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“Sensing” a genetic predisposition to obesity

New research suggests a mechanism by which antenna-like sensory projections, called primary cilia, located on brain cells play a role in the genetic predisposition to and development of obesity. Primary cilia are found on many types of cells, and defects in these structures contribute to a wide range of human diseases collectively called ciliopathies. For reasons that have remained unclear, certain ciliopathies typically result in obesity. Mutations in some genes that produce proteins located in primary cilia cause obesity in both mice and humans, and recent studies have suggested a role in human obesity for the protein ADCY3, which is specifically found in primary cilia of brain cells.

In this study, scientists investigated whether another protein, MC4R, which is found on the surface of brain cells and transmits appetite-regulating information, could be involved in a primary cilia signaling pathway. Several known mutations in the gene encoding MC4R cause severe obesity in people; similarly, in mice, deletion of the gene that produces MC4R induces severe obesity. For the first time, the researchers were able to visualize the precise cellular location of MC4R in the brains of male and female mice by using a fluorescent tag along with imaging technology. The scientists discovered that, in a group of brain cells whose job it is to communicate information about appetite to the rest of the brain, MC4R is located in close proximity to ADCY3 on the primary cilia. Furthermore, when they introduced a known human obesity-associated mutation into the gene encoding MC4R in mice, MC4R no longer traveled to the primary cilia with ADCY3, suggesting that the mutation may cause obesity by disrupting the protein’s localization to cilia. To determine if MC4R and ADCY3 work together at primary cilia to regulate body weight, the researchers blocked the function of ADCY3 specifically in MC4R-containing brain cells in mice. The mice increased their food intake and gained significantly more weight than mice with functional ADCY3.

Taken together, these results suggest that ADCY3 and MC4R work together specifically in primary cilia of brain cells to regulate appetite and body weight, and provide new insight into the role of primary cilia in obesity. Further research could determine if additional proteins have a role in the brain’s primary cilia and may suggest new approaches to treating or preventing obesity.

References

Siljee JE, Wang Y, Bernard AA,…Vaisse C.  Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesityNat Genet. 50:180-185, doi: 10.1038/s41588-017-0020-9, 2018.
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