null How does the hunger-suppressing hormone leptin cross the blood-brain barrier?
Specialized cells called pericytes play a key role, reveals new work from researchers at the RI-MUHC
SOURCE: RI-MUHC. Published this month in Cell Metabolism, a new study by researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) provides an answer to the long-standing question of how the hunger-suppressing hormone leptin enters the brain to curb appetite despite the presence of the blood-brain barrier.
Led by Maia Kokoeva, PhD, a scientist at the RI-MUHC, this study has shown that some of the specialized cells that enwrap brain blood vessels, the pericytes, have a key role in leptin brain access. Leptin is a hormone that is produced by the body’s fat cells and signals satiety to neurons in the brain. However, knowledge of how leptin crosses the blood-brain barrier and gains access to the brain is limited.
“This all started by serendipity, when we imaged the neurons that express the leptin receptor in brains of living mice,” says Kokoeva, who is a member of the Metabolic Disorders and Complications Program. “We were surprised to see many leptin receptor-expressing cells that enwrapped the brain blood vessels like a glove. Further analysis then showed that these cells were pericytes, a cell type that is not well characterized but seems to be involved in controlling the constriction of blood vessels in the brain.”
“Our work found that these pericytes locally control the permeability of blood vessels,” adds Kokoeva. “Mice that are lacking the leptin receptor specifically in pericytes will overeat and gain weight. This suggests that the loss of the leptin receptor reduces blood vessel permeability, and therefore reduces the access of leptin to the areas in the brain that rely on this hormone to control food intake.”
“This finding is important as it provides a new rationale for leptin access to the brain’s appetite control centres,” explains Liliia Butiaeva, PhD, first author and former graduate student of Dr. Kokoeva. “Our data suggests that leptin exits the blood vessel lumen via the junctions that connect the endothelial cells of the vessel wall.”
The research also showed that pharmacological manipulations directly targeting junction tightness also affected leptin signaling and food intake. Additionally, leptin receptor pericytes responded to leptin with an increase in intracellular calcium, which has been previously shown to lead to pericyte contraction, blood vessel constriction, and increased vessel permeability. These results collectively suggest that leptin accesses the brain via leaks in the vessel wall, leaks that are facilitated by leptin receptor pericytes.
“Our findings provide a first insight into a new pathway that allows leptin to traverse the blood-brain barrier and affect appetite,” concludes Kokoeva. “Clearly much more work is needed to decipher the mechanistic details on how the leptin receptor pericytes engage in this pathway. Future research may also address if these pericytes can help explain obesity-linked diseases.”
About the study:
Read the publication in Cell Metabolism
The authors gratefully acknowledge funding from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC).
The authors thank the Molecular Imaging Platform at the RI-MUHC for imaging services.
June 14, 2021