Missing Link Between Genetics And Obesity Identified

Excessive fat accumulation and weight gain may be due to a common genetic variation in the FTO gene, researchers say.

AsianScientist (Feb. 12, 2016) – Taiwanese researchers have revealed how mutations in a gene called FTO result in fat accumulation in mice. Publishing their findings in Science Signalling, the researchers also demonstrate that restoring FTO‘s normal function can reverse weight gain.

After a meal, our body converts excess calories into triglycerides, a type of fat found in blood. These triglycerides are then stored in our adipose tissue, skeletal muscle, and liver, where they can later be released for energy.

High blood concentrations of triglycerides are detrimental as they are often a sign of obesity and metabolic syndrome, both of which increase the risks of heart disease and stroke. Extremely high triglyceride content can also cause acute pancreatitis. FTO, which stands for fat mass and obesity-associated gene, was found to be a risk factor for obesity in 2007 and since then, research has been undertaken to understand its role and function in body weight and metabolism.

In the present study, Dr. Wang Chao-Yung and his team from Chang Gung University focused on adipose tissue as it plays an important role in obesity and is the largest organ in obese patients. They found that feeding mice with a high fat diet increased the concentration of FTO in their adipose tissue at both the mRNA and protein level. They then generated a specific knockout of the FTO gene in the adipose tissue of mice.

Interestingly, the FTO knockout mice had lower triglyceride levels even though they became more obese than normal mice after high fat diet feeding. This finding was surprising, as triglyceride levels are usually higher in obese patients. Upon further research, Wang and colleagues found that mice with no FTO in their adipose tissue had altered triglyceride metabolism.

The team then further employed transcriptome and lipidomics analyses and RNA-immunoprecipitation, which identified Angptl4a as a key mediator between FTO and triglyceride metabolism. Angptl4a is known to stimulate lipolysis in adipocytes.

After FTO knockout, Angptl4 mRNA accumulated in the adipose tissue; however, the protein concentrations decreased significantly. Wang showed that proper translation of Angptl4 mRNA into protein requires FTO activity. Without FTO, Angptl4 mRNA accumulates in cells but not convert into functional Angptl4 protein.

Injections of Angptl4-encoding adenovirus into mice lacking FTO restored triglyceride concentrations to levels similar to that in the control mice, and abolished the excessive weight gain from a high fat diet. These results provide evidence for a functional relationship between Angptl4, FTO and triglyceride metabolism.

Wang and his colleagues now hope to extend these findings into clinical trials to confirm the role of FTO in triglyceride metabolism in humans. In addition, Wang is interested in studying FTO and how it affects epigenetic modifications in adipose mRNA, as well as designing therapeutic approaches to alter these modifications in adipose tissue as part of diabetes or obesity treatments.

The article can be found at: Wang et al. (2015) Loss of FTO in Adipose Tissue Decreases Angptl4 Translation and Alters Triglyceride Metabolism.


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Jeremy is a finishing his PhD in regenerative biology at the Australian Regenerative Medicine Institute (ARMI), Monash University in Melbourne, Australia. In his spare time, he enjoys cooking, traveling, science jokes and teaching Australians how to pronounce his last name.

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