Inflammatory fat: unraveling the injurious biology of obesity

Science News, Feb 28, 2004 by Janet Raloff

The United States is big, and getting bigger each year--at least around its collective waistline. Federal statistics indicate that as of 2001, one in five U.S. adults was obese. That s roughly 45 million people. Almost twice that many fall into the next category, overweight. Some 15 percent of children, ordinarily the most active and trim segment of the population, are also too heavy. These figures are growing at a dizzying pace. For instance, the number of obese adults today is 74 percent higher than it was in 1991.

The problem isn't merely aesthetic. As people get fatter, they become more prone to a host of chronic diseases--including diabetes, atherosclerosis, and cancer--says a team at the Rand Corp. in Santa Monica, Calif., and other researchers.

In the January/February Health Affairs, the Rand group traces a dramatic share of disabilities in U.S. residents under 60 years of age to conditions fostered or aggravated by extra pounds. The team looked at back injury, other musculoskeletal problems, and diabetes. Experiencing the largest rise in obesity-related disabling injuries and illnesses are people aged 30 to 49 years, the team reports.

The economic toll of obesity-related disease is staggering. A study in the January Obesity Research pegs 2003 medical costs from conditions linked to excess weight at $75 billion. Taxpayers subsidize nearly half of these costs through federal Medicare and Medicaid programs, notes the study's lead author, Erie A. Finkelstein of RTI International in Research Triangle Park, N.C. Lost wages and productivity further compound obesity's toll.

Although excess weight has long been linked to chronic disease, only recently have scientists begun homing in on the underlying mechanisms by which fat makes people sick. Increasingly, such studies are putting the blame on inflammation in diabetes, stroke, and cardiovascular disease (SN: 8/11/01, p. 89; 12/6/03, p. 366). However, a nagging question has remained: What aspect of plumping up triggers the tissue irritation that can damage the body?

Two studies now offer a provocative clue. They've found that, with obesity, macrophages--cells in the body's immune army and not typically associated with fat--appear in abundance within fatty tissues. Moreover, macrophages seem to be a primary source of chemicals sparking inflammation in fat and beyond. It's possible that these immune troops have mistakenly read a call to arms and then run amok, bringing down allied cells instead of an enemy.

If the new macrophage-fat connection is confirmed, notes Gokhan S. Hotamisligil of the Harvard School of Public Health in Boston, researchers might succeed in decoupling obesity's link to chronic disease by aiming anti-inflammatory drugs at fatty tissue or the chemicals it spews.

FAT'S COMPANIONS The body component that people call fat, scientists call adipose tissue. Adipocytes, the main cells making up that tissue, store fatty molecules derived from food. Inter spersed with adipocytes is a mix of other cell types known collectively as stromal-vascular cells. These include endothelial, immune, and vascular smooth muscle cells. Normally, adipocytes vastly outnumber all their stromal-vascular neighbors.

As adipocytes increase in size, adipose tissue begins spewing inflammatory chemicals. One, for instance, is tumor necrosis factor-alpha, which can trigger insulin resistance. Which cells within adipose tissue secrete such chemicals had been ill-defined, Hotamisligil says, but "we were always a little biased that adipocytes were the source."

The two new reports now present evidence that the vast majority of inflammation-promoting agents comes from macrophages. Ordinarily, when the body senses disease or injury, it quickly converts some standby white blood cells into active duty as macrophages. Swooping into a damaged area from the bloodstream, macrophages gobble up cellular trash or infectious agents. Meanwhile, they secrete chemicals to rev up an even bigger immune attack by troops such as T cells and B cells.

In fat where there's no injury or infection, there wouldn't seem to be much of a role for macrophages. So, scientists studying obesity hadn't been on the alert for such cells. Moreover, because adipocytes can secrete inflammatory chemicals, scientists assumed they were behind virtually all inflammation associated with obesity.

Yet that's not what researchers recently found. Scientists at Millennium Pharmaceuticals in Cambridge, Mass., had been probing diabetes by studying what genes are turned on in a fat mouse that aren't active in a normal one. The expectation, notes geneticist Hong Chen, had been that obesity would switch on genes that alter the management of lipids or sugars.

"We thought we were working on a metabolic disease," she says, so the team paid special attention to enzymes that affect energy use and storage. The surprise, she told Science News, was that obesity generally turned on genes typically linked to inflammation. In fact, her team reports in the December 2003 Journal of Clinical Investigation, most of the obesity-activated genes have been associated specifically with macrophages.