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Study may lead to new diabetes, heart disease treatments

Jan. 12, 2023, 9:58 AM


by Bill Snyder

Autophagy, a natural process for recycling damaged cellular material, regulates the health of adipose tissue (body fat), which in turn is essential for maintaining proper body temperature and metabolism.

For years autophagy has been an attractive target for researchers seeking new ways to treat metabolic, hormonal and fat storage disorders, including cardiovascular disease and diabetes. The complexity of this pathway, however, has confounded efforts to manipulate it therapeutically.

New findings reported Jan. 3 by researchers at Vanderbilt University Medical Center in the Proceedings of the National Academy of Sciences may help solve this conundrum.

The researchers found that deletion of an autophagy-participating factor named PIK3C3 from the fat cells of mice led to compromised body temperature control, abnormal blood lipid levels, fatty liver and diabetes — abnormalities that resemble those seen in patients with lipodystrophy, a rare fat distribution disorder.

“These findings reveal a crucial role for PIK3C3 in fat tissues, with potential therapeutic implications,” said Luc Van Kaer, PhD, the paper’s co-corresponding author with Lan Wu, MD.

Van Kaer is the Elizabeth and John Shapiro Professor in the Department of Pathology, Microbiology and Immunology, and Wu is research associate professor in the department.

Their research is broadly focused on interactions between the immune and metabolic systems. One area of investigation is the role of autophagy, a cellular “self-eating” process induced by starvation and other types of stress, in the development and function of distinct immune cells, and in the generation of metabolic disease.

The long-term goal is to find ways to manipulate immune and metabolic pathways that aid the development of new therapies for human disease. That’s where PIK3C3 comes in.

PIK3C3 is a lipid kinase (enzyme) important for cellular processes that sort unneeded, old, and damaged cellular components to lysosomes for further degradation and disposal.

The researchers found that deletion of PIK3C3 disturbed autophagy and impaired the capacity of the animals to maintain body temperature.

Deletion also caused generalized lipodystrophy, an abnormal distribution of fatty tissues — too much in some parts of the body, and too little elsewhere — that in humans can lead to severe metabolic, hormonal, and fat storage disorders, including cardiovascular disease and diabetes.

The role of PIK3C3 is complex. While the tissues of mice lacking PIK3C3 became resistant to insulin when the animals were fed a high-fat diet, glucose tolerance, the ability to move glucose from the bloodstream, was preserved.

Understanding how PIK3C3 interacts with other autophagy-participating factors will be critical to developing new therapeutic strategies, the researchers concluded.

Co-authors included Wenqiang Song, PhD, Luke Postoak, PhD, Guan Yang, PhD, Xingyi Guo, PhD, Heather Pua, MD, PhD, Jackie Bader, PhD, Jeffrey Rathmell, PhD, Hanako Kobayashi, PhD, Volker Haase, MD, Katrina Leaptrot, PhD, Alexandra Schrimpe-Rutledge, PhD, Stacy Sherrod, PhD, John McLean, PhD, and Jianhua Zhang, PhD.

This work was supported by National Institutes of Health grants DK081536, DK104817, AI139046, DK105550, CA234920, DK081646, DK020593, DK114809, HL069765, and AR059039, and the American Heart Association.

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