The Thrifty Genotype/Phenotype Hypothesis is wrong

In 1962 James Neel proposes the Thrifty Genotype hypothesis and then the Thrifty Phenotype hypothesis as an addendum of sorts to the original theory. A thrifty gene uses resources carefully. It does not waste them, so the idea goes, because its predecessors dealt with famine by conserving energy. A thrifty phenotype however develops because of pre-natal (intrauterine) famine conditions which signal energy conservation. Given that modernity doles out virtually famineless environments, there is a consequent mismatch with this thrifty character trait. A life-saving adaptation comes back to bite us in the ass; diseases of civilization such as diabetes and obesity ensue. The simplicity of the mismatch hypothesis (an outgrowth of Darwin’s theory of natural seclection) lends undue credence to the Thrifty Gene and Thrifty Phenotype hypotheses, making them alluring, even palatable. Both are perfectly reasonable hypotheses but are wrong.

The hypothesis stumbles when its foundational assumption is challenged. The assumption is that Paleolithic humans feasted and were frugal with those calories to pre-empt recurring famines. The burden of proof clearly lies with proponents of this claim. Accordingly, Allen and Cheer say that “this is far from generally accepted. Nevertheless, the burden is not typically shouldered, most likely because of how entrenched Hobbes’ solitary, poor, nasty, brutish and short description of pre-agricultural societies has become. So what evidence is there for these recurring Paleolithic famines? Not much aside from flimsy extrapolations derived from observing modern hunter-gatherers struggling to feed themselves within dwindling hunting areas losing flora and fauna. There is strong evidence of famines reliably threatening humans once agriculture took off. Do we entertain such assumptions for other species? Not without pertinent climate or archeological evidence. Evidence suggestive of recurring famines seems entirely lacking for pre-Neolithic humans. Many find it hard to accept that the same innovation (farming) responsible for population explosions (putative progress) also regularly incurs famines (an obvious negative). Too bad.

The thrifty phenotype purports to stem from an increased propensity to store energy. It is only logical to consider how insulin dynamics may participate in this. Non-insulin dependent glucose uptake aside, the less insulin you need to get glucose into a cell, the more insulin sensitive you are. The more insulin sensitive you are, the more thrifty your genotype/phenotype, since you require less (insulin) to store a given amount of calories. Thriftiness is maintained in a famine not by being insulin sensitive but by being more insulin resistant. Specifically, you become more peripherally insulin resistant, prioritizing glucose shunting to your brain which cannot do without it. In other words, more of the limited available energy is used for essential functions (thriftiness). This insulin resistance is not pathological, unlike hyperinsulinemia-associated insulin resistance characterizing metabolic syndrome. Rather, the innate capacity to move along either extremes of the insulin sensitivity spectrum is central to how varying energy availability is handled. This thrifty hypothesis is problematic because it pathologizes a normal adaptation.

Watve and Yajnik raise 5 principle objections to the Thrifty genotype/phenotype hypothesis worth considering:

  1. Neel’s arrow of causality indicates that insulin resistance begets obesity. Watve and Yajnik argue obesity begets insulin resistance by pointing out how insulin sensitive Pima Indians are more likely to be overweight.

Point 1 is still an open question. Just as there are different ways one can suffer an infection, it is plausible that obesity could result from insulin resistance in some and in others engender it. However, obesity is most strongly correlated with insulin resistance. This correlation likely strengthens upon adopting more stringent measures of insulin resistance like Kraft’s criteria.

  1. Neel argues lower birth rates would give rise to thrifty phenotypes but this relationship does not bear out empirically.

Point 2 indicates a correlation between diabetes risk factors (as measured by a 2 hour OGTT with insulin assay) and low birth weights. This correlation is robust. The tissue of these infants born underweight is predicted to have a lower resting metabolic rate, reflecting a thrifty phenotype. However, authors Eriksson et al. found that “the muscle tissue of people who had a lower birth weight is more metabolically active than those with a higher birth weight. Yet another correlation bites the dust in the wake of prediction testing.

  1. Food is intermittently available throughout the year in colder climates, predisposing inhabitants to insulin resistance in order to cope with periods of low-food availability. Contradicting this prediction is the observation that ethnic groups inhabiting more northern latitudes do not appear more insulin resistant than their equatorial counterparts.

The prediction in point 3 is that people in colder climate are more insulin resistant and thus more likely to become obese (or diabetic). This correlation does not bear out. Many counter observations  are available.

  1. Obesity might be more of a neurobehavioral disorder than a metabolic one according to O’Rahilly and Farooqi. This is not a convincing argument in and of itself (for many reasons) and is best summed up as ‘moving the goal posts’.

Point 4 is a weak attempt by Watve and Yajnik to argue against an insulinocentric theory of obesity by invoking leptin as the center piece of a neuro-hormonal approach. By now it is clear to anyone paying attention that obesity cannot be explained by insulin dynamics alone. Yes, we should attempt to understand how our brain integrates insulin and leptin signaling into behavioral outputs. Re-branding the problem as neurohormonal does nothing to advance that.

  1. The Thrifty hypothesis does not attempt to account for insulin signaling aspects including but not limited to longevity, reproduction and immunity.

Point 5 argues non-metabolic aspects of insulin are ignored by Neel’s theory. This is correct. However the point is somewhat facile given how much has been learned about insulin since the theory’s inception.

The cure for a disease is not necessarily the reciprocal of its cause. Keeping this in mind, the thriftiness-insulin axis of obesity is seriously dented by Christopher Gardner’s recent study randomizing insulin sensitive and insulin resistant subjects to a low-fat (~57% carbs) or low-carb (~18% carbs) diet. It failed to detect “a significant interaction between diet assignment and IR-IS status.

The Thrifty hypothesis is doomed to fail considering it does not account for the insulin sensitivity of different tissues. In a similar vein, it also fails to distinguish between pathological and adaptive insulin resistance. Finally, Allen and Cheer nicely summarize how this hypothesis falls prey to taking metaphorical reasoning too far, saying <<Mcgarvey states that the wide acceptance of the concept illustrates the generative role of metaphorical thinking in bioanthropology. Whether the concept is correct or not (in the narrow sense), it “allows for the generation of concrete studies of metabolic processes and their fertility, mortality and morbidity concomitants”>>.

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