Leptin was discovered as a hormone produced by fat cells. When reinstated in leptin-deficient mice and humans it drastically reduced their obesity. But individuals who were obese for other reasons had paradoxically high leptin levels, and adding more leptin did not induce significant weight loss.
The Pittsburgh group looked to leptin-binding proteins for an answer. The first that they found was C-reactive protein (CRP), which is famous as a marker for immune reactions but whose exact function remains mysterious. CRP bound to leptin, and inhibited leptin signaling in tissue culture. In mice lacking their own leptin, CRP reduced or eliminated the effects of added leptin on food intake, body weight, blood glucose, and lipid metabolism.
The CRP connection is not completely without precedent, as others have noted inflammation (and elevated CRP) as a complication of obesity. The adipogenic and inflammatory systems also share many of the same mediators, so there is plenty of potential for crosstalk. It is not clear whether this is an accident of evolution or has a particular function.
Zhao's one clue is that low levels of leptin turn on CRP expression. He suspects CRP helped our ancestors to accumulate some fat in the few periods of plenty interspersed amongst the more common lean times. “If leptin worked unimpeded you would have a very difficult time accumulating fat,” he says.
Now that energy rich food is always available, however, the system has become pathological. Zhao's next step is to find out whether those who are morbidly obese have a different set point for CRP expression or accumulation.