Does IRISIN Have a BRITE Future as a Therapeutic Agent in Humans?

Brian A. Irving Christopher D. Still George Argyropoulos 0 ) Geisinger Obesity Institute, Geisinger Health System, 100 N. Academy Ave , Danville, PA 17868, USA The epidemic of obesity has contributed to the rapid rise in comorbid conditions such as cardiovascular disease, type 2 diabetes, sleep apnea, and hypertension among others. Therefore, there is a critical need to develop therapeutic strategies to reduce the prevalence of the disease. Skeletal muscle cells secrete signaling cytokines/peptides (referred to as myokines) that act in autocrine, paracrine, and endocrine fashion. Myokines have been hypothesized to contribute to the immediate and chronic benefits of exercise and may thus serve as attractive therapeutic agents for the treatment of obesity. The recent discovery of the irisin, a proposed myokine, has gained much attention over the last two years as a potential therapeutic agent. Preliminary studies demonstrated that irisin has the potential to induce browning of white adipocytes in mice. If these findings in mice could be translated to humans, irisin could be a potential therapeutic agent for the treatment of obesity. Limitations with the available antibodies, however, have raised concerns regarding the detectability of irisin in circulation. Moreover, the gene encoding irisin, FNDC5, is expressed robustly not only in muscle but also in various white adipose tissues (WAT) in humans, raising the possibility for increased thermogenesis through autocrine mechanisms. Here we will discuss the browning of WAT, the discovery of irisin, and its potential role in improving metabolic health in humans. - Obesity has rapidly become a worldwide epidemic. In parallel, the prevalence of obesity-related comorbid conditions has also escalated, including insulin resistance, metabolic syndrome, type 2 diabetes, hypertension, chronic kidney disease, cardiovascular disease, heart failure, cancer, and dementia [13]. As expected, a recent meta-analysis from the US Centers for Disease Control and Prevention confirms that obesity is associated with increased all-cause mortality [4]. The rapid increase in obesity and obesity-related comorbid conditions has coincided with the rapidly changing landscape of our obesogenic environment [5]. In particular, it has coincided with the systemic reductions in total daily physical activity as well as reductions in vigorous physical activity [5, 6]. Exercise has long been recognized for its pluripotent effects on body composition [7, 8], metabolic health [9], cardiovascular disease [10, 11] and mental health [12]. The underlying mechanism(s) for the clinical benefits of exercise remains to be fully elucidated. Over the past decade, it has become increasingly recognized that skeletal muscle cells secrete signaling cytokines/peptides that act in autocrine, paracrine, and endocrine fashion in response to skeletal muscle contraction (e.g., exercise) [13]. The secreted cytokines/peptides, referred to as myokines, have been hypothesized to contribute to the immediate and chronic benefits of exercise [13]. The recent discovery of irisin by Bostrom et al. [14 ], a putative exercise induced myokine, that is credited for improving metabolic health by its ability to brown white adipose tissue (WAT) in mice has received considerable attention over the last two years. Although it remains to be determined whether irisin has the ability to brown WAT and improve metabolic health in humans, it represents a potentially attractive therapeutic agent for treating obesity and metabolic disease in humans. Here we will briefly discuss the browning of WAT, the discovery of irisin, and the potential role that irisin may play in browning WAT and improving metabolic health in humans. Browning of White Adipocytes Classically, adipose tissue is characterized as either WAT or brown adipose tissue (BAT). Adipocytes from WAT serve as the primary site for lipid storage; whereas adipocytes from BAT are highly specialized cells designed to produce heat through uncoupled respiration that leads to concomitant dissipation of energy [15]. The physical, metabolic, and regulatory characteristics of WAT and BAT have been extensively reviewed elsewhere [1621]. In brief, adipocytes from WAT have a unilocular lipid droplet, few mitochondria, and a relatively low metabolic rate [21]. In contrast, adipocytes from BAT have multilocular lipid droplets, many mitochondria, and a relatively high metabolic rate [21]. The relatively high metabolic rate observed in BAT compared to WAT is due to the presence of uncoupling protein 1 (UCP1), which is negligibly expressed in WAT [21]. The presence of brown adipocytes in WAT has been known for many years. Young et al. [22] were the first to report the presence of brown adipocytes in WAT of female BALB/c mice following cold acclimatization. Subsequently, brown adipocytes were identified in multiple WAT fat pads in rats [23]. Enrichment and activation of BAT represents an attractive therapeutic strategy to combat obesity and metabolic disease. The presence of UCP1 positive cells in WAT can also be pharmacologically enriched by -adrenergic stimuli [2325] as well as PPAR agonist [2628]. Recent evidence has demonstrated that the brown adipocytes (i.e., UCP1 positive cells) found in WAT are actually a distinct sub-population of white adipocytes (referred to as brown-in-white (brite) or beige adipocytes) [15, 26]. Co-culture experiments demonstrated that beige/brite adipocytes treated with rosiglitazone (a PPAR agonist) can be induced to differentiate into adipocytes with thermogenic potential in the absence of classical brown adipocyte-specific markers (e.g., Zic2, Lhx8, Meox3, and PRDM16) [26]. In addition, these beige/brite adipocytes are also characterized as having the white adipocyte-specific marker Hoxc9 while lacking the white adipocyte-specific marker tcf21 [26]. Taken together, these results indicate that the beige/brite adipocytes are truly a distinct subtype of white adipocytes with potentially hidden capacity for higher metabolic rate [26]. In 2012, Wu et al. [15] confirmed that the beige/brite adipocytes found in WAT depots in mice and humans are in fact distinct from classical brown adipocytes that are more abundant in mice as a specialized depot [19, 29]. Specifically, for the first time they demonstrated that the beige/brite adipocytes emerge from non-myf-5 progenitor cells, in contrast to brown adipocytes, which are derived from myf-5 positive progenitor cells [15]. The exquisite regulation of the browning of white adipocytes in response to environmental, hormonal, and metabolic stimuli is quite remarkable. Excellent reviews of the development and regulatory control of beige/brite adipocytes have recently been published [19, 29]. Similar to BAT, enrichment and activation of beige/brite adipocytes represents an attractive therapeutic strategy to combat obesity and metabolic disease. The recent discovery of irisin and its potential t (...truncated)