Discovery of Gpr45 gene activity in brain cilia sheds light on genetic roots of overeating microbiologystudy

Using a tool called Automated Meiotic Mapping (AMM) that was developed at UT Southwestern Medical Center, a team of researchers has identified a gene that appears to be key to regulating food intake.

The findings, published in Science, could lead to new strategies for fighting obesity, a condition that affects about 40% of U.S. adults and more than a billion people worldwide.

“This research uncovers a previously unknown signaling pathway in tiny, antenna-like structures on brain neurons that plays a critical role in controlling appetite, opening new doors for anti-obesity treatments,” said study leader Zhao Zhang, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Internal Medicine at UT Southwestern.

The influx of weight-loss drugs in recent years has revolutionized the health care industry, not only delivering sustained results but also providing significant benefits to cardiovascular health, blood sugar management, and regulation of blood pressure and cholesterol. This latest research opens the door to new targets that could be used alone or with existing weight-loss drugs to control appetite.

Body weight is thought to be influenced by a combination of environmental factors and genetics. However, finding gene variants that contribute to weight gain in humans is challenging because diets and lifestyles vary dramatically, Dr. Zhang explained. Thus, to better understand the genetics of obesity, he and his colleagues turned to forward genetics, enhanced by AMM.

The AMM approach—developed by UTSW Nobel Laureate and study co-author Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine—involves inducing genetic mutations in mice, screening for certain traits, and then identifying the causative mutation in real time based on genotypic analysis and high-speed computation, combining statistical analysis with artificial intelligence.

Using this strategy, the research team homed in on two different mutations in a gene called Gpr45, both of which led affected animals to become obese on a standard diet.

Deleting Gpr45 in healthy mouse embryos using the gene-editing tool CRISPR caused the same result, confirming that this gene plays a key role in regulating body weight. Further experiments showed that the rodents’ unhealthy weight gain, which started by six weeks of age, was caused by significant overeating compared to littermates that didn’t carry the mutations.

Because previous research at UTSW and elsewhere has shown that feeding behaviors are typically regulated by a brain region known as the hypothalamus, Dr. Zhang and his colleagues looked to see whether GPR45, the protein product of the Gpr45 gene, was expressed there.

Not only did they find this protein active in hypothalamic neurons, but they also narrowed its location down to small cellular extensions called primary cilia. Proteins produced by other genes that control appetite, such as MC4R, are also found in primary cilia.

Both MC4R mutations and a growing number of rare genetic disorders known as ciliopathies have been linked to pediatric obesity. But the role of obesity-linked proteins in primary cilia has been unclear.

Dr. Zhang’s team found that GPR45 serves as a transporter, moving a protein known as Gαs from the cell’s interior into primary cilia, where it switches on MC4R to control appetite.

The mutations identified through forward genetics appear to hinder this migration; without GPR45 present in the cilia, MC4R stays off, prompting the animals to overeat.

Two drugs that target MC4R already exist, Dr. Zhang explained, but they are only approved by the Food and Drug Administration to treat obesity caused by rare genetic mutations that affect the MC4R pathway. Because this gene is active in other tissues and the drugs may activate similar receptors, they can’t be used to treat obesity due to other causes.

He suggests that developing drugs to increase GPR45’s activity could offer a novel alternative to fighting obesity.