A novel signaling pathway regulating food intake and energy metabolism

Detailed knowledge of the pathways by which gherlin and leptin signal to AMPK in hypothalamic neurons and lead to regulation of appetite and glucose homeostasis is central to the development of effective means to combat obesity. The team has recently identified CaMKK2 as a component of one of these pathways, shown that it regulates hypothalamic production of the orexigenic hormone NPY, provided evidence that CaMKK2 functions as an AMPKa kinase in the hypothalamus, and demonstrated that CaMKK2 forms a unique signaling complex with AMPKa and b. Acute pharmacologic inhibition of CaMKK2 in wild-type, but not CaMKK2-null mice, inhibits appetite and promotes weight loss consistent with decreased NPY/AgRP mRNAs. Moreover, the loss of CaMKK2 protects mice from a high fat diet induced obesity, insulin resistance, and glucose intolerance. Together, these data underscore the potential of targeting CaMKK2 as a therapeutic.* With this particular invention, Means, et al have developed screening methods for the formation of the protein complex associated with regulation of energy and have used it to screen for compounds on a small scale basis. The screening platform, however, has been adapted to perform on a moderate to high throughput scale and could be used to screen large compound libraries. Additionally, the team has developed key knock-out mice that could be used for animal validation studies.