Irisin: The Surprising Benefits About This Exercise Hormone

Lose Weight, Increase Cognition, and Fight Aging

Irisin is an anti-obesity and anti-diabetes hormone that regulates fat tissue and blood sugar. R




Preptinadropin and irisin are three co-workers in the regulation of energy homeostasisR

Irisin was discovered in animals and then later on in humans in 2012. R

Since irisin works on muscles and fat, it is a myokine and an adipokine. R

Myokines are a type of cytokines that have autocrine, paracrine and endocrine effects, mostly secreted by skeletal muscle. R

Irisin is generated by exercise and acts as an insulin-sensitizing hormone. R

Irisin is so powerful that even moderately increased levels of circulating irisin potently increases energy expenditure, reduces body weight and improves diet-induced insulin resistance. R

Low irisin levels can predict:

  • Metabolic Syndrome R
  • Breast Cancer R
  • Fatty Liver Disease R
  • Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis R
  • Type 2 Diabetes R R
  • Coronary Artery Disease R
  • Major Adverse Cardiac Events (such as Heart Attack)  R
  • Atherosclerosis and Behçet’s Disease R
  • Cholesterol Levels (inversely correlated) R
  • Hyperglycemia R
  • Sleep Apnea R
  • Chronic Kidney Disease R

High irisin levels can predict: 

  • Acute Appendicitis (with high neutorphil count) R
  • Liver Cancer R
  • Type 1 Diabetes R
  • Obesity and Morbid Obesity (probably signaling irisin resistance) R R
  • Polycystic ovary syndrome R
  • Pregnancy (increases throughout pregnancy) R
  • Hypothyroidism R

Higher levels may indicate "irisin resistance" (see caveats). 

Irisin is generally higher in the summer/winter, but lower in the fall/spring. R

It also plays a role in reproductive function. R

Mechanism Of Action


Irisin is comprised of 112 amino acids. R

It is produced in muscles and fat tissue. R

It is also synthesized in the brain (hypothalamus along with Neuropeptide Y), cerebrospinal fluid, heart muscle, along with peripheral tissues, including salivary glands, kidney and liver. R R

Exercise increases expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha). R

This causes the production of fibronectin type III domain-containing protein 5 (FNDC5), the precursor of irisin. R


  • Crosses the blood brain barrier R
  • Enhances expression of IL-15, Fndc5, VEGFβ, Lrg1 and TIMP4 (through PGC1alpha expression in vivo) R
  • Increases AMPK expression R
  • Increases ERK/MAPK pathway R
  • Increases PPARα R
  • Increases BDNF R
  • Increases NO production and phosphorylation of eNOS R
  • Independent of lactate levels R
  • Independent of Growth Hormone R
  • Independent of Leptin R
  • Decreases myostatin (myostatin impairs lipid and glucose metabolism) R
  • Decreases FABP4 (FABP4 increases adipose tissue) R
  • Decreases HbA1c R
  • Reduces ROS (via UCP1) R
  • Reduces IL-6, TNF-alpha, MIP-1α, and MIP-1β R
  • Reduces Orexin, Dopamine (DA) and Norepinephrine (NE) in the hypothalamus, but increases NE in plasma R 


1. Balances Blood Sugar And Fights Diabetes


Irisin improves blood sugar regulation.

It increases glucose tolerance and reduces insulin resistanceR R

Irisin signals via AMP-activated kinase (AMPK) pathway to mediate glucose uptake and fatty acid oxidation. R

It also lowers hemoglobin A1c. R

Irisin may also play an important role in the regulation of maternal–fetal glucose homeostasis. R

Low levels of irisin is associated with impaired carbohydrate metabolism in infants. R

In animal models with Type 1 Diabetes, irisin helped repair cells. R

2. Improves Weight Loss


Irisin improves weight loss.

It does this through PGC1αR

PGC1α is induced in muscle by exercise and stimulates many of the best known beneficial effects of exercise in muscle: mitochondrial biogenesis, angiogenesis and fiber-type switching. R

PGC1α induces FNDC5R

FNDC5 is the precursor of irisin. R

FNDC5 promotes the conversion of white fat to brown fat (thermogenesis via PPARα). R R R

FNDC5 influneces UCP1, which also contributes to the browning of white fat. R

Brown fat has more mitochondria than white fat, so it is able to burn faster and give you more energy. R

Irisin can also decrease food intake. R

When rats were injected with irisin into the hypotalamus, they ate less. R

3. Supports The Skeletal System


In mice, irisin released from skeletal muscle during exercise acts directly on bone by increasing cortical bone mineral density, bone perimeter and polar moment of inertia. R

It may promote bone formation so that bones can better adapt to the increased load during persistent exercise. R

It can do it without browning response of adipose tissue when given at a lower dose. R

It may help with osteoperosis. R R

It also provides resistance to muscular dystrophy and denervation-linked muscular atrophy.

Irisin has also been shown to be positively correlated with bone mineral density in adolescent women. R

4. Is Anti-Aging


Irisin legnthens telomeresR

Telomere shortening is a genetic marker of agingR

Irisin also decreases with age. R R

Increasing irisin may therefore decrease aging.

5. Is Anti-Cancer

Irisin expression may help hepatic cancer. R

It has also shown to protect normal cells and create apoptosis (cell death by 22-fold) in cancer cells. R

Irisin levels are lower in hepatic and breast cancers, suggesting a possible protective role. R R

6. Protects The Heart, Brain and Vascular System


A mouse study showed that irisin might have a preventive role in atherosclerosis. R

Administration of irisin protected against endothelial injury and ameliorated atherosclerosis by inhibition of oxidative stress. R

Also, irisin decreased the plaque area and the infiltrating macrophages and T lymphocytes in the plaques, and down-regulated the mRNA expression of inflammatory cytokines in the aortas. R

Higher irisin levels may contribute lower total cholesterol in both men and women. R

It also decreases the oxidative stress from LDL cholesterol. R

In rats with hypertension, irisin was able to lower blood pressure by increasing nitric oxide (via AMPK-Akt-eNOS- NO Pathway). R  

HDAC4 overexpression can induce cell death, increase lactate leakage, and mitochondrial dysfunction. R

Irisin is able to significantly attenuate all of these effects and help with reoxygenation, making it beneficial for stroke, heart attack, and other hypoxic events. R

Thus, irisin may be the reason why we don't suffocate in anaerobic exercise. 

7. Is An Anti-Inflammatory And Anti-Oxidant

Irisin can attenuate inflammation of macrophages (shifting them towards a M2 state). R

It can also reduce levels of IL-6, TNF-alpha, MIP-1α, and MIP-1βR

Irisin can prevent oxidative stress in the liver (through the inhibition of protein arginine methyltransferase-3). R

Since irisin works on UCP1, it can decrease reactive oxygen species (ROS). R

8. Is An Anti-Depressant

In an animal study, irisin was able to ameliorate depressive-like behaviors by regulating energy metabolism. R

9. Increases Brain Function


Irisin increases cognitive function. R

In animals, FNDC5 inhibition reduces neurogenesis, while overexpression stimulates neural differentiation. R

It can also increase brain derived neurotrophic factor (BDNF). R

By working on BDNF, irisin may also work on the dopaminergic system, enhancing the motivation/reward system. R

Irisin also works on GABA and the GABAergic system. R

Dysfunction of the GABAergic system may contribute to cognitive impairment in humans. R

Specifically, individuals with Alzheimer’s disease have decreased cerebral GABA in the brain and CSF50. R

Furthermore, GABA levels in human CSF decrease with aging, which has been associated with cognitive impairment. R

The expression of irisin in the GABAergic brain cells might, to some extent, explain its effects on the central nervous system-mediated functions. R

Irisin upregulates PGC-1αR

PGC1α deficient mice show a significant brain deficiency. R

PGC-1α is usually under-expressed in Parkinson’s disease and Lewy body disease patients. R

PGC-1α by dietary treatment might benefit cognitive function and synaptic plasticity in Alzheimer’s disease by preventing Aβ production in the brain. R




  • rs3480
    • GG associated with decreased risk of obesity and lower body mass index values R
    • (GGAAG) was identified as the protective haplotype against risk of obesity R
  • rs1746661
    • G allele associates with higher triglyceride levels R
  • rs157069
    • TT genotype associated with higher fasting insulin and HOMA-IR R
    • TT lower circulating irisin levels (p = 0.016) R


UCP1 expresses irisin in the body (fatty tissue and skeletal system). R

UCP2-5 express irisin in the brain and may play roles for certain brain functions. R

Testing and Levels

In one study, irisin levels were 3.6 ng/mL in sedentary individuals and increased to 4.3 ng/mL in individuals undergoing aerobic exercise. R

During pregnancy, IL1β, IL-5, IL-7, and IP-10 can predict irisin levels. R

Irisin is higher in women than men (and similarly girls vs boys). R R

Estrogens play a role in irisin levels, so it is a good idea to get that checked. R

How To Increase Irisin



A high fat diet increases browning of tissue (by upregulation of UCP1). R


Irisin is dependent on muscle contraction and intensity of an exercise. R

So the more intense the exercise, the more irisin you'll produce. R

It is important to note that chronic exercise does not increase irisin levels well, but single bouts of exercise increase it significantly. So, this may explain why extensive marathon training may be detrimental to health. R

Also, it is important to know that the more fat you have, the higher your irisin levels can get after exercise. R

Irisin is also dependent of muscle mass. R

Exercise increases irisin more in lean women than lean men. R

From order of greatest irisin release to least:

  • Resistance Exercise (High Intensity Strength Training, increases irisin more than endurance training) R R
  • Endurance training (Increases irisin levels 2x more than aerobic exercise) R
  • HIIT (High Intensity Interval Training, irisin levels increase after 6 hours for 13 hours.) R
  • Acute aerobic exercise R 
  • Swimming (shown in rats) R
  • Low Intensity Exercise R

Cold and Heat Thermogenesis


  • Growth Hormone R R R
  • Leptin R
  • Deficiency in Estradiol (so an ovariectomy could decrease irisin) R
  • Myostatin Inhibition R


  • CoQ10 (enhances UCP1 uncoupling to increase brown fat) R R
  • Holy Basil (increased IGF1 and irisin if combined with resistance training) R 
  • Metformin R R
  • Fenofibrate R R



  • Going Into Labor R
  • Recombinant GST-Irisin (in vitro) R
  • FoXO1 actiavtion R

Decrease Irisin

  • Fasting R
  • Short Term Caloric Restriction (in subcutaneous fat) R
  • Insulin (decreased irisin in plasma, but increased irisin in hypothalamus) R
  • Chronic Bad Sleep R
  • Increasing Myostatin R
  • AMPK inhibition R
  • ROCK1 activation (inhibits UCP1 and PGC1a, reducing browning of fat) R
  • TGF-beta R


Obesity/insulin resistance may promote “irisin resistance”. R

That would mean higher levels of circulating irisin would have less of an effect on fat tissue.

Taking the actions above would help with irisin resistance.

More Research

  • Exogenously administered irisin induces the browning of subcutaneous fat and thermogenesis, and it presumably could be prepared and delivered as an injectable polypeptide. R