Metabolism: Another way to keep thin?
Published online 13 October 2010
A highly truncated receptor protein variant retains the ability to modulate metabolic activity in mice
Fig. 1: A transgenic mouse with over-expression of OB-Re (right) has lower body weight and body fat content than its wild-type littermate (left).
The brain relies heavily on signals transmitted by fat cells in order to recognize when it is time to stop eating and start exercising. These signals, which take the form of leptin molecules, are detected by a family of specialized leptin receptors in the hypothalamus, called OB-R. Malfunctions in the signaling process are known to cause obesity in both animal models and humans.
The body produces several alternative versions of OB-R, some of which appear to be incapable of initiating the signal cascades normally induced by leptin molecules. The most enigmatic of these receptor variants is OB-Re, which completely lacks a membrane anchor and is released directly into the bloodstream. Weiping Han at the A*STAR Singapore Bioimaging Consortium, Cai Li at the University of Texas Southwestern Medical Center in the USA and co-workers1 have now teamed up in an effort to uncover the functions of OB-Re. Normally, such a study would be performed by creating a mouse strain in which the receptor gene is disrupted. However, since OB-Re and other OB-Rs are encoded by the same stretch of DNA, the researchers instead created transgenic animals that produced artificially elevated levels of OB-Re. Surprisingly, the results they obtained were the exact opposite of what they initially predicted.
“As the soluble form shares the same leptin-binding sites with the long-form receptor, we thought that the soluble form would function as a negative regulator in leptin signaling by binding to leptin and thus reducing free leptin availability,” says Han. “However, we were completely wrong.” After 16 weeks, OB-Re-overexpressing mice weighed less than their normal counterparts (Fig. 1), and magnetic resonance imaging revealed a significant reduction in the proportion of body fat in these animals. The transgenic animals also displayed notable changes in metabolic activity, consuming less food but more oxygen. These mice also had higher levels of circulating leptin, with the majority of hormone in complex with receptor molecules.
The researchers have developed several models that might explain these unexpected findings. One possibility is that this soluble receptor form prevents the clearance of leptin from the bloodstream, thereby prolonging its activity. However, Han and Li suggest that the receptor could also be modulating energy metabolism via some yet-unknown leptin-independent mechanism. “We are following up on this question,” says Han. “If the soluble leptin receptor has an independent function on its own, it may be quite interesting to pursue targeting it for the treatment of obesity.”
The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium
- Lou, P.-H., Yang, G., Huang, L., Cui, Y., Pourbahrami, T., Radda, G.K., Li, C. & Han, W. Reduced body weight and increased energy expenditure in transgenic mice over-expressing soluble leptin receptor. PLoS ONE 5, e11669 (2010). | article