Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies

Abstract

Key pointsr Considerable controversy exists regarding the role of irisin, a putative exercise-induced myokine, in human metabolism.r We therefore studied irisin and its precursor Fndc5 in obesity, type 2 diabetes and exercise. r Complex clinical studies combined with cell culture work revealed that Fndc5/irisin was decreased in type 2 diabetes in vivo, but not in muscle cells in vitro, indicating that diabetes-related factor(s) regulate Fndc5/irisin in vivo.r Several attributes of type 2 diabetes, such as hyperglycaemia, triglyceridaemia, visceral adiposity and extramyocellular lipid deposition were negatively associated with adipose tissue Fndc5 mRNA and circulating irisin. Moreover, mimicking diabetic status in vitro by treating muscle cells with palmitate and glucose lowered Fndc5 mRNA.r Neither exercise training nor an acute exercise bout modulated circulating irisin or muscle Fndc5 expression. However, the associations between intensity of habitual physical activity, muscle volume, strength, contractility and circulating irisin provide a link between irisin and positive outcomes of increased physical activity.Abstract Irisin was identified as a myokine secreted by contracting skeletal muscle, possibly mediating some exercise health benefits via 'browning' of white adipose tissue. However, a controversy exists concerning irisin origin, regulation and function in humans. Thus, we have explored Fndc5 gene and irisin protein in two clinical studies: (i) a cross-sectional study (effects of type 2 diabetes (T2D) in drug-naive men) and (ii) an intervention study (exercise effects in sedentary, overweight/obese individuals). Glucose tolerance and insulin sensitivity were assessed. Maximal aerobic capacity and muscle strength were measured before and after training. Body composition (magnetic resonance imaging), muscle and liver fat content ( 1 H-magnetic resonance spectroscopy (MRS)) and in vivo muscle metabolism ( 32 P-MRS) were determined. Skeletal muscle and subcutaneous abdominal adipose tissue samples were taken in the fasted state and during euglycaemic hyperinsulinaemia (adipose tissue) and before/after exercise training (muscle). We found that muscle Fndc5 mRNA was increased in prediabetes but not T2D. tissue and irisin in plasma were reduced in T2D by 40% and 50%, respectively.

New insights into the effects of irisin levels in HIV-infected subjects: correlation with adiposity, fat-free mass, and strength parameters

“…Although the skeletal muscle is the tissue with the highest expression of FNDC5/ irisin (2), other tissues, including the adipose tissue, are responsible for secreting irisin (6,7,23). Additionally, the expression of irisin is upregulated in individuals characterized as obese when compared with others who have a normal weight and are anorexic.…”

“…In sedentary, overweight, and obese individuals, plasma irisin levels were positively associated with maximal contraction force and rate of force development after 12 weeks of resistance and endurance training (23). A decrease in irisin secretion contributes to muscle insulin resistance in high-fat diet mice (28).…”

Regulation of De Novo Adipocyte Differentiation Through Cross Talk Between Adipocytes and Preadipocytes

“…Both studies adhere to the ethical guidelines of the 2000 Declaration of Helsinki, and all study participants provided witnessed written informed consent before entering the study. Details of the study groups and the techniques for clinical parameter assessment have previously been published (14,15). Vim expression was analyzed in 24 samples, and the other targets were analyzed in a subpopulation of 16 patients.…”

Obese with higher FNDC5/Irisin levels have a better metabolic profile, lower lipopolysaccharide levels and type 2 diabetes risk

“…Some authors have suggested a possible "irisinemia" as a compensatory effect of organism to try maintain the metabolic homeostasis by irisin secretion (27). However, the better hypothesis must be the negative influence of hyperglycemia and serum lipids on FNDC5/irisin levels, since free fatty acid and glucose in vitro stimulation decrease expression/secretion of these peptides (28). Our metabolic results associated a cluster of FNDC5/irisin levels bring similar clinical evidence of this in-vitro study, and consolidate the studies that observed lower levels of FNDC5/irisin correlated with dysfunctions and metabolic diseases (6,8,29,30).…”

“…Our present results seem to indicate that this negative LPS influence in browning process could also involve a decrease of FNDC5/irisin, one of the main stimulator of these process. Reinforce this idea the higher fat intake in SIG because the increase of fat, specially the saturated type, is related to LPS absorption, thus the LPS increase could be an inhibitor of FNDC5/ irisin, as observed by excess of glucose and free fat acids (28), which could explain the LPS as a negative regulator of browning (33). Previous study found a positive correlation between FNDC5/irisin levels and carbohydrate intake (34), indicated, together with our result that FNDC5/irisin and macronutrients might have an important interaction that certainly needs to be deeply addressed in future researches, as well as better analyze the relationship between FNDC5/irisin and LPS.…”