Thrifty genes for obesity and the metabolic syndrome — time to call off the search?

Abstract

Over the last 50 years there has been a major epidemic of obesity and associated co-morbidities, the so-called ‘metabolic syndrome’, mostly in the western world but with an increasingly global dimension. The development of such chronic diseases has a strong genetic component, yet the timescale of their increase cannot reflect a population genetic change. Consequently, the most accepted model is that obesity and its sequelae are a result of a gene-environment interaction, an ancient genetic selection to deposit fat efficiently that is maladaptive in modern society. Why we have this genetic predisposition has been a matter of much speculation. Following the seminal contribution of Neel, 1 there has been a broad consensus that over evolutionary time we have been exposed to regular periods of famine, during which fatter individuals would have enjoyed a selective advantage by their greater survival. Consequently, individuals with genes promoting the efficient deposition of fat during periods between famines (‘thrifty genes’) would be favoured. In the modern environment this genetic predisposition prepares us for a famine that never comes, and an epidemic of obesity with all the attendant chronic illnesses follows. In this review I present details of the evidence supporting the famine hypothesis and then show that this idea has five fundamental flaws. In essence, famines are a relatively modern phenomenon and occur only about once every 100–150 years. Consequently, most human populations have only experienced at most 100 famine events in their evolutionary history. Famines involve increases in total mortality that only rarely exceed 10% of the population. Moreover, most people in famines die of disease rather than starvation and the age distribution of mortality during famine would not result in differential mortality between lean and obese individuals. A simple genetic model shows that famines provide insufficient selective advantage over an insufficient time period for a thrifty gene to have any penetration in the modern human population. Over the 40 or so years since Neel proposed the thrifty gene hypothesis, no convincing candidates for these genes have been discovered. My analysis suggests that perhaps it is time to call off the search.