Inflammatory fat: unraveling the injurious biology of obesity.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 musculoskeletal /mus·cu·lo·skel·e·tal/ (-skel´e-t'l) pertaining to or comprising the skeleton and muscles.
Relating to or involving the muscles and the skeleton. 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 obesity-related disease Clinical nutrition Any condition linked in part to obesity–eg, cardiovascular disease, gallbladder disease–cholecystitis, cholelithiasis, gout, adverse lipid profile, ↑ post-operative complications–poor wound healing, 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 Medicare and Medicaid
U.S. government programs in effect since 1966. Medicare covers most people 65 or older and those with long-term disabilities. Part A, a hospital insurance plan, also pays for home health visits and hospice care. programs, notes the study's lead author, Erie A. Finkelstein of RTI International in Research Triangle Park Research Triangle Park, research, business, medical, and educational complex situated in central North Carolina. It has an area of 6,900 acres (2,795 hectares) and is 8 × 2 mi (13 × 3 km) in size. Named for the triangle formed by Duke Univ. , 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 Cardiovascular disease
Disease that affects the heart and blood vessels.
Mentioned in: Lipoproteins Test
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 Macrophages
White blood cells whose job is to destroy invading microorganisms. Listeria monocytogenes avoids being killed and can multiply within the macrophage. 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 The Harvard School of Public Health is (colloquially, HSPH) is one of the professional graduate schools of Harvard University. Located in Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill, next to Harvard Medical School and Cambridge, Massachusetts, in Boston, researchers might succeed in decoupling Decoupling
The occurrence of returns on asset classes diverging from their normal pattern of correlation.
Take for example stock and corporate bond returns, which normally rise and fall together. obesity's link to chronic disease by aiming anti-inflammatory drugs Anti-inflammatory drugs
A class of drugs that lower inflammation and that includes NSAIDs and corticosteroids.
Mentioned in: Antirheumatic Drugs at fatty tissue or the chemicals it spews.
FAT'S COMPANIONS The body component that people call fat, scientists call adipose tissue adipose tissue (ăd`əpōs'): see connective tissue.
or fatty tissue
Connective tissue consisting mainly of fat cells, specialized to synthesize and contain large globules of fat, within a . 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 endothelial /en·do·the·li·al/ (-the´le-al) pertaining to or made up of endothelium.
A layer of cells that lines the inside of certain body cavities, for example, blood vessels. , immune, and vascular smooth muscle Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.
Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that 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 Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. , which can trigger insulin resistance Insulin Resistance Definition
Insulin resistance is not a disease as such but rather a state or condition in which a person's body tissues have a lowered level of response to insulin, a hormone secreted by the pancreas that helps to regulate the level . 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 White blood cells
A group of several cell types that occur in the bloodstream and are essential for a properly functioning immune system.
Mentioned in: Abscess Incision & Drainage, Bone Marrow Transplantation, Complement Deficiencies 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 T cells
A type of white blood cell produced in the thymus gland. T cells are an important part of the immune system. Infants born with an underdeveloped or absent thymus do not have a normal level of T cells in their blood. 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 ge·net·i·cist
A specialist in genetics.
a specialist in genetics.
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 The Journal of Clinical Investigation (JCI or J Clin Invest) is a leading biomedical journal, which is radically different from many of its peers in having a high impact factor (in 2006, 15.754) and offering all its contents entirely free. , most of the obesity-activated genes have been associated specifically with macrophages.
It was the last thing that the team had expected, says Chen, now at Novartis Institutes for BioMedical Research in Cambridge.
UNEXPECTED CROWDS About the same time that the Millennium Pharmaceuticals team was making its odd findings in diabetic mice, Anthony W. Ferrante Jr. of Columbia University's Naomi Berrie Diabetes Center in New York and his colleagues were getting a similar surprise from their study of obese mice. The Columbia team wanted to know which genes switch on as a mouse gradually fattens up. Like Chen, Ferrante had expected the action to be among genes regulating metabolic processes. Yet of the 100 genes that were most active in the obese animals, most were specific to macrophages.
Ordinarily, a few macrophages reside in the fat pads of even slim mice. The Columbia team found that the activity of macrophage-linked genes increased at a gradual pace initially, as an animal fattened up. The number of macrophages present in a plumping animal's adipose tissue also rose gradually.
However, among the most obese animals that the Columbia group investigated, the macrophages' proportion of all adipose-tissue cells sometimes reached 40 or 50 percent. Such astounding a·stound
tr.v. a·stound·ed, a·stound·ing, a·stounds
To astonish and bewilder. See Synonyms at surprise.
[From Middle English astoned, past participle of astonen, densities, Ferrante recalls, "knocked our socks off!"
The Columbia team also found far more macrophages in the adipose tissue of obese people than of slim ones.
One issue was where all those macrophages could have come from. Had they developed within the fat by conversion of some subset of stromal-vascular cells there, or were the macrophages infiltrators from blood?
To establish which source predominates, Ferrante's team did transplants on some of their mice. The researchers irradiated mice to kill the bone marrow, then injected new marrow from mice whose cells carry a different form of a distinguishing surface protein. Bone marrow produces blood, so if the macrophage macrophage /mac·ro·phage/ (mak´ro-faj) any of the large, mononuclear, highly phagocytic cells derived from monocytes that occur in the walls of blood vessels (adventitial cells) and in loose connective tissue (histiocytes, phagocytic population in fat arrives via the bloodstream, the cells should carry the foreign marrow's protein marker. If the macrophages were made within fat, they wouldn't have that marker.
In the December 2003 Journal of Clinical Investigation, Ferrante's group showed that by 6 weeks after a transplant, 85 to 90 percent of all the macrophages in the adipose tissue of obese mice carried proteins characteristic of the foreign marrow.
The big question is: Why, as animals become obese, do macrophages move into fat tissue in large numbers and start spewing potentially dangerous amounts of inflammatory compounds?
One scenario that Hotamisligil favors is that, as individuals consume more fat than their adipocytes can handle, some of those fat cells break open or leak. The macrophage clean-up crews then swoop in to sop up the material released. As these recruits identify leaky or bursting fat cells, they may attack them and send out chemical signals for backups. The end result: inflammation.
The inflammation scenario might also explain a seemingly odd aspect of the Millennium group's findings. When the researchers examined mice with a genetic predisposition to diabetes, they observed a gradual increase in macrophage-gene activity with growing obesity. However, the animals' prediabetic symptoms came on suddenly, after 16 weeks of being overfed o·ver·feed
tr. & intr.v. o·ver·fed , o·ver·feed·ing, o·ver·feeds
To feed or eat too often or too much.
Adj. 1. overfed - too well nourished
nourished - being provided with adequate nourishment . The mice seemed to reach a threshold at which their cells suddenly lost their sensitivity to insulin and inflammation spiraled out of control.
EVOLUTIONARY UNDERPINNINGS Because the two new studies highlight an apparently pivotal role of macrophages in obesity-related inflammation, they're "real eye-openers and potentially quite important," says Robert H. Eckel of the University of Colorado Health Sciences Center The University of Colorado Health Sciences Center (UCHSC) is part of the University of Colorado System. It has recently been merged with the University of Colorado at Denver (UCD) to form the University of Colorado at Denver and Health Sciences Center. in Denver. Not only do they "open the door" to new interpretations of obesity's role in inflammation, he says, but they also call attention to the interrelatedness in·ter·re·late
tr. & intr.v. in·ter·re·lat·ed, in·ter·re·lat·ing, in·ter·re·lates
To place in or come into mutual relationship.
in between immunology and metabolic diseases, such as diabetes.
Hotamisligil agrees. Increasingly, he says, researchers are coming to see many chronic diseases as having almost comparably strong immune and metabolic components. That's because the mammalian liver, adipose tissue, bone marrow, and other critical features of the immune and metabolic systems all evolved from a single primordial organ, he says.
Such a multifunctional organ is economical, Hotamisligil notes. In simple organisms, it integrates cellular responses that the human body must coordinate among separate organs. For instance, "while fighting a pathogen, you shouldn't be depositing fat into adipose adipose /ad·i·pose/ (ad´i-pos)
2. the fat present in the cells of adipose tissue.
Of, relating to, or composed of animal fat; fatty. [tissues]--because you'll need that energy for combat," he explains. However, during calm periods, the body needs to divert excess energy into storage for the proverbial rainy day.
As that primitive fat repository evolved into separate organs, the new ones retained a common responsiveness to major cues, such as inflammation or energy intake, Hotamisligil says. That's why viewing diseases such as type 2 diabetes type 2 diabetes
See diabetes mellitus. as being largely hormonal is probably an oversimplification o·ver·sim·pli·fy
v. o·ver·sim·pli·fied, o·ver·sim·pli·fy·ing, o·ver·sim·pli·fies
To simplify to the point of causing misrepresentation, misconception, or error.
v.intr. , he says.
Last year, Luc Penicaud of the University Paul Sabatier CNRS CNRS Centre National de la Recherche Scientifique (National Center for Scientific Research, France)
CNRS Centro Nacional de Referencia Para El Sida (Argentinean National Reference Center for Aids) in Toulouse, France, and his colleagues reported evidence of another sign of connectedness between fat and immunity. They showed that certain inflammatory chemicals can signal preadipocytes--the precursors to fat cells--to mature into macrophages. Moreover, the team found that obese mice host more preadipocytes and macrophages in their fat tissue than lean mice do. These findings not only tissue, Penicaud says, but also point to the plasticity of adipose tissue: It can store fat or fight disease.
FAT CHANCE Mounting evidence that inflammatory secretions from adipose tissue can foster disease has raised hope that these immune attacks might be treatable with anti-inflammatory
A little more than 2 years ago, Steven E. Shoelson of Harvard University's Joslin Diabetes Center Joslin Diabetes Center is the world’s largest and most respected diabetes research center, diabetes clinic, and provider of diabetes education. It is located in the Longwood Medical and Academic Area in Boston, Massachusetts. in Boston and his colleagues reversed obesity-related insulin resistance in mice with high doses of aspirin. The anti-inflammatory drug worked by neutralizing IKK-beta, an inflammatory secretion associated with obesity, say the researchers.
Nine months later, a team led by Gerald I. Shulman of the Yale University School of Medicine treated nine obese diabetic people with high-dose aspirin for 2 weeks. The regimen temporarily improved the volunteers' responsiveness to insulin, leading to better control of their blood sugar. Indeed, the trial yielded blood sugar improvements comparable to those achieved with met-formin, a common antidiabetes drug. The aspirin therapy also lowered fat concentrations circulating in volunteers' blood.
However, Shulman and his coauthors argued in the May 2002 Journal of Clinical Investigation that aspirin has too many side effects for long-term use against diabetes: "We would strongly advocate against its use for treatment of type 2 diabetes." Rather, the study's findings suggest new directions for drug development.
Such efforts might have to specifically target inflammatory molecules arising in adipose tissue, says Eckel. Macrophages offer infection-fighting benefits elsewhere in the body, so "you probably wouldn't want to shut down their activity systemically," he explains.
Better yet, Hotamisligil says, target new drugs at critical chemical processes that occur before macrophages multiply in fat and trigger the inflammation. Unfortunately, no one yet has a clue to what most of those upstream processes might be.