Abstract
Thermogenic brown and beige adipocytes might open up new strategies in combating obesity. Recent studies in rodents and humans have indicated that these adipocytes release cytokines, termed “batokines”. Irisin was discovered as a polypeptide regulator of beige adipocytes released by myocytes, primarily during exercise. We performed global RNA sequencing on adipocytes derived from human subcutaneous and deep-neck precursors, which were differentiated in the presence or absence of irisin. Irisin did not exert an effect on the expression of characteristic thermogenic genes, while upregulated genes belonging to various cytokine signaling pathways. Out of the several upregulated cytokines, CXCL1, the highest upregulated, was released throughout the entire differentiation period, and predominantly by differentiated adipocytes. Deep-neck area tissue biopsies also showed a significant release of CXCL1 during 24 h irisin treatment. Gene expression data indicated upregulation of the NFκB pathway upon irisin treatment, which was validated by an increase of p50 and decrease of IκBα protein level, respectively. Continuous blocking of the NFκB pathway, using a cell permeable inhibitor of NFκB nuclear translocation, significantly reduced CXCL1 release. The released CXCL1 exerted a positive effect on the adhesion of endothelial cells. Together, our findings demonstrate that irisin stimulates the release of a novel adipokine, CXCL1, via upregulation of NFκB pathway in neck area derived adipocytes, which might play an important role in improving tissue vascularization.
Highlights
Recent studies indicated the presence of thermogenic adipose tissue, capable of dissipating energy as heat under sub-thermal conditions in healthy human adults (Cypess et al, 2009; Leitner et al, 2017)
We have previously reported that human DN adipose tissue biopsies released significantly higher amounts of interleukin (IL)-6, IL8, monocyte chemoattractant protein 1 (MCP1) as compared to subcutaneous ones, which was further enhanced upon irisin treatment (Kristóf et al, 2019)
A recent publication proposed the receptors for irisin to be integrins, Integrin subunit alpha V (ITGAV) and Integrin subunit beta (ITGB) 1/3/5 (ITGB1/3/5) (Kim et al, 2018)
Summary
Recent studies indicated the presence of thermogenic adipose tissue, capable of dissipating energy as heat under sub-thermal conditions in healthy human adults (Cypess et al, 2009; Leitner et al, 2017) These are located in cervical, supraclavicular, axillary, mediastinal, paravertebral, and abdominal depots (Saito et al, 2009; van Marken Lichtenbelt et al, 2009; Virtanen et al, 2009); supraclavicular, deep-neck (DN), and paravertebral having the highest amounts. Together these depots account for 5% of basal metabolic rate in adults, highlighting their importance in combating obesity and type 2 diabetes mellitus (van Marken Lichtenbelt and Schrauwen, 2011) In rodents, these thermogenic adipocytes are either classical brown or beige depending on their origin and distribution (Rosen and Spiegelman, 2014; Kajimura et al, 2015). Understanding the roles of batokines in the human body is an area of active research (Villarroya et al, 2019; Ahmad et al, 2021)
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