The number of molecules controlling appetite and body weight continues to grow! A new satiety-inducing molecule, secreted by the hypothalamus, has been identified and named "nesfatin-1" (short for: NEFA/nucleobindin2-encoded satiety- and fat-influencing protein). In this study (Identification of nesfatin-1 as a satiety molecule in the hypothalamus. S. Oh et al., Nature 443:709, 2006), the investigators were searching for appetite regulating molecules by identifying genes that were stimulated when cells were exposed to the anti-diabetic drug, troglitazone.
One gene, called NUCB2, was chosen for further evaluation because it was expressed in both the hypothalamus and in fat cells (a feature common to many appetite controlling proteins), and had additional characteristics that suggested it was a secreted molecule that might be important in appetite control.
In the brain, the researchers found that NUCB2 is secreted from cells in the hypothalamus in the region that controls appetite. Like many other appetite control peptides, the smaller fragment, nesfatin, is cleaved from the larger protein (NUCB2), and it is this nesfatin fragment that seems to mediate the appetite suppressing effects. When this small protein is administered to rats, it dramatically reduces food intake and results in weight loss (total body weight and fat) compared to controls. The authors carried the study further to try to sort out where this molecule fits into the known pathways controlling appetite and obesity. In rats in which the leptin system was impaired, nesfatin seemed to work fine, suggesting that nesfatin and leptin work separately to control weight. In contrast, when nesfatin was administered to mice that had their melanocortin system disturbed, nothing happened. This suggests that the nesfatin normally acts through the melanocortin system (this system the includes melanocyte-stimulating hormone and the MC3R and MC4R receptors, and has previously been implicated as an important pathway controlling appetite and body weight). Exactly how nesfatin fits into this pathway remains to be determined, but it does suggest that nesfatin or drugs made to mimic the action of nesfatin may offer a new approach to controlling weight. It will also be of interest to see if this molecule, or its targets, is missing or abnormally low in PWS.
