Thrifty Genes and Metabolic Flexibility

Why Weight Gain is Easy and Weight Loss Sucks

I think it’s fair to say that most people can just look at a dozen doughnuts and gain weight. Those who are able to eat whatever they want, as much as they want, whenever they want are probably able to do so because of an idea that I think is interesting to explore: The “Thrifty Gene Hypothesis.”

The short and sweet version of this is that the evolutionary ability to easily store fat was crucial to survival during long periods of famine — possibly a routine experience pre-agriculture. The species that is more adapt to store fat to prepare for long periods of fasting (i.e. winter, drought, etc.) was more likely to survive those periods in order to later reproduce. In an evolutionary context, the ability to store fat meant the ability to survive. There hasn’t been an identification of a single gene that would regulate this (to my knowledge) and there have been other similar theories (thrifty phenotype, for example), but most of them seem to revolve around the same basic principle that something in human genetic makeup makes humans naturally predisposed to store fat for survival. Intuitively, it makes sense. Is it supported by the data? I’m not quite sure yet.

What about the people who never get fat and athletes? IMO, probably different genes. It’s why professional athletes are professional athletes and not bums like the rest of us.

Which brings me to my next topic: metabolic flexibility.

This is a pretty intriguing concept that mostly revolves around the Randle Cycle (also known as the glucose fatty-acid cycle). The principle behind this is that glucose and fatty-acids are in constant competition for fuel utilization. Under the assumption that ATP supply is controlled by ATP demand, only a given amount of ATP will be required to meet the demands of the cell in preference of the ability of a given substrate. If the cell prefers glucose, it will use glucose to produce ATP. Of course the body will always use a little bit of both substrates for fuel, but normal healthy humans seem to have the ability to switch between the primary use of glucose for energy or the primary use of fatty-acids for energy. In other words, when glucose is high (like in fed states), the body will primarily use glucose for energy and switch off lipolysis. Vice versa during conditions with high fatty-acids (like fasting).

Basic Randle Cycle. I didn’t make any of these images, but it sure does look like my basic drawing abilities

And there are some pathways to support this cycle:

Inhibition of fatty-acid oxidation by glucose (Malonyl CoA inhibits CPT1 and subsequent beta-oxidation)
Inhibition of glycolysis by fatty acid oxidation (over-abundance of citrate inhibits phosphofructokinase and glycolysis)

It’s been proposed that in many chronic-diseased states (diabetes, heart failure, etc.) there is an inherent inability to utilize these metabolic pathways in a functional manner. In terms of the Randle Cycle and diabetes, an inability to metabolize glucose has been proposed to be the result of too much fatty acid oxidation and thereby leads to insulin resistance and carbohydrate intolerance.

In terms of a healthy human and en evolutionary context, I think these two concepts are extremely important ideas. Metabolic flexibility would have been essential to human survival. The innate ability to switch fuels for metabolism would be extremely crucial to store and preserve fat during times of feeding and use fat (and ketones) during times of starvation. During feeding (especially with carbohydrate), the body responds by increasing insulin secretion and glucose uptake. The resulting cascade of events basically results in the shutdown of lipolysis (Randle Cycle) in preference of glucose utilization. Whatever fat is ingested during feeding will be directly stored, and whatever glucose is available will be used or stored as glycogen, thereby making fat storage immediate and easy.

Note: de novo lipogenesis is very inefficient and it seems that less than 2% of ingested carbohydrates become fatty acids.

[Correction: DNL is actually much higher in the postprandial state. Still, most of the fat that becomes stored is going to be dietary fat in the case of the fed state with carbohydrates present.]

During fasting, the lack of glucose and insulin would illicit an increase in lipolysis and a shift toward the utilization of fats for fuel. This would eventually begin the ketogenesis cascade and all of the subsequent events that I’ve mentioned before (including inhibition of lipolysis!).

In modern times, we have no need for the metabolic shift (arguably, most people in the world don’t have to worry much about famine). This could be a big impact as to the prevalence of chronic diseases and their complications.

So basically, “Thrifty Genes” and metabolic flexibility are part of the reason why humans may have survived harsh conditions; and why weight loss sucks. The body is simply predisposed to harnessing and saving as much fat as it can by shutting down lipolysis and increasing storage during feeding, and by tightly regulating lipolysis during ketonemia. These attributes are great for feeding-fasting conditions, but detrimental to our current state of life.