Irisin exerts dual effects on browning and adipogenesis of human white adipocytes

Abstract

To better understand the role of irisin in humans, we examined the effects of irisin in human primary adipocytes and fresh human subcutaneous white adipose tissue (scWAT). Human primary adipocytes derived from 28 female donors' fresh scWAT were used to examine the effects of irisin on browning and mitochondrial respiration, and preadipocytes were used to examine the effects of irisin on adipogenesis and osteogenesis. Cultured fragments of scWAT and perirenal brown fat were used for investigating signal transduction pathways that mediate irisin's browning effect by Western blotting to detect phosphorylated forms of p38, ERK, and STAT3 as well as uncoupling protein 1 (UCP1). Individual responses to irisin in scWAT were correlated with basal expression levels of brown/beige genes. Irisin upregulated the expression of browning-associated genes and UCP1 protein in both cultured primary mature adipocytes and fresh adipose tissues. It also significantly increased thermogenesis at 5 nmol/l by elevating cellular energy metabolism (OCR and ECAR). Treating human scWAT with irisin increased UCP1 expression by activating the ERK and p38 MAPK signaling. Blocking either pathway with specific inhibitors abolished irisin-induced UCP1 upregulation. However, our results showed that UCP1 in human perirenal adipose tissue was insensitive to irisin. Basal levels of brown/beige and FNDC5 genes correlated positively with the browning response of scWAT to irisin. In addition, irisin significantly inhibited adipogenic differentiation but promoted osteogenic differentiation. We conclude that irisin promotes "browning" of mature white adipocytes by increasing cellular thermogenesis, whereas it inhibits adipogenesis and promotes osteogenesis during lineage-specific differentiation. Our findings provide a rationale for further exploring the therapeutic use of irisin in obesity and exercise-associated bone formation.

Physiology and role of irisin in glucose homeostasis

“…In humans, irisin seems to induce WAT browning in specific types of adipocytes and fat depots 71 . Human preadipocytes from SAT demonstrate a decrease in differentiation to mature adipocytes after irisin treatment, whereas the expression of genes and/or proteins related to browning (for example, UCP1, PPARγ and PRDM16) remains unaffected or is even decreased 53,71,72 . Furthermore, irisin does not affect browning-related gene expression in human perirenal adipose tissue, which has high expression of UCP1 and is therefore considered to be BAT 72 .…”

Browning of subcutaneous fat and higher surface temperature in response to phenotype selection for advanced endurance exercise performance in male DUhTP mice

“…It is known that brite adipocytes, converted from white adipocytes, exhibit properties of brown adipocytes like expression of UCP1 and a proposed mechanism for the induction of browning in WAT may occur by irisin derived from muscle after contraction (Bostrom et al 2012) or from the fat independent of physical exercise (Roca-Rivada et al 2013). A number of studies has demonstrated that the addition of exogenous irisin or irisin precursors (FNDC5) induced browning of white fat cells both in rodent (Zhang et al 2014; Bostrom et al 2012) and in human white fat cells (Zhang et al 2016; Huh et al 2014; Lee et al 2014). Fat cell browning in response to irisin treatment further induced cellular thermogenesis in mature human white fat cells (Zhang et al 2016).…”

“…A number of studies has demonstrated that the addition of exogenous irisin or irisin precursors (FNDC5) induced browning of white fat cells both in rodent (Zhang et al 2014; Bostrom et al 2012) and in human white fat cells (Zhang et al 2016; Huh et al 2014; Lee et al 2014). Fat cell browning in response to irisin treatment further induced cellular thermogenesis in mature human white fat cells (Zhang et al 2016). Because irisin may represent an early marker of fat cell browning and thermogenesis, it may have the potential as a novel anti-obesity drug (Bostrom et al 2012) or in a more general view could be seen as an attractive tool for the manipulation of energy metabolism in vivo.…”

Irisin Signaling Pathway is up Regulated by Resistance Training in Ovariectomized Rats

“…Irisin is a recently discovered hormone and there is little evidence on factors that may modulate its signaling. Is well established in the literature that RT promotes irisin release, and also increases cellular thermogenesis and reduces fat storage by suppressing formation of new adipocytes [19,20,[39][40][41]. Therefore, maintaining optimal irisin concentrations seems to be important, especially in our ovariectomy model, which has strong evidences of being a precursor of obesity and other metabolic disorders [42][43][44][45].…”

“…We found that the Ovx-Sed group presented similar values of irisin levels when compared to Sham-Sed group (Figure 3). However, it is already known that irisin increases cellular thermogenesis by up regulating UCP1, thus it is important to analyze and consider the UCP1 concentrations in WAT [41,46].…”