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The Sedentary (R)evolution: Have We Lost Our Metabolic Flexibility?


The Sedentary (R)evolution: Have We Lost Our Metabolic Flexibility?

Jens Freese et al. F1000Res.


During the course of evolution, up until the agricultural revolution, environmental fluctuations forced the human species to develop a flexible metabolism in order to adapt its energy needs to various climate, seasonal and vegetation conditions. Metabolic flexibility safeguarded human survival independent of food availability. In modern times, humans switched their primal lifestyle towards a constant availability of energy-dense, yet often nutrient-deficient, foods, persistent psycho-emotional stressors and a lack of exercise. As a result, humans progressively gain metabolic disorders, such as the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, certain types of cancer, cardiovascular disease and Alzheimer´s disease, wherever the sedentary lifestyle spreads in the world. For more than 2.5 million years, our capability to store fat for times of food shortage was an outstanding survival advantage. Nowadays, the same survival strategy in a completely altered surrounding is responsible for a constant accumulation of body fat. In this article, we argue that the metabolic disease epidemic is largely based on a deficit in metabolic flexibility. We hypothesize that the modern energetic inflexibility, typically displayed by symptoms of neuroglycopenia, can be reversed by re-cultivating suppressed metabolic programs, which became obsolete in an affluent environment, particularly the ability to easily switch to ketone body and fat oxidation. In a simplified model, the basic metabolic programs of humans' primal hunter-gatherer lifestyle are opposed to the current sedentary lifestyle. Those metabolic programs, which are chronically neglected in modern surroundings, are identified and conclusions for the prevention of chronic metabolic diseases are drawn.

Keywords: Evolution; Hunter-Gatherer Lifestyle; Metabolic flexibility; Sedentary Lifestyle; Western diseases.

Conflict of interest statement

No competing interests were disclosed.


Figure 1.
Figure 1.. Metabolic flexibility in the hunter-gatherer lifestyle.
The brain orchestrates its energy needs by either “pulling” energy from storage organs (from inside the body) in the daily foraging mode, in the short-term fight-flight mode or during long-term hunger in the starvation mode. If food is available, the brain is supplied with energy substrates through a “push” of nutrients (from outside the body) in the rest mode. If all programs are activated occasionally, the metabolic system holds the energetic equilibrium and body weight remains stable.
Figure 2.
Figure 2.. Metabolic inflexibility in the sedentary lifestyle.
The “brain pull” (energy allocation from storage organs to the central nervous system) is compromised by “pushing” energy-rich nutrients into the metabolic system continuously. As a consequence, the foraging and starvation modes are both permanently unattended, which leads to a constant fueling of adipocytes, and in the long run to lipotoxicity, sarcopenia, low-grade inflammation and all associated metabolic diseases.

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Cited by 3 PubMed Central articles


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Grant support

The author(s) declared that no grants were involved in supporting this work.

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