Silencing Fat Protein FSP27 Improves Insulin Sensitivity

Highlights

Fat-specific protein 27 (Fsp27), is a lipid droplet-associated protein that prevents lipid mobilization and promotes lipid storage in cells.
Silencing FSP27 reduced levels //of visceral fat, increased insulin sensitivity in both adipose tissue and liver.

Turning off a protein found in liver and adipose tissue significantly improves blood sugar levels, as well as reduces body fat in an animal model.

Angel Baldan, who is associate professor of biochemistry and molecular biology at Saint Louis University, and members of his laboratory examined how lipids are metabolized in both the liver and fat tissue.

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‘Reducing the levels and activity of FSP27 decreases lipid storage in cells and may be beneficial in treating those who are obese or overweight and insulin-resistant.’

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CIDEC (cell death-inducing DFFA-like effector C), also known in mice as Fsp27 (fat-specific protein 27), is a lipid droplet-associated protein that prevents lipid mobilization and promotes intracellular lipid storage. They found that mice treated with antisense oligonucleotides reduce the expression of the protein FSP27.

Fatty liver, marked by high triglyceride levels in the liver, is the most frequent cause of chronic liver disease and contributes to metabolic syndrome, the cluster of factors that raise the risk of heart disease, diabetes and other health conditions.

"Obesity and fatty liver disease are intimately connected and pose a severe public health burden, given their high and growing prevalence in both adults and children," Baldan said.

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In search of better options to treat fatty liver, Baldan looked to one of the proteins that regulate the metabolic fate of lipid droplets.

"When I think of fatty liver disease, I think of fatty hepatocytes -- liver cells. Each cell has many lipid droplets, and those droplets contain triglycerides. The lipid droplets aren't skinny-dipping in the cells, though. They are coated by proteins. One such proteins is called 'fat-specific protein 27', or FSP27," Baldan said.

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FSP27 is a lipid droplet-associated protein that prevents lipid mobilization and promotes lipid storage within the cell. In normal livers, this protein is essentially not present. The amounts of FSP27, however, rapidly increase in the liver after fasting or following a high-fat diet, and they correlate with the accumulation of triglycerides in the liver. In fact, this protein is necessary to accumulate triglycerides in the liver.

Fasting generates a physiological response in which the body turns to stored fat for energy, and as that fat is mobilized from the adipose tissue, it reaches the liver, causing triglycerides to accumulate there.

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FSP27 is necessary for triglyceride accumulation, Baldan hypothesized that obese mice would benefit from silencing this protein.

Baldan and his team studied two groups of mice with obesity, high blood sugar and fatty liver disease: one that consumed a high-fat diet (the dietary model) and another that was genetically modified to have this trait (the genetic model). Both groups of mice then were treated with or without antisense oligonucleotides to silence Fsp27.

Silencing FSP27 resulted in a robust decrease in visceral fat, increased insulin sensitivity in both adipose tissue and liver, and improved whole-body glycemic control in both models. However, despite the improved function of the liver the researchers did not see decreased triglyceride accumulation in the liver. Baldan and his team are currently exploring ways to potentiate the anti-FSP27 treatment to also reduce fatty liver.

Overall, the team found that reducing the levels and activity of FSP27 may be beneficial in treating those who are obese or overweight and insulin-resistant, and that the therapeutic silencing of FSP27 in the mice fed a high-fat diet reduces body fat without worsening fatty liver disease.

"This study suggests that turning FSP27 down has potential as a therapy for insulin-resistant obese or overweight patients," Baldan said.

Reference

Angel Baldan et al., Therapeutic silencing of Fat Specific Protein 27 improves glycemic control in mouse models of obesity and insulin resistance, Journal of Lipid Research(2016), http://www.jlr.org/content/early/2016/11/24/jlr.M069799.

Source-Medindia