How leptin, a hormone that regulates metabolism and body weight interacts with an important brain receptor, has given researchers from the University of Michigan insight into possible ways of combating obesity, metabolic disorders, and some inflammatory diseases, says a report published in Molecular Cell in October 2012.
Leptin was discovered in 1995, and has since been of great interest to scientists seeking new treatments for Type 2 diabetes and obesity. Leptin, like insulin is a hormone. It is part of a network of regulatory hormones which control how energy is consumed and used up in the body. Resistance to leptin, or a lack of it have been associated with obesity.
Leptin resistance may occur for a number of different reasons; the authors describe them as “complex reasons”. Sometimes, leptin resistance is caused by a malfunction of the brain’s leptin receptor.
By acquiring a better understand of how leptin and its receptor interact, researchers believe they will be able to find new treatments for metabolic disorders and obesity. The structure of the signaling complex between leptin and its receptors has not been researched properly, the authors explained.
Georgios Skiniotis used electron microscopy to get the first picture of leptin and its receptor interacting. He found that the leptin receptor is similar to other receptors of the same family. He explained that this could help researchers find new targets for treating hormone-related conditions.
Skiniotis said:
“It is exciting not only because it might help with developing new drugs. We now better understand the design and mechanisms of signaling through this class of receptors, which brings us to a whole new set of intriguing questions.”
In the journal, Skiniotis and team explain how the receptor is formed by two swiveling hinged legs, which carry on swiveling until they come into contact with leptin. When leptin binds to the receptor, the legs become rigid.
As soon as the leptin binds to the receptor and the two legs become rigid, they send a signal to the Janus kinase, an enzyme. Inhibiting the Janus kinases could help improve several conditions linked to inflammation or metabolic disorders, such as diabetes type 2, rheumatoid arthritis and psoriasis. Psoriasis patients have higher levels of leptin. Several drugs have been investigated for treatments related to the Junus kinases.
The Director of the Life Sciences Institute, Alan Saltiel, explains that Skiniotis’ work may pave the way for research into a range of illnesses and conditions.
Saltiel said:
“This study may help solve an important issue we’ve been struggling with for some time,” he said. “Since leptin is a master regulator of appetite, understanding why resistance to its effects develops in obesity has been a major obstacle to discovering new drugs for obesity and diabetes. Developing a clear picture of how leptin can bind to its receptor may be the first step in overcoming leptin resistance.”
Leptin has been extensively researched. Below are examples of some findings:
- A signaling pathway in the brain was identified which may induce cellular leptin resistance, a problem that undermines the body’s ability to acknowledge that it is full and should stop eating.
- Females with elevated levels of leptin have fewer depressive symptoms. This inverse relationship is not associated with BMI (body mass index), researchers found.
- A lack of leptin contributes to hypothalamic amenorrhea. Treating women with a synthetic form of leptin may restore fertility and reduce the risk of bone fractures in very thin women.
- A rise in leptin levels may promote colorectal neoplasms by activating colorectal cancer stem cells. In other words, leptin may promote colorectal cancer.
Written by Christian Nordqvist