Starvation is among the most ancient of selection pressures. Starvation defenses activated when nutrients become scarce permit animals to survive until nutrients are plentiful again. The thrifty gene hypothesis suggests that genes evolved to permit starvation survival in times of feast or famine are maladaptive today when nutrients are abundant, predisposing individuals to obesity and associated diseases such as type 2 diabetes and cancer. 

 

The Soukas Lab identified a thrifty genetic pathway that activates doubling to tripling of starvation survival when protein translation genes are inhibited. This work, published in 2017 in Cell Reports, identified connections of cellular proteostasis machinery (the genes that regulate protein balance) to fat balance and starvation survival. Turning off protein synthesis tripled fat stores and starvation survival while turning off proteasomal genes, which encode gene products that degrade proteins, led to very low body fat stores and tremendous shortening of starvation survival. 

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Surprisingly, the proteostasis machinery controls starvation survival not through increasing the amount of protein breakdown products (amino acids) available as fuels, but rather by activating the master starvation regulator AMPK. AMPK in turn is the key executor of starvation defenses. 

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In the Soukas Lab, we continue to work on the 475 genes that emerged from our genome-wide screen for fat regulatory genes, with particular emphasis on those genes that modulate starvation survival. We hypothesize that genes that evolved to help organisms survive starvation may play a role in the development of obesity and diabetes.