Irisin: a new molecular marker and target in metabolic disorder

Abstract: Irisin is a newly discovered exercise-mediated myokine which regulates energy metabolism and has been the subject of much recent research. Irisin plays an important role in metabolic diseases making it a potential new target to combat obesity and its associated disorders, such as T2DM. However, the results of several recent studies investigating the effects of irisin have been controversial. The present review will introduce the discovery of irisin, the role of irisin in metabolic disorders, possible mechanisms, and unanswered questions for future research.

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Alex’s Notes: Irisin is a newly discovered polypeptide that may play a role in energy metabolism. It has gained much attention lately, similar to leptin following its discovery, as a potential target for combating obesity and its comorbidities. Why? Because irisin is remarkable in several respects.

Irisin is a myokine that is secreted by muscle tissue in response to muscle contractions and PGC-1α and acts to “brown” white adipose tissue. Impressively, nanomolar concentrations of irisin, in vitro, increase uncoupling protein-1 (UCP1) expression of white adipocytes by 50-fold, and viral delivery of irisin that causes only a moderate increase (~3 fold) in circulating levels stimulates a 10-20 fold increase in UCP1, increased energy expenditure, and an improvement in glucose tolerance of high fat fed mice. Since these blood levels are within the range experienced by humans after exercise, it is not fat-fetched to assume that irisin has at least a partial role in the beneficial effects of exercise on the browning of adipose tissues and increases in energy expenditure.

The therapeutic benefits are obvious

Yes, they are, and many studies have investigated the associations of irisin with obesity and metabolic syndrome. One study examined irisin levels in middle-aged women with BMIs ranging from 20 to 47 kg/m2 and found irisin to increase with increasing fat-free mass and BMI. Additionally, this study investigated the irisin response to gastric bypass surgery in obese persons and found concentrations to fall significantly after six months, in tandem with weight loss. Another study investigating anorexic, normal-weight, and morbidly obese persons also found positive associations of irisin with BMI, body mass, and fat mass.

While irisin was originally identified as a myokine, there is evidence to suggest that white adipose tissue, especially in obesity, is an important source. It could be that irisin acts as a protective factor against obesity through an attempt to simulate the browning of white adipocytes. However, during pathological states of obesity, irisin simply cannot keep up with the increasing fat storage and cannot maintain energy balance. Wow, this really does sound a lot like leptin doesn’t it?

Recall that irisin’s secretion is regulated by PGC-1α, which is important for mitochondrial biogenesis and metabolism. Expression and activity of PGC-1α has been shown to be lower in persons with type-2 diabetes, and observational evidence suggests that reductions of irisin are a downstream consequence. It has been shown that irisin levels are lower in persons with new-onset diabetes compared to healthy controls. Similarly, irisin levels were significantly lower at the time of birth in women with gestational diabetes compared to healthy pregnant women, while cord-blood irisin levels were not significantly different.

In the new-onset diabetes study referenced above, it was also shown that irisin was significantly negatively correlated with HbA1c and 2-hour plasma glucose during an oral glucose tolerance test (OGTT). Moreover, the 2-hour plasma glucose response was a significant independent predictor of irisin levels, which would explain why persons with poor glucose management have lower serum irisin concentrations in observational studies.

In another very recent study, 136 obese persons underwent a successful eight week hypocaloric diet intervention, but of those who regained the lost weight during the follow-up period, 50% were classified as insulin resistant compared to only 25% of those who maintained the weight loss. It was found that the increased risk of insulin resistance during the follow-up period was related to high irisin levels at baseline.

Irisin is also inversely associated with liver fat, and has been shown to be higher in persons with non-alcoholic fatty liver disease (NAFLD) compared to healthy controls, even after adjustment for BMI, waist circumference, gender, age, and insulin resistance. Serum irisin levels are also greater in persons with polycystic ovary syndrome (PCOS).

Bottom line

Irisin is the new kid on the block and appears to be implicated in many processes similar to leptin. Also similar to leptin, this has spurred attention towards it as a therapeutic agent for the treatment of chronic diseases. While the evidence is slim currently, it should be interesting to see what the future holds for this little guy.


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