While it was previously thought that variants of a gene called FTO were primarily associated with obesity, the research team discovered that this link actually involves another gene, IRX3, which is located a large distance from FTO on the genome. Through a genome-wide association study, they determined that the obesity-associated variants of FTO enhance the expression of the distant IRX3 gene in the brain. The “switch” that can tune IRX3 expression up or down is found inside FTO. Through IRX3, this switch activates neurons in the hypothalamus – a region of the brain that acts as the body’s control centre for appetite and energy homeostasis.
Building on this finding, scientists tested the role of IRX3 by comparing two groups of mouse models. The first, a group of genetically-modified mouse models, had the IRX3 gene inactivated, while in the other group the gene was active. Both groups of mice were fed the same diets and maintained equal levels of physical activity throughout the observation period. With normal diets and levels of physical activity, the group without the IRX3 gene stayed nearly 30 per cent leaner than the mice with the gene. When they consumed higher-fat diets, the group that lacked IRX3 maintained their weight and fat levels, while those with the active gene gained nearly twice as much weight and developed metabolic disorders.
The major difference the scientists observed was in the amounts and types of fat the mice developed. The group without IRX3 developed less white adipose tissue (fat), which stores excess energy. Instead, they formed more brown fat, which burns excess energy. This boost in energy consumption made these mice thinner than the control group, which developed more white fat. These findings show that IRX3 controls a group of neurons in the brain that activates brown fat to increase energy expenditure.
“These observations pinpoint the importance of IRX3 as a master regulator of energy homeostasis and its central role in how the brain controls energy expenditure,” says Dr. Chi-Chung Hui, co-senior author, Head & Senior Scientist in the Developmental & Stem Cell Biology program at SickKids and Professor of Molecular Genetics at the University of Toronto.
After performing glucose and insulin tolerance tests, the research team also found that over time, the mice lacking IRX3 were able to process glucose more efficiently than their obese counterparts, suggesting protection against diabetes.
IRX3 codes for a protein that controls gene expression in different cells in the body, including the brain, other organs and fat cells.
This new discovery will help shape future research into obesity prevention, as scientists delve deeper into the molecular actions of IRX3 and the relationship between loss of IRX3 function and increased formation of brown fat.
“We’re interested in what IRX3’s targets are and what they alter. The goal is to identify downstream targets of IRX3 that become models for drug targeting,” says co-senior author Dr. Marcelo Nóbrega, Associate Professor of Human Genetics at the University of Chicago.
“Identifying IRX3 as the “fat” gene contributing to obesity and possibly diabetes is a significant step forward in understanding obesity in humans,” says co-senior author Dr. Jose Luis Gomez-Skarmeta, Geneticist at the Andalucian Center of Developmental Biology in Spain.
“Knowing how IRX3 functions in the hypothalamus will not only lead to a better understanding of how the brain controls energy expenditure, it will also provide the foundation for developing new therapeutic approaches to combat human obesity,” says Hui, whose SickKids team included Dr. Kyoung-Han Kim.
Overweight and obesity affects about one in three people in North America. One in three Canadian children is overweight or obese.
Collaborators in the study included Mount Sinai Hospital in Toronto and Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Spain.
The study is funded by the Canadian Institutes of Health Research, National Institutes of Health, Spanish Ministerio de Economia y Competetividad, Heart and Stroke Foundation of Canada, Andalusian Government and SickKids Foundation.
About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca.
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