Abstract
Irisin is processed from fibronectin type III domain-containing protein 5 (FNDC5). However, a controversy exists concerning irisin origin, regulation and function. To elucidate the relationship between serum irisin and FNDC5 mRNA expression levels, we evaluated plasma irisin levels and FNDC5 gene expression in the hypothalamus, gastrocnemius muscle and different depots of adipose tissue in models of altered metabolism. In normal rats, blood irisin levels diminished after 48-h fast and with leptin, insulin and alloxan treatments, and serum irisin concentrations increased in diabetic rats after insulin treatment and acute treatments of irisin increased blood insulin levels. No changes were observed during long-term experiments with different diets. We suggested that levels of circulating irisin are the result of the sum of the irisin produced by different depots of adipose tissue and skeletal muscle. This study shows for the first time that there are differences in FNDC5 expression depending on white adipose tissue depots. Moreover, a considerable decrease in visceral and epididymal adipose tissue depots correlated with increased FNDC5 mRNA expression levels, probably in an attempt to compensate the decrease that occurs in their mass. Hypothalamic FNDC5 expression did not change for any of the tested diets but increased with leptin, insulin and metformin treatments suggesting that the regulation of central and peripheral FNDC5/irisin expression and functions are different.
Highlights
IntroductionAttempting to correlate plasma irisin levels with metabolic disorders such as obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) (both associated with metabolic syndrome), the results were not consistent among the various studies (reviewed by[15])
Attempting to correlate plasma irisin levels with metabolic disorders such as obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), the results were not consistent among the various studies
The animals subjected to caloric restriction (CR) displayed signs of increased insulin sensitivity because they had the lowest basal glucose and insulin levels
Summary
Attempting to correlate plasma irisin levels with metabolic disorders such as obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) (both associated with metabolic syndrome), the results were not consistent among the various studies (reviewed by[15]). FNDC5 inhibition reduces neurogenesis[17], while its overexpression stimulates neural differentiation[18], and pharmacological doses of irisin increase the proliferation of mouse hippocampal neuronal cells[19] similar to the effects of endurance exercise, a process associated with the increased expression of brain derived neurotrophic factor (BDNF)[20]. Irisin appears colocalized with neuropeptide Y (NPY) in the neuronal cells of the paraventricular nucleus[21]. These findings support the idea that irisin has both peripheral and central functions. The main aim of this study was to test the hypothesis that metabolic status regulates both central and peripheral FNDC5 mRNA expression levels and irisin synthesis and secretion. We used different models of altered metabolism: rats reared with a high-fat diet (HFD) or caloric restriction (CR) for three months, fasting, and treatments with leptin, insulin, metformin, alloxan and alloxan plus insulin
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