Fighting fat with… fat?

What do explosives and weight loss have in common?*

To find out we need to go back to World War One, to a munitions factory in France. People working with explosives were running high temperatures and losing weight. Some dangerously so. This was no fever, due to some viral or bacterial infection. It was due to a chemical they were using, similar in structure to TNT: dinitrophenol (DNP). Later, in the 1930s, DNP popped up again, this time marketed as a treatment for obesity. It failed due to its high toxicity.

We now know how DNP causes these bizarre effects; it short-circuits a key process used by cells to store energy in chemical form, releasing it as heat instead. We’ve since discovered that this is a trick mammals are born to do to. A type of fat, called ‘brown adipose tissue’, or BAT, does the same trick as DNP, only deliberately and safely. It burns off fat, keeping us warm without the need to shiver.

But this could be just the tip of the iceberg; BAT could be doing far more than keeping us warm, as researchers from the Harvard Medical School now suggest. By transplanting BAT from one mouse to another, they tried to see if you could fight fat with fat, but there are wider implications than weight.

Much like our bodies have different organs with different functions, so too do our cells: organelles. Brown fat cells differ from their white cousins in one noticeable way; they have far higher numbers of an organelle called mitochondria. Mitochondria use the energy from electrons, sequentially stripped from the raw materials of metabolism—sugar and fats, to pump protons across a membrane, like pumping water behind a dam.

Mitochondrial ATP Synthase. Image kindly provided by Professor Sir John Walker FRS, http://www.mrc-mbu.cam.ac.uk/research/atp-synthase

Mitochondrial ATP Synthase. Image kindly provided by Professor Sir John Walker FRS, http://www.mrc-mbu.cam.ac.uk/research/atp-synthase

Much like the water in a hydroelectric dam the protons can only shoot back to the other side through a specific channel, and as they do, their energy is captured. The force of the protons moving through this channel is used—and I really can’t stress enough just how cool this is—to turn a rotor, like in a power plant. The rotor is part of an enzyme complex called ATP synthase, which uses the protons energy to make ATP, the cell’s currency of energy, and it spins at something like 150 times a second, each complete turn flicking out a three new molecules of ATP.

DNP disrupts this, blasting a hole in the dam, shuttling protons back across the membrane, circumventing ATP synthase, dissipating their energy as heat rather than capturing it in chemical form. It was eventually discovered that brown fat cells do a similar thing, but they use a special protein called ‘thermogenin’ to do it.

Since the discovery of thermogenin we’ve found out a lot more about BAT. For example, we know it becomes more active in response to cold or excess feeding, and that it plays a role in the body’s energy balance. But just how big is that last role? In principle, if you increase the amount of brown fat, an individual should become more metabolically active, burning off more energy, more fat.

That’s just what the researchers at Harvard Medical School set out to find out. They took BAT from male mice, and transplanted it into age and sex matched mice. The results were compelling.

By 8-12 weeks after transplant, mice who received the transplanted BAT had lower body weight, and a decrease in fat mass compared to controls. When they increased the amount of BAT transplanted, the effects were greater. Fat really can fight fat.

But other studies have shown similar findings; so the Harvard team didn’t stop there. They also looked at insulin sensitivity—insulin is the hormone that stimulates cells to take up glucose from blood.  They found that transplanted BAT also improved the mouse’s response to insulin; they were able to remove excess glucose more quickly. When the mice were fed a high fat diet, which induces insulin resistance, the mice who received BAT returned to a normal level of insulin sensitivity, reversing the effect.

This could have future implications for the treatment, or management, of diabetes. In type 2 diabetes, more common in overweight and obese individuals, cells stop responding to insulin; they become resistant. Finding new ways to increase insulin sensitivity in type 2 diabetes has long been a goal in medicine, but with obesity on the rise throughout the world, it is now more urgent than ever.

The team then went one step further; they discovered that the levels of circulating messenger molecules called FGF-21, norepinephrine and particularly IL-6 were increased in the BAT transplanted mice. Using genetic engineering they produced a strain of mouse that can’t produce IL-6, when they transplanted the BAT from these mice into normal mice, they showed no improvement in insulin sensitivity. As the researchers say, this strongly suggests that IL-6 is “critical for the beneficial effects of BAT transplantation…”

IL-6 is a complicated molecule. What we know of it already suggests it has many, sometimes even paradoxical, effects in the body: it can be both pro and anti-inflammatory, it’s important in managing fevers and fighting infections and it’s produced by a number of different types of cell. Unravelling all of these functions, how, when and why they happen is still a huge task.

But it does give the team new directions to look in. What other beneficial effects might BAT and IL-6 have on metabolism? What might be the effect of BAT on type 1 diabetes, where the body no longer produces insulin? How does it impact on the effects of exercise? The list goes on, and it could provide some great new clues for treating obesity and a number of metabolic diseases.

The team certainly aren’t the first to look at brown adipose tissue, others are working on drugs that are mimics of FGF-21 for example, or to increase the amount of brown fat cells in the body, or stimulate them into action. But their work does offer some promising new angles to explore human disease and treatment, as well as the growing issue of weight loss.

 

ResearchBlogging.org Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng YH, & Goodyear LJ (2012). Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. The Journal of clinical investigation PMID: 23221344

 

Image Credits: Top image Jason Dunn

 

*No, this is nothing to do with food poisoning…