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GTF2IRD1 molecule

GTF2IRD1 molecule reduces obesity and diabetes in mice

The researchers discovered that GTF2IRD1 levels inversely correlated with the amount of fibrosis in the subcutaneous fat tissue of these individuals

UC San Francisco researchers have discovered a new biological pathway in fat cells that could explain why some people with obesity are at high risk for metabolic diseases. The new findings, demonstrated initially in mice and supported by data from human patients, could lead to new biomarkers to predict who is at risk and guide treatments to reduce the medical burden of obesity.

"It turns out that only about 30 percent of people with obesity are really high risk,” said Dr Suneil Koliwad, assistant professor in the UCSF Diabetes Center and one of the new study's two senior authors. “The problem is that fundamentally we don't know why some people with obesity go on to develop diabetes and others don't.”

The research, ‘Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis, Cell Metabolism’, published in Cell Metabolism, suggests that the link between obesity and diabetes may depend on fat cells' ability to control adipose fibrosis - an accumulation of collagen in fat tissue that cause it to become stiff and inflexible - which is known to be linked to increased inflammation and metabolic dysfunction.

The research was initiated by Dr Shingo Kajimura, an associate professor of cell and tissue biology in UCSF's School of Dentistry, member of the UCSF Diabetes Center and the paper's other senior author. Kajimura is known for discovering that human fat cells can shift between two states - energy-storing white fat and energy-burning beige fat, which helps your body generate heat in response to cold temperatures. Kajimura's team had previously shown that mice with more beige fat are protected against obesity and diabetes, and has been working to identify the biological factors that cause white fat to transform into beige fat, with the aim of developing therapies for obesity.

As part of an unbiased high-throughput screen to identify such cold-sensitive molecules, Kajimura's team has now identified a new signalling molecule in fat cells that appears to reduce the risk of obesity and metabolic disease in mice by a totally different mechanism. The molecule, a transcription factor called GTF2IRD1 – also responds to cold temperatures, but rather than causing beige fat cells to burn more calories for heat, it acts by reducing fat cells' production of the collagen molecules that contribute to fibrosis in fat tissue.

In mice fed a high-fat diet that typically leads to obesity, the researchers found that boosting GTF2IRD1 levels in fat cells dramatically reduced fat fibrosis and improved glucose metabolism, while impairing or blocking GTF2IRD1 had the opposite effect, resulting in heightened fibrosis and impaired glucose metabolism.

"These were surprising and exciting results," said Kajimura. "We used to think that adipose tissue fibrosis was just a consequence of ‘unhealthy fat’, but this study suggests that fibrosis is an important therapeutic target to prevent obesity and metabolic disease in humans."

Based on these findings, Kajimura struck up a collaboration with Koliwad's team, who analysed the expression of GTF2IRD1 by fat cells in a cohort of 48 human subjects with varying degrees of obesity participating in Koliwad's ongoing Inflammation, Diabetes, Ethnicity, and Obesity (IDEO) study.

The researchers discovered that GTF2IRD1 levels inversely correlated with the amount of fibrosis in the subcutaneous fat tissue of these individuals: people with the highest levels of the transcription factor almost universally exhibited less fibrosis, while those with the lowest levels of GTF2IRD1 had more fibrosis. 

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