The Thrifty Gene
Theory
By Aimee Velk

What is the thrifty gene theory?

posits that the human genome is evolved
for survival in the late Paleolithic era
(50,000 to 10,000 BC)

humans were subject to intermittent bouts
of feast & famine and constant physical
activity

early humans may have benefitted by
prioritizing storage of nutrients during
times of plenty

That’s not beneficial today.

sedentary lifestyle + abundant energydense diet

Genetic adaptation may not occur as fast
lifestyle change

Possible link to modern increase in
T2DM & obesity

What is meant by the thrifty gene?

Collective term for storage-promoting
action

Perixisome proliferator-activated
receptor (PPAR) transcription factor

Ligand-activated receptors

What is meant by the thrifty gene?

protein (3 isoforms, ą, γ, & δ,) which
influences genetic expression

acts on region of genome associated
with metabolic genes

i.e. they influence genetic expression
during the construction of mRNA inside
the nucleus of a cell
The Clinical Studies
Intervention 1

13 dyslipidemic men
w/ central obesity

Received dose of PPARδ agonist or placebo

Focused on effect of
PPAR- δ on lipoprotein
metabolism
Intervention 2

8 healthy 25 yo. men

All subjects fasted
intermittently for 15
days

Focused on possible
link b/w PPAR-γ &
insulin sensitivity
Intervention 1: PPAR-δ

3-wk. wt. maintenance before study

6-wk double-blind crossover trial
w/2-wk wash-out period b/w trials

Serum concentrations of lipoproteins
were averaged
Results

PPAR-δ activity induced by agonisit:

decreased TAG content of
lipoproteins

positively changed LDL composition
Mean VLDL, IDL, LDL, and HDL triglyceride (A) and cholesterol (B) content ± sem during
placebo (closed square) and GW501516 (open square). *, P < 0.05.
Ooi E M M et al. JCEM 2011;96:E1568-E1576
©2011 by Endocrine Society
Relevance

Ligand activation of PPAR-δ may
result in favorable genetic regulation
of lipid metabolism

Evidence of a strong relationship
between PPAR-δ and lipid
metabolism supports the thrifty gene
hypothesis.
Intervention 2: PPAR-γ

Intermittent Fasting for 15 days:
-fasting for 20 hrs every other day
for 15 days

Measured insulin response in subjects
before and after trial
Results

After Fasting:
-Increased glucose infusion rate
-steadier blood glucose levels
Relevance

Faster glucose infusion rate
demonstrates better insulin function,
increased sensitivity

Steady BG demonstrates better
glucose control
Limitations

Small, 13 participants and 8
participants

Limited to 1 demographic
Questions?