Scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have discovered a key biological reason why obesity increases the risk of Type 2 diabetes, and it boils down to size — specifically the size of fat cells.
The study, published in Cell Reports, could lead to the development of new therapies for Type 2 diabetes and other chronic diseases that work by helping fat stem cells differentiate and make new, smaller fat cells.
While researchers have known that obesity disrupts the body’s ability to make new fat cells, they haven’t been able to pin down why. The findings shed new light on this link, establishing for the first time that obesity limits the body’s ability to produce crucial cellular building blocks called ribosomal factors.
Without sufficient ribosomal factors, fat stem cells lack the machinery to differentiate to produce functioning fat cells. Instead, energy gets trapped and they become enlarged.
“Fat tissue has gotten a bad rap, but it’s actually essential for maintaining normal glucose metabolism,” said senior author Dr. Claudio Villanueva, an associate professor of integrative biology and physiology at UCLA. “What happens in obesity is that we have too much fat tissue and it’s also not functioning optimally.”
Fat tissue stores energy from food, but when it’s not functioning properly, the excess energy is then rerouted to be stored elsewhere in the body like in the liver, causing fatty liver disease, or in the heart, leading to cardiovascular diseases like atherosclerosis or stroke.
When obese, diabetic mice — whose fat cells were four to five times larger than those found in lean mice — were given a drug called rosiglitazone, their ribosomal factors increased to normal levels, which triggered their fat stem cells to differentiate to produce new, smaller fat cells. The fat tissue, in turn, was then able to function properly in storing energy and generating key hormones that regulate metabolism.
“What's fascinating is that when given the drug, the mice remained obese, but their Type 2 diabetes essentially disappeared,” said Villanueva, who is also a member of the UCLA Broad Stem Cell Research Center. “It's like replacing one overstuffed storage unit with several smaller ones – the system just works better.”
The findings suggest that enlarged fat cells impair fat tissue function and play a crucial role in diabetes development.
Rosiglitazone is currently being used to treat Type 2 diabetes, but what hasn’t been clear, until now, is what the drug is doing on a molecular level to improve glucose metabolism.
“Understanding exactly how this drug works to restore the body’s ability to metabolize glucose is really important because it now gives us more pathways to target to make new drugs to treat diabetes that are more effective or have less side effects,” Villanueva said.
The implications of this research also extend beyond diabetes treatment. Since obesity is a major risk factor for many other serious health conditions, finding new therapeutics that will restore ribosomal factors to improve glucose metabolism and fat tissue function could also lead to novel treatment strategies for other diseases caused by obesity.
The discovery has a personal significance for Villanueva, who developed an early interest in metabolic health because he has family members who have Type 2 diabetes and experience complications from the disease.
“I’m originally from Nicaragua,” he said. “Latinos have a higher risk for developing obesity and Type 2 diabetes, so I’m hopeful this work will have a positive impact on my community.”
Additional authors of the study include Mirian Krystel De Siqueira, Gaoyan Li, Yutian Zhao, Siqi Wang, In Sook Ahn, Mikayla Tamboline, Andrew D. Hildreth, Jakeline Larios, Alejandro Schcolnik-Cabrera, Zaynab Nouhi, Zhengyi Zhang, Marcus J. Tol, Vijaya Pandey, Shili Xu, Timothy E. O’Sullivan, Julia J. Mack, Peter J. Tontonoz, Tamer Sallam, James A. Wohlschlegel, Laura Hulea, Xinshu Grace Xiao and Xia Yang.
The study received support from the National Institutes of Health, the American Heart Association, the Iris Cantor UCLA Women’s Health Center, the Fonds de Recherche du Québec – Santé and the UCLA Broad Stem Cell Research Center.
