The role of sex adiposity and gonadectomy in the

Authors: M Zügel S Qiu R Laszlo E Bosnyák C Weigt D Müller P Diel J M Steinacker U Schumann

Publish Date: 2016/04/07

Volume: 54, Issue: 1, Pages: 101-110

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Abstract

A sexual dimorphism has been reported for the adipomyokine irisin at rest and in response to exercise The effects of male and female sex adiposity and gonadectomy on irisin secretion have not been investigated before The objective of this study was to elucidate the effects of sex adiposity and gonadectomy in the regulation of irisin secretion as well as PGC1α/FNDC5 mRNA and protein expression We hypothesized that a lack of female sex hormones by ovariectomy reduces irisin levels and inhibits skeletal muscle expression of PGC1α and FNDC5 Circulating irisin was measured in vivo in serum samples of healthy and obese men and women at rest and in response to acute exercise The effects of gonadectomy on serum irisin PGC1α and FNDC5 muscle mRNA and protein expression were investigated in ovariectomized OVX and orchiectomized ORX Wistar rats Serum irisin at rest was not significantly different between men and women lean or obese However in response to acute aerobic exercise irisin levels increased significantly more in lean women versus men p ≤ 005 In obese individuals resting irisin concentrations were significantly higher compared to lean subjects p ≤ 0001 and the irisin response to acute exercise was blunted Only the lack of gonadal hormones in OVX but not ORX rats increased serum irisin levels p ≤ 001 and resulted in significantly increased body weight p ≤ 001 adipose tissue content p ≤ 005 muscle FNDC5 mRNA p ≤ 005 and protein p ≤ 001 expression without altering PGC1α expression Testosterone treatment in ORX rats leads to increased PGC1α mRNA content and reduced PGC1α protein content without affecting FDNC5 expression or serum irisin levels We show that a sexual dimorphism exists for the acute irisin response to exercise in normalweight but not in obese subjects OVX which is associated with increased adiposity and insulin insensitivity increases basal FNDC5 expression and serum irisin without altering PGC1α expression This may be an early sign for metabolic disturbances associated with menopause such as a developing irisin resistance or an attempt of the organism to improve glucose metabolismMaintaining energy homeostasis in response to metabolic perturbations is a major challenge for any multicellular and complex organism involving multiple and sometimes redundant physiological responses 1 The identification of brown BAT and browninwhite brite adipose tissue in humans 2 3 has sparked major interests in BAT biology with the longterm goal to develop treatment strategies for metabolic diseases An elaborate communication network exists between stimuli such as cold exposure sympathetic activation and factors secreted from metabolically active organs such as skeletal muscle myokines and adipose tissue adipokines working together to regulate BAT and brite adipose tissue activity Adipomyokines are considered to mediate many of the beneficial effects of regular exercise for human health Although the precise mechanisms are still under investigation new studies show that crosstalk between the skeletal muscle and adipose tissue secretomes with various tissues and organ systems may play an important role for metabolic function body weight regulation and brain health 4The novel adipomyokine irisin was identified by Bostrom et al in a search for PGC1α target genes coding for secreted proteins They identified the transmembrane protein FNDC5 fibronectin type 3 domaincontaining protein 5 as a PGC1α target which is cleaved to produce soluble irisin They later used adenoviral overexpression of FNDC5 in the liver of mice to show that transgenic mice exhibited enhanced oxygen consumption increased amounts of white adipose tissue WAT browning and improved glucose tolerance and insulin sensitivity 5 There may however be other molecules regulating FNDC5/irisin other than PGC1α since increased PGC1α after electrical stimulation of myotubes exercise mimetics or exercise training in vivo does not necessarily lead to an activation of FNDC5 expression 6 7 8 9 Recently the extracellular signalrelated kinase ERK signaling pathway has been suggested to control FNDC5 expression through a nongenomic pathway during neural differentiation of mouse embryonic stem cells 10 In turn the browning effects of irisin have been shown to depend on the activation of ERK and p38 protein kinase signaling cascades 11 Activation of AMPK may also be involved in FNDC5/irisin activation FNDC5 expression in skeletal muscle was shown to be dramatically reduced in resting muscles of AMPK musclespecific knockout mice compared to wildtype mice 12 In response to muscle contractions AMPK and FNDC5 activation were abolished even though PGC1α was increased in wildtype and knockout mice suggesting that AMPK may be required for the regulation of FNDC5 independent of PGC1α Interestingly myostatin knockout mice exhibit not only increased muscle mass but also browning of WAT which was shown to be driven by AMPK 13 Inhibition of AMPK significantly reduced PGC1α and FNDC5 expression 13 However other studies do not confirm a critical role for AMPK in the regulation of irisin secretion Treatment with the antidiabetic drug metformin increased intramuscular FNDC5 expression and circulating irisin and AMPK inhibition did not abolish this effect 14 The regulation and the physiological actions of irisin are not yet fully understood and further studies are required to identify putative irisin receptors and study the underlying mechanisms responsible for activating FNDC5/irisinIrisin is predominantly secreted from skeletal muscle subcutaneous and visceral adipose tissue 15 16 However a recent immunohistochemical study showed that a number of other tissues such as the liver brain testis spleen and the stomach are also able to produce irisin 17Numerous studies have investigated the potential factors triggering irisin secretion Acute aerobic exercise has been shown to transiently increase irisin levels in humans 7 18 19 20 and mice 21 A recent study suggests that resistance exercise induces a greater irisin response than endurance exercise 22 However this may be due to the low endurance exercise intensity performed in this study Exercise intensity appears to be a relevant factor for irisin secretion since no changes in serum irisin levels were detected after low intensity exercise 8 23 In contrast to acute exercise chronic exercise training has either no effects or even lowers resting irisin levels 7 A recently published metaanalysis from our group revealed that chronic exercise training was associated with a moderate and significant overall effect on decreasing circulating irisin compared with controls 24 Exercise training chronically stimulates numerous signaling molecules and cascades acting in concert to improve skeletal muscle substrate uptake and oxidation such as GLUT4 expression and translocation 25 26 perhaps reducing the need for elevated resting irisin levels or increasing irisin sensitivity Interestingly shivering due to cold exposure also stimulates irisin secretion proportional to shivering intensity and similar in magnitude to intense acute exercise 27 Also acute bouts of wholebody vibration exercise transiently elevate circulating irisin levels 28 Together these findings suggest that muscle contraction is the main stimulus for irisin secretionIrrespective of the controversy regarding a point mutation within the start codon of FNDC5 and its consequences for the secretion of irisin in humans 9 irisin has the potential to be developed as a pharmacological agent since injections of recombinant irisin in obese diabetic mice led to significant reductions in body weight improved glucose homeostasis 11 and reduced triglyceride levels 11Recent data advocate the existence of a sexual dimorphism regarding irisin secretion levels at rest which were shown to be higher in girls versus boys 29 and in women versus men 30 Furthermore after 3 weeks of sprint interval training irisin levels were increased in women and slightly decreased in men 31 Our hypothesis that a lack of female sex hormones by ovariectomy reduces irisin levels and inhibits skeletal muscle expression of PGC1α and FNDC5 is supported by findings of a positive association between 17βestradiol E2 and irisin 32To date no data exist on the effects of sex on irisin levels in response to acute exercise in lean and obese participants and on the lack of sex hormones by gonadectomy on irisin secretion Therefore the aim of this study was to further elucidate the role of sex adiposity and gonadectomy on circulating irisin levels and skeletal muscle PGC1α/FNDC5 expression in I lean and obese men and women at rest and in response to acute exercise and II ovariectomized OVX or orchiectomized ORX Wistar rats

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