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, https://us.fotolia.com/id/64121171.

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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]

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

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

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

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

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

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

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.

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

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.

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, https://us.fotolia.com/id/117838736.

What about his weight? How does it compare to other boys? Data from: http://www.cdc.gov/growthcharts/cdc_charts.htm

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

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

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

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

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.

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

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

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]

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]

Sequencing Receptor No mutations

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

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

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

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

Predict child’s outcome with leptin treatment Data from: http://www.cdc.gov/growthcharts/cdc_charts.htm Data from: Wabitsch M et al. N Engl J Med 2015;372:48-54

Child’s weight after leptin treatment Data from: http://www.cdc.gov/growthcharts/cdc_charts.htm Data from: Wabitsch M et al. N Engl J Med 2015;372:48-54

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