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Irisin |
Shivering stimulates irisin secretion through a mechanism mimicked by muscle contraction during exercise |
Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development .
Paul Lee1, Joyce D. Linderman1, Sheila Smith1 et al., Cell Metabolism, Volume 19, Issue 2, 302-309, 4 February 2014 ; doi:10.1016/j.cmet.2013.12.017
 | Shivering stimulates irisin secretion in humans.
Nonshivering cold exposure increases FGF21, which may be a brown adipokine.
• Irisin and/or FGF21 upregulates brown-fat-like program in human adipocytes
• Exercise may be a shivering mimic exemplifying muscle-fat thermogenic crosstalk.
Figure from: Cell Metabolism, Volume 19, Issue 2, 302-309. |
 
In total of ten healthy adults, seven subjects reported shivering and shivering activity and has been quantified by surface electromyography (EMG), also showed irisin increased during cold exposure. By quantification with either by ELISA (Phoenix's EK-067-29 , at the left panel) or by immunobloting (at the right panel ), the serum irisin changes correlated the strongest with shivering among all cold-induced thermogenesis components. Circulating irisin rose in the seven subjects who shivered, and changes in irisin levels correlated positively with shivering activity. Such a good correlation between Phoenix's EK-067-29 and immunobloting analysis was also supported by previous publication of Wen, M.S. et al (PLos One 8, e64025. 2013.), which further validate the usefulness of Phoenix's EK-067-29 for the measurements of serum irisin.
Figure from: Cell Metabolism, Volume 19, Issue 2, 302-309, 4 February 2014. doi:10.1016/j.cmet.2013.12.017
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The adipocytes were treated with 100 nM of PBS vehicle, or FNDC5 (from Abnova), or irisin (from Phoenix Pharmaceuticals) in cellular respirattion experiments. FNDC5 and/or irisin enhanced adipocyte basal level of oxygen consumption rate (OCR), as measured using an extracellular fluid bioanalyzer. FNDC5 and irisin treatments increased the level of basal OCR (0.22 pmol/min/mg protein at the PBS treatment) to a level of 0.41 and 0.37 pmol/min/mg protein, respectively. Both the oligomycin-insensitive uncoupled respiration and maximal uncoupled respiration were increased following FNDC5 and or Irisin treatment. Treating adipocytes with irisin instead of FNDC5 resulted in a similar extent of fat browning on gene, protein, and functional levels, and suggests both FNDC5 and Irisin in the circulation could be biologically active at adipose tissue.
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