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Leptin breakthrough

Study finds key to leptin resistance

How leptin binds to its receptor and could begin explain leptin resistance
The interaction between leptin and its receptor using electron microscopy. The two legs of the receptor become rigid by binding to leptin and signal to an enzyme called the Janus kinase. (Credit: Image courtesy of University of Michigan)

Researchers at the University of Michigan have determined how leptin, the hormone regulator of appetite, interacts with a key receptor in the brain. The findings could have significant implications as to why some patients develop resistance to leptin. The research "Ligand-Induced Architecture of the Leptin Receptor Signaling Complex," has been published online in the journal, print Molecular Cell.

"This exciting not only because it might help with developing new drugs," said Georgios Skiniotis, a faculty member at the Life Sciences Institute and assistant professor in biological chemistry at the U-M Medical School. "We now better understand the design and mechanisms of signalling through this class of receptors, which brings us to a whole new set of intriguing questions."

Although there can be several complex reasons behind leptin resistance, in some cases the underlying cause is malfunction of the leptin receptor in the brain.

An understanding of how leptin and its receptor interact could lead to new treatments for obesity and metabolic disorders, but the structure of this signalling complex has evaded researchers for years. Superficially, little is known about the structure of the How leptin binds to its receptor and could begin explain leptin resistance (LEP-R) complex.

As a result, the researchers applied single-particle electron microscopy to characterise the architecture of the extracellular region of LEP-R alone and in complex with leptin.

The results showed that unliganded LEP-R displays significant flexibility in a hinge region within the cytokine homology region 2 (CHR2) that is connected to rigid membrane-proximal FnIII domains. Leptin binds to CHR2 in order to restrict the flexible hinge and the disposition of the FnIII “legs”.

Through a separate interaction, leptin engages the Ig-like domain of a second liganded LEP-R, resulting in the formation of a quaternary signalling complex. The researchers suggest that the membrane proximal domain rigidification in the context of a liganded cytokine receptor dimer is a key mechanism for the transactivation of Janus kinases bound at the intracellular receptor region.

Skiniotis also traced similarities between the leptin receptor and other receptors of the same family, which may provide insight into new targets for treatment of other hormone-related diseases.

“This study may help solve an important issue we've been struggling with for some time,” said Alan Saltiel, director of the Life Sciences Institute. “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.”

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