Obesity is now considered an epidemic by the World Health Organization; they estimate that 2.8 million people die every year because they are overweight or obese. While it was once a problem in rich countries, it’s now a global problem that impacts every income level. Researches are working to understand the physiological changes that occur both before and while people are overweight. Some of those changes might happen in the brain, which has a critical role in regulating when we feel hungry, and when we feel full.
Researchers at the Institute of Diabetes and Obesity (IDO) of Helmholtz Zentrum München and the lab of Claudia Doege at Columbia University have explored how neurons in the hypothalamus are involved in obesity; their work has been reported in Nature Metabolism.
"Whether we're hungry or feel full is largely determined in the brain -- specifically in the hypothalamus," explained co-lead author of the report Dr. Alexandre Fisette, IDO scientist. "Two groups of neurons in the hypothalamus control body weight and energy balance via various molecular messengers. Like yin and yang, they help strike a good balance."
Neurons in the hypothalamus are known for the molecular messengers, or peptides they produce, like AgRP or POMC, which are thought to encourage or discourage feeding, respectively. Together, hunger and food intake are carefully regulated in the brain.
"In our recent study we discovered that a transcription factor called Tbx3 plays a key role in this mechanism," said co-lead study author Carmelo Quarta. Transcription factors help control gene expression. "Specifically, in the absence of Tbx3, the neurons responsible for producing a feeling of satiety are no longer able to synthesize the expected molecular messengers."
When the relationship between neuronal populations and their peptides is disrupted in the hypothalamus, it can lead to obesity, which can cause many other health problems. The researchers differentiated human hypothalamic neurons from stem cells, but when Tbx3 was lost, that differentiation didn’t happen properly, and the peptide that should be made by those neurons, POMC, couldn’t be detected.
“Both in a preclinical model and in fruit flies, the absence of Tbx3 leads to a kind of identity crisis of satiety neurons, resulting in obesity," said Fisette.
“In preliminary experiments with human neurons, we were able to show that they are no longer able to carry out their function in the absence of Tbx3,” added Quarta.
“Humans with genetic defects in the Tbx3 gene have long been reported to suffer from obesity,” added study director Dr. Matthias H. Tschöp, CEO of Helmholtz Zentrum München and Chair for Metabolic Diseases at the Technical University of Munich. “Our study explains for the first time the underlying mechanisms and once again focuses attention on the central role of the brain in regulating energy metabolism. We hope that Tbx3 may come into consideration one day as a target for drug therapies."
Learn more about how the body controls hunger and satiety from the video.