Genetics of Obesity: The thrifty gene hypothesis

A look at the genetics and epigenetics of Obesity and the Thrifty Gene hypotehsis

1. The Thrifty Gene Hypothesis

2. James Neel-1962
Genes that predispose us to obesity
were advantageous in early human
history when starvation was an issue.
Early Humans went through cycles of
feast and famine and thus more
efficient at food storage and utilization
were more likely to survive and
reproduce during famine.

3. Feast-Famine Cycle

4. Physical Activity
Chakravarthy and Booth (2004)
Physical activity was as important as food related
adaptations
Early humans went through Physical-Activity cycle
that mimics feast-famine cycle physiologically.
People who were more capable physically of
surviving the hunt or gathering food, would
survive and pass down their genetics

5. Physiological response to Feasting and Recovery from
Exercise, as well as to Famine and Exercise are
remarkably similar
Combined these similar processes provide a much
larger genetic drive for “thrifty genes”
Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and evolutionary understanding
of modern chronic diseases. J Appl Physiol, 96(1), 3–10.

6. Feast-Famine and Physical
Activity Cycle Model
Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and evolutionary understanding
of modern chronic diseases. J Appl Physiol, 96(1), 3–10.

7. Modern Problem
Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and evolutionary understanding
of modern chronic diseases. J Appl Physiol, 96(1), 3–10.

8. Critiques and Problems

9. Complex-Not just one gene

10. The Natural Selection Driver
Death
Minor famine’s occurred
frequently throughout
history, but severe
Famines much less
frequent (~150years)
Birth
During even minor
famine’s, reproduction is
reduced because lower
body fat intake
negatively impacts
reproduction
Prentice, A. M., Hennig, B. J. & Fulford, A. J. (2008). Evolutionary origins of the obesity epidemic: natural selection of thrifty
genes or genetic drift following predation release? International Journal of Obesity, 32, 1607–1610.

11. When did genetic changes
start?
Hunter-Gather era
Rate of selection calculations show that 99% of us
would have the thrifty genes if started back then.
(Speakman, 2008).
Why aren’t we all fat?
Thrifty genes not meant to make fat, but rather enhance
fuel storage, utilization, and efficiency.
Agricultural era
Genes related to glucose and fat metabolism have
been positively selected within the last 10,000
years (Voight, 2006)

12. We all have thrifty genes?
Stoger Thrifty phenotype hypothesis
because energy efficiency and fitness was
essential to early man, “unthrifty” genes
never were allowed to become established
Endurance hypothesis (Brambley and
Lieberman, 2004)

13. If we all have thrifty
genes, then why is
obesity seemingly
more heritable in
certain groups like
the Pima Indians?

14. Thrifty Epigenome: The
missing link?
Old theory: Have the gene or don’t
New theory: The function (the degree of
expression) of the gene matters
Epigenetics- manipulates how the gene functions
(whether it’s turned on/off, and the degree of
transcription)
Genome=Hardware
Epigenome=Software
Most susceptible to change while fetus is in development
Genetic imprinting- can be passed on for a couple
generations
Short term adaptation to the environment

15. Epigenome adapts to the predicted
environment when in utero.
Mother experiences famine, epigenome
overeacts and up regulates genes for food
storage and utilization

16. Mismatch
When
predicted
environment
does NOT
equal actual
environment
disease
(obesity)
occurs
Godfrey, K. M., Lillycrop, K. A., Burdge, G. C., Gluckman, P. D. & Hanson, M. A. (2007). Epigenetic mechanism and the mismatch concept of the
developmental origins of health and disease. Pediatric Research, 61(5), 5–10.

17. Evidence
Ravelli et al. (1976)
Obesity much higher in individuals whose
mother went through famine during
pregnancy
Dong et al. 2005)
Found Genetic imprinting in obesity related
genes

19. Conclusion
Obesity is a polygenic problem
Very complex- not a single gene issue
It not only matters whether one has a combination of
genes, but how they function.
Eaton et al. (1988) put it best when they said that
we have “ ‘Stone Age’ genes and ‘Space Age’
circumstances.”
Physical Activity and food were likely intricately linked
from the start of mankind and it’s a mistake to
consider one and not the other.

20. References
 Bramble, D. M. & Lieberman, D. E. (2004). Endurance running and the evolution of Homo. Nature, 432, 345–352.
 Bribeescas, R. G. (2001). Serum leptin levels and anthropmetric correlates in ache Amerindians of eastern Paraguay. Am J Phys
Anthropol, 115, 297–303.
 Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and
evolutionary understanding of modern chronic diseases. J Appl Physiol, 96(1), 3–10.
 Dong, C., Lie, W. D., Geller, F., Lei, L., Li, D., Gorlova, O. Y., Hebebrand, J., Amos, C. I., Nichols, R. D. & Price, R. A. (2005).
Possible Genomic Imprinting of Three Human Obesity–Related Genetic Loci. The American Journal of Human Genetics, 76(3),
427–437.
 Eaton, S. B., Konner, M. & Shostak, M. (1988). Stone agers in the fast lane: chronic degenerative diseases in evolutionary
perspective. Am J Med, 84, 739–749.
 Godfrey, K. M., Lillycrop, K. A., Burdge, G. C., Gluckman, P. D. & Hanson, M. A. (2007). Epigenetic mechanism and the mismatch
concept of the developmental origins of health and disease. Pediatric Research, 61(5), 5–10.
 Midgeley, A. W., McNaughton, L. R., & Jones, A. M. (2007). Training to enhance the physiological determinants of long-distance
running performance: can valid recommendations be given to runners and coaches based on current scientific knowledge. Sports
Med, 37(10), 857–880.
 Neel, J. V. (1962). Diabetes mellitus a ‘thrifty’ genotype rendered detrimental by ‘progress’? Am J Hum Genet, 14, 352–353.
 Prentice, A. M., Hennig, B. J. & Fulford, A. J. (2008). Evolutionary origins of the obesity epidemic: natural selection of thrifty
genes or genetic drift following predation release? Internationa Journal of Obesity, 32, 1607–1610.
 Prentice, A. M. (2005). Starvation in humans: evolutionary background and contemporary implications. Mech Ageing Dec, 126,
976–981.
 Ravelli, G. P., Stein, Z. A. & Susser, M. W. (1976). Obesity in young men after famine exposure in utero and early infancy. N Eng
J Med, 295, 349–353.
 Speakman, J. R. (2008). Thrifty genes for obesity, an attractive but flawed idea, and an alternative perspective: the ‘drifty gene’
hypothesis. International Journal of Obesity, 32, 1611–1617.
 Stoger, R. (2008). The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes? BioEssays, 30(2),
156–166.
 Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. (2006). A map of recent positive selection in the human genome. PLoS
Biol, 72.