Genetics / molecular biology

Understanding obesity from the inside out: new lab method reveals roles of GABA in the control of appetite and metabolism

By Ana María Rodríguez, Ph.D.

 Aminoglycoside (AG)-mediated nonsense suppression of the pre-mature termination codon (PTC). Without treatment of AG, the majority of PTC-bearing mRNAs is rapidly degraded by the process of nonsense-mediated decay (NMD), whereas only a small fraction of the transcripts can be translated into truncated, non-functional peptides. In contrast, AG, such as geneticin (G418), promotes readthrough of PTCs during the translation, thereby restoring full-length functional proteins. Of note, a random amino acid (blue spheres) is incorporated into the PTC locus through AG-mediated non-sense suppression. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3645-50. doi: 10.1073/pnas.1602049113.


Aminoglycoside (AG)-mediated nonsense suppression of the pre-mature termination codon (PTC). Without treatment of AG, the majority of PTC-bearing mRNAs is rapidly degraded by the process of nonsense-mediated decay (NMD), whereas only a small fraction of the transcripts can be translated into truncated, non-functional peptides. In contrast, AG, such as geneticin (G418), promotes readthrough of PTCs during the translation, thereby restoring full-length functional proteins. Of note, a random amino acid (blue spheres) is incorporated into the PTC locus through AG-mediated non-sense suppression. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3645-50. doi: 10.1073/pnas.1602049113.

The average American is more than 24 pounds heavier today than in 1960. Around the world, obesity has more than doubled in the last 40 years. Obesity is a major risk factor for chronic diseases, including diabetes, cardiovascular diseases and cancer and it is a problem of high- and low-income countries affecting adults and children alike. Obesity has raised much interest in the research arena and at Baylor College of Medicine, Technion-Israel Institute of Technology  and the University of Washington, researchers are studying it from the inside out.

The researchers developed a new laboratory method that allowed them to identify GABA as a key player in the complex brain processes that control appetite and metabolism. The team’s results were published in the journal Proceedings of the National Academy of Sciences.

Dr. Qi Wu, assistant professor of pediatrics and nutrition at the USDA/ARS Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital, led the team that for several years searched for new laboratory methods to better study the function of GABA in the brain.

GABA is a chemical messenger produced by brain cells. It binds to other brain cells via specific receptors and reduces the cells’ activity. Research has implicated GABA in the complex neurological processes that control fear and anxiety, and also in those related to the control of appetite and metabolism. But direct proof of the role GABA plays in weight control has been elusive in part for the lack of better methodology to precisely control GABA production by brain cells.

A new experimental method to uncover the role of GABA in the control of appetite

Qi Wu, Ph.D.

Qi Wu, Ph.D.

“We developed a new experimental system based in in-frame, nonsense mutations and aminoglycosides (Figure), which allowed us to abruptly stop the synthesis of GABA in adult animals,” Wu said. “We were able to silence the genes involved in the synthesis of GABA in a particular set of cells located in the hypothalamus, the brain area that controls appetite. As a results, these cells, called AgRP neurons, stop producing GABA as quick as in four days.”

Wu and colleagues then observed the changes in weight and the behavior of these mice lacking GABA in their brain area for control of appetite.

The researchers studied two groups of mice; 2-month old young adults, and 8-month old mice. The young adult mice without GABA stopped eating, lost tremendous amount of weight, increased their physical activity, and became glucose intolerant. On the other hand, the much older mice only lost their appetite temporarily.

The findings are significant to the study of obesity as they strongly indicate that GABA is a potential candidate for targeted drug design that may lead to medications that help control appetite and metabolism.

“Our hope is that the new and better methodology we have developed will be used by other genetics labs as a tool for selectively silencing other genes,” Wu said.

Other researchers involved in this work are Wu lab team members Fantao Meng, Yong Han, Dollada Srisai, Mónica Farías and Yong Xu; Valery Belakhov and Timor Baasov from Technion-Israel Institute of Technology; and Richard D. Palmiter from the University of Washington.

This work was supported by the Pew Charitable Trust; American Diabetes Association Junior Faculty Award #7-13-JF-61; Baylor Collaborative Faculty Research Investment Program grants; USDA/ARS CRIS grants; new faculty start-up grants from Baylor College of Medicine and the University of Iowa; NIH grants R01DK093587, R01DK101379, and R01-DA24908. The authors include an HHMI Investigator, a Pew Scholar of Biomedical Sciences and a Kavli Scholar.

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