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Wired for obesity: how genes involved in brain development affect body weight

Researchers have identified key genes that guide brain circuit development and link this process to body weight regulation. It is known that a part of the brain called the hypothalamus plays a critical role in body weight regulation. But, the exact molecules involved remain unclear.

In this study, scientists investigated the role of a group of molecules called semaphorins, which are abundant in the hypothalamus during development and are released by brain cells allowing them to communicate with other brain cells. The researchers first tested DNA samples from children and adults (male and female) and found that individuals with severe early-onset obesity had mutations in several genes involved in semaphorin signaling pathways. These mutations are rare, but, collectively, appeared more frequently in the people with severe early-onset obesity than in healthy individuals. To investigate the role of semaphorins further, they used a zebrafish model to test whether altered semaphorin signaling in the hypothalamus influenced body weight. They found that deletions in seven of the genes that code for semaphorins, or proteins they interact with, caused weight gain and/or an increased percentage of body fat. In addition, deletion in two other genes decreased zebrafish body fat percentage. These results suggest that disruption of semaphorin signaling pathways has an impact on energy balance, or the relationship between calories consumed and calories burned. Next, studying mouse hypothalamic cells in laboratory culture dishes with other cells that had normal or mutant semaphorin genes, they found that several semaphorin gene variants stunted the outgrowth of projections from the hypothalamic cells, preventing cells from growing properly and forming appropriate cellular connections. Lastly, the researchers genetically modified mice to deplete the protein “receptor” on the surface of hypothalamic brain cells on which semaphorins exert their effects. Hypothalamic cell cultures from the male mice that were studied showed that genetic loss of semaphorin action through loss of the receptor blocked the outgrowth of cell projections, suggesting a role of semaphorin signaling in the formation of connections between cells in the brain. Moreover, the genetically modified mice had significantly higher body weights and reduced energy expenditure (calorie burning) compared to their normal littermates.

Taken together, these results suggest that semaphorin signaling plays a role in the connections between different brain regions and the development of brain circuitry that governs body weight. Further studies on human semaphorin gene variants could inform our understanding of obesity in people and possibly lead to prevention and treatment strategies.

van der Klaauw AA, Croizier S, de Oliveira EM,…Farooqi IS. Human semaphorin 3 variants link melanocortin circuit development and energy balance. Cell. 176: 729-742, 2019.