Blind Spot for Sedentarism: Redefining the Diseasome of Physical Inactivity in View of Circadian System and the Irisin/BDNF Axis

Abstract

Introduction: The term “diseasome of physical inactivity” was coined by Pedersen to explain clustering of chronic diseases linked to physical inactivity. Accordingly, physical inactivity per se contributes to the accumulation of visceral fat, which, generates chronic low-grade systemic inflammation, contributes to emergence of chronic, non-communicable diseases. Diversity of these disorders posits the possible involvement of a supraphysiological system.Methods: Hypothesis driven literature search and deductive reasoning was used to review relevant literature and formulate a novel theory.Results: We have identified the circadian system, omnipresent in virtually every cell, as a possible vehicle for brain muscle crosstalk, explaining some aspects of the diseasome of physical inactivity This system is hierarchically organized, with the suprachiasmatic nucleus (SCN) being the master clock that entrains to the dark/light cycle and synchronizes subsidiary molecular clocks in the periphery. Insufficient photic entrainment also causes chronic disease evolution. The recently identified irisin, was shown to induce brain-derived neurotrophic factor (BDNF) production in several brain areas. BDNF assumes significant role in gating light's influence in the retinohypothalamic synapse, by having a permissive effect on glutamate signal transduction underlying photic entrainment.Conclusions: Here we provide theoretical evidence to support the hypothesis that irisin may facilitate photic entrainment of the SCN, via BDNF. By this irisin opens up possible pathways for peripheral non-photic entrainment signals to exert influence on the master clock that is otherwise resistant to these. Furthermore, we suggest that intertwining processes of circadian, redox, inflammatory, and myokine systems lay underneath the diseasome of physical inactivity.

Irisin Stimulates the Release of CXCL1 From Differentiating Human Subcutaneous and Deep-Neck Derived Adipocytes via Upregulation of NFκB Pathway

“…Irisin can exert non-thermogenic effects on several tissues, including the liver ( Tang et al, 2016 ), central nervous system ( Ferrante et al, 2016 ; Zsuga et al, 2018 ), blood vessels ( Han et al, 2015 ), or the heart ( Xie et al, 2015 ). In mouse osteocytes, irisin acts via a subset of integrin receptor complexes, which are assembled from ITGAV and either ITGB1, ITGB3, or ITGB5 ( Kim et al, 2018 ).…”

Irisin/BDNF signaling in the muscle-brain axis and circadian system: A review

“…It was reported that a single injection of irisin into the third brain ventricle caused an enhanced motor activity along with a reduction of resting time in rats [ 48 ] . Moreover, it was suggested that irisin released during the exercise could mediate muscle-brain crosstalk by linking the activity and circadian rhythms, thus providing the capacity to react adaptively to the environment [ 56 ] , which is consistent with the concept of entrainment of the SCN clock by exercise, and with the proposed involvement of irisin in the mechanism of entrainment [ 11 , 15 , 56 ] .…”

“…One study found that a time-restricted feeding at ZT0-4 (zeitgeber time) produced a significant long-term delay of the activity offset in mice [ 74 ] , further indicating an important role for the insulin-like growth factor 2 (IGF2)/potassium chloride cotransporter 2 (KCC2) signaling in these behavioral changes. It is also suggested that the SIRT1/PGC-1α amplifying loop is involved in the entraining effect of restricted feeding [ 56 ] , which involves the activation of PGC-1α by stimulation of free fatty acid and β-hydroxybutyrate synthesis, or SIRT1-associated modulation of the NADH/NAD + ratio [ 17 , 75 ] . It was hypothesized that PGC-1α, either by local production or by the induction of irisin expression, might increase BDNF levels to the amount sufficient for the facilitation of glutamate transmission and entrainment of the SCN clock [ 56 ] .…”

“…It is also suggested that the SIRT1/PGC-1α amplifying loop is involved in the entraining effect of restricted feeding [ 56 ] , which involves the activation of PGC-1α by stimulation of free fatty acid and β-hydroxybutyrate synthesis, or SIRT1-associated modulation of the NADH/NAD + ratio [ 17 , 75 ] . It was hypothesized that PGC-1α, either by local production or by the induction of irisin expression, might increase BDNF levels to the amount sufficient for the facilitation of glutamate transmission and entrainment of the SCN clock [ 56 ] .…”

Irisin: A bright or a dark future?

“…This could represent a great advance in the understanding of neurodegenerative diseases, such as Alzheimer's disease, and could open the door for future therapeutic approaches in the management of these disorders, leading to an improvement of brain function. 8,[62][63][64][65] Irisin has already been studied as a molecular diagnostic marker for cardiovascular diseases. Decreased circulating irisin levels are associated with increased cardiovascular risk.…”