Research may improve obesity and type 2 diabetes treatments

Advanced treatments for obesity and type 2 diabetes are edging closer to reality through research underway at Wright State University. The developing treatments depend on the functions of a mysterious protein.

The protein, lipin-1, has long existed. But it was only recently, less than a decade ago, that scientists began to tease apart the roles it plays in the human body. “There’s still a lot about this protein that we don’t know. It has very broad applications,” said Hongmei Ren, Ph.D., assistant professor of biochemistry and molecular biology at the Boonshoft School of Medicine and the College of Science and Mathematics.

Ren has studied the protein and its two other isoforms for years. It’s clear, however, that she and other scientists considering the protein have barely scratched the surface of its potential.

Lipin-1 has a lot of functions. It has roles in lipid metabolism, affecting cardiac and skeletal muscle function. In patients who have a deficiency, they commonly exhibit severe rhabdomyolysis, muscle atrophy and weakness accompanied with impaired mitochondrial function.

“We found that lipin-1 deficiency caused blockages of dysfunctional mitochondrial clearance,” Ren said. “That could potentially affect skeletomuscular organization, alignment, muscle mass, and muscle fiber development.”

Due to a lack of sensitive antibodies, current detection methods limit further understanding of the role of mitophagy, or mitochondrial degradation, in muscle wasting.

“We recently generated a unique model which will allow us to track the effect of lipin-1 deficiency on mitophagy and muscle damage processes,” Ren said. “The efforts have improved understanding of the role of lipin-1 in mitochondrial clearance.”

Ren’s team is trying to figure out the role of lipin-1 and the molecular signaling pathways it uses for regulating mitophagy.

“Our unique models are allowing us to better understand the physiological roles of the protein in mitophagy and how it impacts skeletal muscle function,” Ren said.

If her team can unlock those mysteries, it may be possible to use the knowledge to better regulate cell activities, such as mitochondrial clearance, that are useful in improving mitochondrial quality control and the production of ATP.

Getting there has proven complicated, in part because of the protein’s many different roles. Lipin-1 also has a nuclear function, acting as an agent for gene expression. Past studies have shown the protein can be recruited to the surface of mitochondria and regulate lipid composition. In addition, enzymes of lipin-1 are important for cellular signaling and fission. The actual mechanisms involved are still not fully understood.

Ren’s research group is also working to explore the role of lipin-1 in brown fat development. “Hopefully, we can identify how it regulates brown adipose tissue development and understand the signaling pathways regulating the process,” Ren said. “This could allow us to convert white fat to brown fat, which could one day serve as a therapeutic strategy for obesity and type 2 diabetes.”

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