A mathematical model of weight loss under total starvation: evidence against the thrifty-gene hypothesis

Abstract

SUMMARYThe thrifty-gene hypothesis (TGH) posits that the modern genetic predisposition to obesity stems from a historical past where famine selected for genes that promote efficient fat deposition. It has been previously argued that such a scenario is unfeasible because under such strong selection any gene favouring fat deposition would rapidly move to fixation. Hence, we should all be predisposed to obesity: which we are not. The genetic architecture of obesity that has been revealed by genome-wide association studies (GWAS), however, calls into question such an argument. Obesity is caused by mutations in many hundreds (maybe thousands) of genes, each with a very minor, independent and additive impact. Selection on such genes would probably be very weak because the individual advantages they would confer would be very small. Hence, the genetic architecture of the epidemic may indeed be compatible with, and hence support, the TGH. To evaluate whether this is correct, it is necessary to know the likely effects of the identified GWAS alleles on survival during starvation. This would allow definition of their advantage in famine conditions, and hence the likely selection pressure for such alleles to have spread over the time course of human evolution. We constructed a mathematical model of weight loss under total starvation using the established principles of energy balance. Using the model, we found that fatter individuals would indeed survive longer and, at a given body weight, females would survive longer than males, when totally starved. An allele causing deposition of an extra 80 g of fat would result in an extension of life under total starvation by about 1.1–1.6% in an individual with 10 kg of fat and by 0.25–0.27% in an individual carrying 32 kg of fat. A mutation causing a per allele effect of 0.25% would become completely fixed in a population with an effective size of 5 million individuals in 6000 selection events. Because there have probably been about 24,000 famine events since the evolution of hominins 4 million years ago, there has been ample time even for genes with only very minor impacts on adiposity to move to fixation. The observed polymorphic variation in the genes causing the predisposition to obesity is incompatible with the TGH, unless all these single nucleotide polymorphisms (SNPs) arose in the last 900,000 years, a requirement we know is incorrect. The TGH is further weakened by the observation of no link between the effect size of these SNPs and their prevalence, which would be anticipated under the TGH model of selection if all the SNPs had arisen in the last 900,000 years.

Measuring Energy Metabolism in the Mouse – Theoretical, Practical, and Analytical Considerations

“…I will therefore also draw on some examples in the literature of studies on such animals. Several other publications contain useful information on similar issues that are directly pertinent to the measurement of energy metabolism in the mouse and the reader may also wish to consult these, in particular the papers by Weir (1949), Kleiber (1961), Ferrannini (1988), Simonson and deFronzo (1990), Bursztein et al (1989), Elia and Livesey (1992), Even et al (1994), Arch et al (2006), Lighton (2008), Tschoep et al (2012), Even and Nadkarni (2012), Speakman et al (2013). …”

Mind the Gap: Race/Ethnic and Socioeconomic Disparities in Obesity

“…A considerable body of scientific evidence has shown that obesity is a heritable condition [55, 56]. Several decades ago, this observation led to the development of the “thrifty gene” hypothesis (TGH) [57], which posits that human populations subjected to millennia of feast-or-famine conditions naturally select for genes that promote rapid weight gain in times of food surplus.…”

“…First, human genes are only loosely tied to race/ethnic background; indeed, there is substantially more genetic variability within than between race/ethnic groups [60]. Second, while recent genome-wide association studies affirm that specific genes—including the fat mass and obesity associated gene ( FTO ) and melanocortin 4 receptor gene ( MC4R )—are associated with obesity [55], these associations are not consistently observed across race/ethnic groups and explain only a small proportion of population variability in body weight [55, 56, 61]. This makes the notion of a thrifty gene (or genes) seem unlikely as a singular explanation for large race/ethnic disparities in obesity.…”

If Body Fatness is Under Physiological Regulation, Then How Come We Have an Obesity Epidemic?

“…This idea has been called the thrifty gene hypothesis (11, 18, 41, 50, 56 -58, 77, 78). During complete starvation, individuals storing more fat can survive longer than individuals who store less (65,71), hence the thrifty gene hypothesis posits that, under conditions of uncertain food supply, genes promoting fat storage will be positively selected. The probability of a catastrophic failure of supply, however, diminishes as the duration of the period without food increases (FIGURE 3A).…”