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Obesity

The two faces of fat

No longer viewed as inert packets of energy, fat cells are two-faced masterminds of metabolism. Kendall Powell weighs up the differences between 'fat' fat cells and thin ones.

Unwanted, unloved, yet often overabundant, few have much regard for fat. Scientists, too, long thought of fat cells as good-for-nothing layabouts unworthy of attention; containers stuffed with energy to be released at the body's command. So stuffed, in fact, that many other parts of the cell were thought too squeezed to function.

Credit: J. KAPUSTA

So when, in the early 1990s, graduate student Gökhan Hotamisligil at Harvard Medical School in Boston caught fat tissue doing something biologically remarkable, at first he did not believe his own data. He repeated the work many times, but it always came out the same: fat from obese mice was producing TNFα — the hot inflammatory molecule of the day because of its role in autoimmune disorders such as arthritis. After he and his colleagues published their observation in Science1, others in the field remaned sceptical. Hotamisligil says he was invited to speak at meetings “for entertainment purposes”.

Since then, fat cells have had an image change. This started with the 1995 discovery that fat secretes leptin, a hormone that tells the brain “I'm full, stop eating”. In retrospect, it makes sense that fat should tell the body how much energy it is storing and how much more to take in. But when it came to obesity-related problems such as type 2 diabetes and cardiovascular disease, fat was still not seen as an active player. These conditions were thought to be caused by an excess of nutrients from overeating, or a glut of fatty molecules spilling out of storage into the bloodstream.

More than a decade on, fat has a higher status. Scientists know that fat cells pump out ten or more molecules called adipokines that carry messages to the rest of the body. And 'fat' fat cells — those common in the obese and which are themselves bloated with lipids — send different molecular messages from 'thin' fat cells.

The signals from 'fat' fat are thought to directly promote insulin resistance and to trigger inflammation, which may, in turn, cause type 2 diabetes, cardiovascular disease, increased cancer risk and other obesity-associated problems. This means that it might be possible to treat these conditions without shedding the fat itself. Some remedies might be as simple as using anti-inflammatory drugs that have been around for more than a century; others might involve persuading obese fat cells to behave like skinny ones.

Society may still view fat with resignation or even revulsion, but biologists have moved on. “No one appreciated the higher functions of fat,” says Barbara Kahn, a diabetes and obesity researcher at Harvard's Beth Israel Deaconess Medical Center in Boston. “The fat cell's got to be put on the map now.”

An animal fat cell, or adipocyte, is a giant droplet of triglyceride molecules — each composed of fatty acids and glycerol — plus a life-support system of other organelles squashed to the side. After a meal, fatty acids and glucose enter the blood. Fat cells absorb the fatty acids, and the liver converts excess glucose into more fatty acids, which fat cells take up and store. In obesity, when the body is swimming in excess fats and glucose, fat cells pack more in and expand.

Sugar daddy

Fat and glucose control are linked: overweight people tend to develop insulin resistance and then type 2 diabetes, conditions in which the hormone insulin no longer promotes normal glucose uptake and fails to stem glucose production by the liver. But researchers generally assumed fat was a bystander in these problems. They thought the defect must lie in muscle and the liver, which take up and metabolize the vast majority of blood glucose.

Then, in 2001, Kahn's group showed that fat tissue was managing much of the body's response to insulin. The researchers used genetic engineering to eliminate a glucose transporter molecule from the surface of mouse adipocytes, and found that the animals' muscle and liver cells also became insulin resistant — just as much as those from obese mice2. This suggested that obese fat cells make a circulating factor that makes other tissues resistant to insulin.

In 2005, Kahn identified that molecule as RBP4 (ref. 3), which works partly by blocking the action of insulin in muscle and liver. The team went on to show that obese and type 2 diabetic patients have higher levels of RBP4 in their blood compared with healthy controls4. “Fat cells are really conducting the orchestra, telling the sugar where to go,” says Evan Rosen, who also studies obesity at Beth Israel Deaconess but was not involved in the studies.

Little and large: fat cells in lean mice (left) send different chemical signals from those in fat mice (right). Credit: H. J. LEE & S. SHOELSON

Because of its link to human disease, RBP4 is one of the stars of a growing list of molecules secreted at higher levels by 'fat' fat cells compared to 'thin' ones — or vice versa. They include adiponectin, which is the opposite of RBP4 in that it improves the action of insulin, and is secreted in large quantities by normal fat cells but less so by 'fat' fat cells. Last year, a group led by diabetes researcher Philipp Scherer of the University of Texas Southwestern Medical Center in Dallas showed that mice lacking adiponectin suffer severe insulin resistance in the liver5.

To some researchers, it now seems obvious that fat should control the uptake of glucose, because it may limit further fat accumulation. Lean fat cells produce signals such as adiponectin that promote glucose uptake into tissues and its accumulation as more fat. “We view it as a starvation signal, in essence, signalling that the fat cell is willing to accept additional [stores],” says Scherer. When the fat cells fill up, the signal drops. Cells that become full of fat produce signals such as RBP4 that help stop cells in the body from sucking up glucose and laying down more fat. The glucose instead stays in the bloodstream, where it triggers the problems associated with diabetes.

Inflammatory acts

Engorged fat cells are complicated characters. Over the past decade it has become clear that they send out distress signals, such as TNFα, that can trigger inflammation, and that these contribute to insulin resistance. In their Science study, Hotamisligil and his adviser, Bruce Spiegelman of the Dana Farber Cancer Institute in Boston, used a molecule to soak up the TNFα from 'fat' fat cells and found that obese animals got back their insulin sensitivity.

We now know that obese fat cells also produce other inflammatory substances such as the cytokine interleukin-6 (ref. 6). In addition, immune cells called macrophages invade obese fat tissue7, where they begin contributing to a downward spiral of inflammation. There is overwhelming evidence that obesity and type 2 diabetes are accompanied by chronic, low-level inflammation of fat tissue, says Spiegelman.

Researchers are now trying to work out what causes a 'fat' fat cell, one clogged with lipids, to start secreting a different set of molecules. Hotamisligil's team thinks that the answer may lie in the endoplasmic reticulum (ER) — the cell's centre for folding and processing many proteins. Perhaps because it is crammed with excess lipids and its metabolism is overworked, the ER is unable to properly fold proteins8.

This type of cellular stress makes overstuffed fat cells stop making 'healthy' molecules such as adiponectin and begin making 'unhealthy' ones such as RBP4 and TNFα. These trigger insulin resistance in other cells and start the cycle of inflammation, increasing insulin resistance. This chronic inflammation and insulin resistance is now thought to be largely responsible for the plethora of higher disease susceptibilities that obesity brings, including cardiovascular disease, diabetes and cancer.

Fat cells' dynamic new image is changing the way that some researchers think about treating these obesity-related conditions. Treatment usually focuses on losing the fat. But if the problem lies in the adipokines produced by 'fat' fat and the insulin resistance and inflammation they cause, it might be possible to deal with these problems while leaving the fat intact. This approach is needed, some experts say, because of the large number of patients who cannot or will not lose weight.

Reducing RBP4 or raising adiponectin levels in obese patients are two potential treatments for type 2 diabetes. But clinical trials are a long way off because the exact way in which these proteins work is unknown. More likely in the near future is that molecules such as adiponectin and RBP4 may be used as biomarkers in the blood to indicate which overweight patients have higher levels of misbehaving 'fat' fat, and are therefore at risk of diabetes.

Steven Shoelson at Harvard's Joslin Diabetes Center is working on the idea that the chronic inflammation found in the obese causes their diabetes, and he leads a clinical trial to test whether this can be reversed. Starting this year, his team will give half of 120 type 2 diabetics a 14-week course of salsalate, an anti-inflammatory drug similar to aspirin that has been used for more than 150 years. Shoelson was partly inspired to carry out the trial by research published in 1876 — long before the discovery of insulin — suggesting that salsalate could treat diabetics9.

Steven Shoelson is trialling a simple painkiller against the inflammation that accompanies diabetes. Credit: M. J. MALONEY

Hot fat

Treatments that make 'fat' fat cells act like lean ones may be another way to tackle obesity. Diet and exercise do this by starving the body, prompting fat to release its stores into the blood for use in the muscles. But diet and exercise are hard to stick to. And liposuction, which sucks out some of the 'fat' fat cells, is probably not the answer, because the remaining cells are still 'fat' and produce disease-causing molecular signals. So some researchers are trying to exploit the molecular differences between different types of fat cell to convince 'fat' fat cells to reduce their own girth.

In one such effort, Dominique Langin, a clinical biochemist at the Louis Bugnard Institute in Toulouse, France, hopes to exploit the properties of brown fat, a tissue that burns fuel to create heat. Human newborns have a small pad of brown fat on their back, but it quickly disappears. Adults are thought to have only a tiny number of brown fat cells among a mass of white ones.

By switching on a gene called PGC-1α, Langin's team converted human white fat cells to brown-like ones in the lab dish10. The gene seems to switch on others normally active in brown fat. Langin suggests that white fat cells could be converted into brown ones, so that they burn up their fat inside the cell without releasing it into the bloodstream and clogging up arteries. But a drug that can turn on PGC-1α in human white fat is still distant, he says.

Hotamisligil hopes to correct aberrant fat cells by relieving the stress on their ER. Last year, his laboratory fed obese and diabetic mice two chemicals that help proteins fold correctly in the ER of fat and liver cells. This improved the animals' ability to control glucose levels11. Because both chemicals are already used to treat other diseases, Hotamisligil says he wants to try testing them as a diabetes treatment in the near future.

If this works, it will show that fat cells are not only doing something interesting — as Hotamisligil suspected 14 years ago — but that they can be manipulated for medical use. It takes a lot of willpower to convert a fat body into a thin one. But 'fat' fat cells may be more amenable to a change of character.

(see Location, location, location)

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Powell, K. The two faces of fat. Nature 447, 525–527 (2007). https://doi.org/10.1038/447525a

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