Can Evolution Inform Human Health? Game Theory, Genetic Conflict, and Obesity.

Can evolutionary biology inform medical research? Medicine, necessarily, focuses on proximate causes: the “what” and “how” of disease. Evolutionary thought can contribute a third dimension: the “why,” the adaptive significance and evolved history of humans and pathogens. Darwinian fitness is not the same as desired human health. Some medical interventions, without a good understanding of evolution, can be ineffective-- or worse, harmful to our well-being. For example, many labs are researching an enigmatic tissue known as “brown fat” with the hopes of treating obesity. However, brown fat has an unusual evolutionary history with potential consequences for health interventions.

What is brown fat? When you think of fat, you are probably thinking of white fat, critical stores of energy largely found on our hips and torsos. Our bodies evolved to make white fat as insurance against hard times to come. That’s why we have so much trouble getting rid of it!

“Brown fat,” on the other hand, is the body’s furnace. Mammals stay warm in three ways: by shivering or using our muscles, by huddling together or basking in the sun, or by activating our brown fat to make heat. “Brown fat” comes in two distinct forms. The first type is found mostly near our shoulder-blades and is critical for newborn mammals (although it is also found in adults). The second type is interspersed within white fat, and is more properly called “beige” or “brite” fat (as in, a mix between “brown” and “white” -- you can’t make this stuff up). White fat cells can be induced to turn into these energy-burning “brite” fat cells, which gobble up energy to produce heat. Some recent work even suggests that exercise may prompt this conversion. Now, researchers are actively investigating “cold therapy” treatments intended to transform white fat into energy-burning brite fat.

But brown fat is still not well-understood, and medical treatments without a grounding in evolutionary research can sometimes backfire. Our bodies have evolved many physiological “backup channels” to resist interference and change. If we start running three miles a day, our appetite increases so that we eat more calories. Likewise, a recent study related to brown fat and obesity found totally paradoxical results: mice without functional, energy-burning brown fat are actually resistant to obesity—but only at certain temperatures. What the heck is going on here?

That brings me to the evolutionary role of brown fat—and what an interesting, and oft-overlooked, role it is. In short, brown fat bears genetic signatures of a long-lasting evolutionary battle of the sexes.

Brown fat generates heat, and heat is a public good. Game theory teaches us that public goods present an opportunity for free-riding. Imagine a litter of six mouse pups huddling together to stay warm. Mouse pups gain energy by suckling their mother’s milk, and burn energy to make heat for the huddle. However, a “selfish” mouse pup could guzzle his mother’s milk and then mooch off of his siblings, absorbing their heat without producing any of his own.

Here’s where it gets interesting: mammalian fathers have an evolutionary imperative to produce selfish babies. In mice, and many other mammals, mothers care for the babies. Further, a single litter can be made of half-siblings with one mother but multiple fathers. From the fathers’ points of view, they want their own babies to survive but don’t care about the health of the other pups in the litter. It is in the fathers’ best interests for their own pups to be free-riders—to take lots of milk from their mother, but save their energy rather than producing heat. In other words, the fathers “want” their own pups to be selfish.

In contrast, the mother “wants” her babies to be cooperative. All of the babies are equally related to the mother, so she wants them all to survive. From her point of view, each pup should get an equal amount of milk, and each pup should contribute equally to generating heat.

That is the evolutionary battle of the sexes: the mother’s interests do not line up with the fathers’ interests, as expressed through the pups*.

Amazingly enough, biologists can see tell-tale evidence of this conflict in genes connected to brown fat, or “furnace genes.” Genetic imprinting is a type of epigenetics whereby both the mother and the father “tag” some of the genes they pass on in order to advance their own evolutionary interests. That means that identical genes can have different expression depending on whether you inherit the gene from your mother or father. And as expected, mothers tag furnace genes to boost heat production in their babies, while fathers tag furnace genes to decrease heat production. In other words, mothers are “trying” to make their babies cooperate while fathers are “trying” to make their babies selfish.

This dynamic is called the Huddler’s Dilemma, a reference to the classic economic concept of the Prisoner’s Dilemma. Cuddling is more complicated than it first seems!

This peculiar evolutionary history matters, because millions of research dollars are being poured into labs around the nation and the world to uncover the role of brown fat in fighting obesity. What might evolutionary theory say about extreme cold therapy, the proposed intervention to convert white fat to energy-burning brown fat? Extreme cold is a physiological message; it tells our body “winter is coming!” This may inadvertently trigger unwanted metabolic pathways. A “smart” body will make some brown fat cells to stay warm, sure; but it will also start packing on energy stores to prepare for the seeming onrush of winter. In other words, it will start laying on the white fat. And this does not even include a guess about how the unique epigenetic history of brown fat might interact with cold exposure. This is, of course, only speculation—albeit speculation backed up by a history of unanticipated consequences to health interventions.

In short, brown fat has evolved through a peculiar history of evolutionary conflict. The more we learn about this enigmatic tissue, the better our medical solutions will be.

* For the biologically curious, I am compelled to make a point of distinction: I have used language such as “the mother wants,” when in reality that is incorrect (although convenient, for our own intuition). It is more correct to adopt a “gene’s-eye-view.” Truly the conflict here is not between the mother and father, but between genes present in the mother’s body (maternal genes) and genes from the mother sitting in the baby’s body (madumnal genes). But I digress.

Dakota McCoy (Pennsylvania and St. Hilda’s 2013) is a graduate student in biology at Harvard University in Professor David Haig’s lab. She is studying cooperation, conflict, and brown fat production on a Department of Defense NDSEG Fellowship. Dakota received an MPhil in Geography and the Environment under the supervision of environmental economist Professor Cameron Hepburn (Australia-at-Large & Magdalen 2000), who was the first to introduce her to game theory.