The melanocortin system is known to be involved in energy homeostasis; however, the mechanisms underlying the development of melanocortin circuits (and therefore their role in metabolic disorders such as obesity) have been largely unknown. New research now suggests that class 3 semaphorin signalling is a key factor in the development of melanocortin circuits in the hypothalamus, and that genetic variants that disrupt this pathway are associated with obesity in humans.

Previous work has shown that semaphorins are axon guidance molecules that direct the development of neuronal circuits. “Based on these studies, we hypothesized that semaphorin 3 signalling might be required for the normal development of pro-opiomelanocortin (POMC) circuits and that the loss of signalling in POMC neurons would have an effect on weight and energy balance,” explain authors Sebastien Bouret and Sadaf Farooqi.

Analysis of exome sequencing data from 573 patients with severe early-onset obesity allowed the researchers to identify 40 variants in the genes encoding the class 3 semaphorins and their receptors. These rare variants were enriched in patients with severe early-onset obesity compared with control individuals. In mice, deletion of a semaphorin 3 receptor disrupted the development of POMC neurons in the hypothalamus and resulted in reduced energy expenditure and weight gain.

“This study demonstrates for the first time that axon guidance cues are involved in the development of brain circuits involved in energy balance,” say Bouret and Farooqi. The researchers are planning additional studies to characterize the effect of semaphorins in mature hypothalamic neurons, and to investigate the role of other axon guidance molecules. “These further studies will inform understanding of the mechanisms that underlie human disorders characterized by hypothalamic dysfunction,” conclude Bouret and Farooqi.