Obesity- Regulating Brain Signaling Pathway Genes

Further investigations involving cultured cells and genetically engineered zebrafish and mice indicated that SEMA-3 mediated signaling drives development of melanocortin circuits in the hypothalamus that are involved in energy homeostasis; results provide insight into the development of hypothalamic circuits that regulate appetite and metabolism.

Melanocortin neurons play roles in weight regulation, and neural circuits in the hypothalamus play roles in the regulation of energy and homeostasis, how these circuits in the hypothalamus are being organized is not fully understood, explains Sebastien Bouret, PhD, who goes on to add that they want to know how the brain puts itself together and what governs that process. Understanding how brain cells form specific and complex connections, and how this process can be disrupted may provide insight into development of childhood obesity and hypothalamic disorders.

Class 3 semaphorins are involved in development of neuron subsets; rare variants in SEMA3 genes that disrupt signaling are associated with hypogonadotropic hypogonadism. Genes encoding SEMA3 and their receptors are hypothesized to contribute to development of neurons involved in regulating body weight; some with severe early onset with obesity might carry functional variants of these genes.

Sequencing data from an initial set of 573 subjects with severe early onset obesity was analyzed which found 40 rare variants in 13 genes involved in semaphorin signaling; the rare functional variants were found to be enriched in a larger cohort of 982 severely obese subjects when compared to 4,449 healthy controls. SEMA3 signaling gene variants acted to disrupt normal signaling through multiple molecular mechanisms, many of which reduced secretion and/or receptor mediated signaling; given the rarity of variants it was noted that associations did not reach statistical significance at single gene level, larger scale comparisons are needed.

Semaphorins act as communication system between brains cells like a road map of sorts to guide cells towards/away from other cells. Sophie Croizier, PhD blocked semaphorin signaling in lab grown hypothalamic cells to investigate what happens when inactivated, and found brain cells no longer grew as they are supposed to and connections between cells failed to establish.

CRISPR technology was used to disrupt some of the identified SEMA3 signaling related genes in early zebrafish embryos; testing revealed deletion of 7 of the genes to be associated with the animals developing increased body weight and/or fat. Additional testing using engineered mice yielded similar results; suggesting semaphorins are guiding and shaping development of hypothalamic circuits that regulate calorie intake.

The team concluded that rare heterozygous variants in SEMAs, their receptors, and co-receptors in those with severe early onset obesity have been identified, by demonstrating deletions of several genes in the pathway increased weight related phenotypes establishing a role for these molecules in energy homeostasis, which might modulate body weight and/or fat mass by several mechanisms; cumulatively the studies demonstrate SEMA3 mediated signaling drives development of hypothalamic melanocortin circuits involved in energy homeostasis.