U of I study shows benefits of hormone found in fat tissue

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"Fat is a very complex and active tissue-it has important functions beyond providing energy and insulating us from the cold," said Freund, a professor in the U of I College of Medicine's Department of Pathology and a faculty member in the U of I Division of Nutritional Sciences.

"We now know that leptin, a hormone secreted by fat tissue, plays a key role in regulating the immune system. When we exposed mice to hypoxia (simulating an event, such as a heart attack, in which a part of the body is deprived of oxygen), leptin triggered the immune system to increase production of an anti-inflammatory molecule, interleukin-1 receptor antagonist (IL-1RA)," he said.

"And, when we gave non-obese mice leptin injections, they recovered three times faster. Leptin did not hasten recovery though in IL-1RA knockout mice," Sherry said. That earlier work was published in a recent issue of Brain, Behavior, and Immunity.

In the Endocrinology study, one group of mice was fed a high-fat diet for 12 weeks (Sherry described this group as being in a mildly obese, pre-diabetic state), while another group was fed a normal diet. The obese mice recovered from acute hypoxia five times faster than the mice fed normal diets.

In a second experiment, Freund and Sherry examined macrophages (or immune cells) that were resident in peritoneal fat tissue from both groups of mice. In mice fed the high-fat diet, there was a very significant increase in IL-1RA as compared to mice fed the normal diet (330 pg vs.15 pg).

"Our hypothesis is that the macrophages from animals fed the high-fat diet are making more IL-1RA because they're 'living' in an environment of significantly increased leptin. Obesity can be considered a state of hyperleptinemia," said Sherry.

The scientists then isolated the stromal vascular fraction of the fat tissue-which contains the macrophages-from three obese mice and injected it into the peritoneal cavity of a normal mouse. "Within 3 hours we saw an 836 percent increase in the IL-1RA serum level of the normal mouse and an accelerated recovery from hypoxia," Sherry said.

To confirm that IL-1RA was implicated in this accelerated recovery, normal mice were given injections of IL-1RA, and their recovery matched that of mice fed the high-fat diet.

Finally, Freund and Sherry injected IL-1RA antiserum into the obese animals an hour before exposing them to hypoxia.

"We expected the antibodies to bind all the IL-1RA so it couldn't affect recovery," she said. "And, sure enough, these animals didn't recover until 6 hours after the hypoxic event, basically the same pattern we saw with non-obese animals."

"So we were able to prove through several different mechanisms that in cases of obesity, there's a significant increase in the anti-inflammatory molecule IL-1RA, which helps animals recover from a traumatic loss of oxygen. The obese mice recovered faster because of the leptin-induced increase in IL-1RA," said Sherry.

Sherry repeated that obesity is a predisposing factor in many inflammatory conditions and encouraged people who are at a healthy weight to maintain that weight.

"However, obese persons do have about six times more circulating IL-1RA, which again is the anti-inflammatory molecule that aids recovery in oxygen-starved parts of the body," she noted.

"Once a health problem is established, there are certain conditions-congestive heart failure, rheumatoid arthritis, and other diseases that involve the utilization of oxygen-in which obese persons have been shown to have a better prognosis. And there is a legitimate discussion among physicians about how such patients should deal with their excess weight," said Freund.

University of Illinois at Urbana-Champaign