Promoting fat breakdown may help prevent diabetes in FA: Study
Treated mice showed higher frataxin levels, lower diabetes risk
Boosting the breakdown of fat promoted higher levels of frataxin, the deficiency of which is a hallmark of Friedreich’s ataxia, and reduced the risk of diabetes in a mouse model of the disease.
The study, “Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich’s ataxia mouse model,” was published in Scientific Reports.
FA is caused by mutations in the FXN gene, which carries instructions for making the frataxin protein. This protein is key for the functioning of mitochondria, the structures within cells responsible for producing energy. Lack of frataxin in people with FA results in impaired cell function, particularly in those of the nervous system and muscles.
Besides well-known motor symptoms, patients with FA can develop diabetes and insulin resistance, a condition in which cells no longer respond to the action of the hormone insulin.
The mechanisms driving insulin resistance and, as a result, high glucose (sugar) levels in this patient population remain largely unknown. To shed light on this, researchers in China used a mouse model of FA genetically engineered to have low levels of human frataxin.
Older mice, younger mice
Results first showed that frataxin deficiency led to insulin resistance in older mice (those aged 40 weeks, or about nine months), but not in control mice carrying normal levels of frataxin.
As the animals gained weight, the scientists attributed insulin resistance to impairments in adipose (fat) tissue. They then found that lipogenesis, a process that converts carbohydrates and other molecules into fatty acids, was enhanced, whereas lipolysis, the breakdown of triglycerides into free fatty acids, was suppressed. Fat tissue was also higher in FA mice than in the controls.
Markers of inflammation, such as the genes coding for interleukin-6, TNF-alpha, and interleukin-1 beta were increased in the FA mice, particularly in adipose tissue. Oxidative stress, a type of cellular damage that arises when toxic oxidative molecules outweigh levels of antioxidants needed to combat them, also was increased in adipose tissue.
The FA mice, however, only developed diabetes when they reached 16 weeks, or about four months, “suggesting a late diabetes manifestation under FXN-deficient condition,” the investigators wrote. But younger FA mice already showed lower expression, or activity, of genes related with the breakdown of fats.
In further experiments, the researchers confirmed that lack of frataxin in adipocytes (fat cells) reduced these cells’ sensitivity, or response, to insulin and inhibited lipolysis. Experiments using adipocytes then showed that boosting lipolysis using a molecule called forskolin compensated for insulin resistance. In mice, boosting lipolysis by fasting or exposure to cold increased Fxn activity.
Feeding mice a high-fat diet for three months led to worse outcomes for FA mice compared with controls. FA mice gained more body weight and fat tissue. Their livers also showed signs of fat accumulation and damage, as indicated by elevated blood levels of liver damage markers aspartate transaminase and alanine transaminase.
Eight-week oral administration of pioglitazone, a medication prescribed for diabetes, increased sensitivity to insulin, reduced the size of adipocytes, and increased the activity of the Fxn gene. No changes in body weight were observed, however.
Overall, “we expected that increasing the lipolysis levels in adipocytes could improve [ease] insulin resistance caused by FXN deficiency,” the scientists wrote. “The intervention at a young age might maximize the benefits.”
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