Trial Allowed to eat as much as he wanted
From array of breakfast foods
Ate 680 Calories
279 Cals is average for that age
Clear case of hyperphagia
Licensed image ©Squirrel|Fotolia,

14. What about his weight? How does it compare to other boys?
Data from:

15. Our child’s weight by age
Age (mos)
Weight (kg) 2 6 14 12 18 22 24 26 30 33 36 42 48
Data from Wabitsch M et al. N Engl J Med 2015;372:48-54

16. Data from: http://www.cdc.gov/growthcharts/cdc_charts.htm
Data from: Wabitsch M et al. N Engl J Med 2015;372:48-54

17. What about his BMI? What is his BMI? At age 2.5 yrs
Overweight?
Obese?
At age 2.5 yrs
33 kg
0.94 m tall (69th percentile for height)
BMI = weight in kg/(height in meters)2

18. CQ#8 According to the BMI calculation, the child is best described as:
Off the charts!!!
CQ#8 According to the BMI calculation, the child is best described as:
Underweight
Healthy weight
Overweight
Obese

19. So let’s assume there is a problem with leptin signaling
Generate specific hypotheses about the problem in leptin signaling in this child as well as ideas for how you could test your hypotheses.

20. Measure leptin levels Normal (for amount of adipose tissue)
i.e. elevated due to high adipose
Which hypothesis does this rule out?

21. What are we left with? Non-functional leptin Non-functional receptor
How to distinguish?

22. If he had a leptin protein mutation
Changes structure of leptin molecule (non-functional)
Leptin can’t bind to receptor
CQ#9: Would leptin injections be a viable therapy?
Yes No
[be prepared to explain]

23. If he had a leptin receptor mutation
Leptin can’t bind
Or if it can bind, receptor can’t activate
CQ#10: Will leptin injections be a viable therapy?
Yes No
[be prepared to explain]

24. Sequencing
Receptor
No mutations

25. Leptin Sequences (portion of the leptin gene)
Patient on top; wild type beneath
CAA ATA TCC AAC TAC CTG GAG AAC
CAA ATA TCC AAC GAC CTG GAG AAC
Can you find a difference?
Data from Wabitsch M et al. N Engl J Med 2015;372:48-54

26. Leptin Sequences (portion of the leptin gene)
Patient on top; wild type beneath
CAA ATA TCC AAC TAC CTG GAG AAC
CAA ATA TCC AAC GAC CTG GAG AAC
Can you find a difference?
Data from Wabitsch M et al. N Engl J Med 2015;372:48-54

27. Sequencing Leptin If leptin can’t bind receptor:
Mutation prevents binding to receptor
If leptin can’t bind receptor:
Is satiety signal received?

28. Treatment? What strategies may work?
General strategies for obesity & weight-loss
Specific/tailored to his situation
Leptin treatment

29. Predict child’s outcome with leptin treatment
Data from:
Data from: Wabitsch M et al. N Engl J Med 2015;372:48-54

30. Child’s weight after leptin treatment
Data from:
Data from: Wabitsch M et al. N Engl J Med 2015;372:48-54

32. video