Wired for Obesity

Published on 
February 11, 2019

Scientists pinpoint a set of genes that may wire the body weight center of the brain

Eating and exercise have the power to shape our bodies but those activities are controlled by hard-wired circuits in the brain. This means that when these neural circuits are developing is a critical time for determining how our brains will regulate our body weight, even in adulthood. What remains a mystery is just how these circuits achieve the proper wiring. Why do certain brain cells connect to one area while specifically avoiding other, nearby cells? Understanding how brain cells in the hypothalamus form these specific, complex connections – and how this process can be adversely affected – could provide insight into the development of childhood obesity.

In a study published recently in the journal Cell, investigators at Children’s Hospital Los Angeles and the University of Cambridge uncover key genes that guide the process of brain development. These genes instruct the body to build a set of molecules that act as a road map, guiding developing neurons to form circuits in the body weight center of the brain.

Sebastien Bouret, PhD of the Saban Research Institute at CHLA leads a team of researchers that study the formation of these circuits. “We know that the brain, in particular an area called the hypothalamus, has a very important role in the regulation of food intake and blood sugar,” explains Dr. Bouret, who is also an associate professor of pediatrics at the Keck School of Medicine of USC. Researchers have focused on the hypothalamus for years in an effort to study the epidemic of obesity, which affects nearly 14 million children and adolescents in the United States. “What we don’t yet understand,” he says, “is how these circuits in the hypothalamus are being organized. We want to know how the brain puts itself together and what exactly governs that process.” Understanding this is key because circuits must be established properly in order for the brain to ultimately perform complex functions like maintaining proper weight.

Enter the semaphorins – small signaling molecules found in abundance in the developing hypothalamus. Bouret wondered whether these semaphorins could help form body weight circuits. Dr. Sophie Croizier, who led the study in Dr. Bouret’s lab, blocked semaphorin signaling in cells of the hypothalamus. She discovered that brain cells no longer grew the way they were supposed to, showing that semaphorin provides an essential map for them to follow. In addition to connections failing to establish, loss of semaphorin action in a preclinical model also caused elevated body weight. “What we are seeing is that semaphorins are guiding and shaping development of hypothalamic circuits that ultimately regulate calorie intake,” explains Dr. Bouret.

But the story does not stop here.

Professor Sadaf Farooqi, PhD, FRCP, FMedSci from the University of Cambridge was also analyzing genetic information from individuals with obesity. Dr. Farooqi’s team tested 1,000 DNA samples and found that individuals with early-onset obesity harbored more rare mutations in genes involved in semaphorin signaling than healthy individuals. The finding that people with obesity have these mutations shows that semaphorins are important in maintaining healthy body weight. “We have now discovered the genes that establish the precise neural connections that form these circuits,” says Dr. Agatha van der Klaauw, who led the study in Dr. Farooqi’s lab and is co-first author on the paper.

This study reveals a much clearer picture of what occurs in the developing brain. Semaphorin signaling appears to shape the physical architecture of the brain and influence circuitry governing body weight.