By Thomas G. Brock, Ph.D.
What does a good workout have in common with Zeus, the Greek King of the Gods? A recent study suggests that a protein secreted during exercise targets adipose tissue, ultimately improving both obesity and glucose homeostasis. This protein has been named irisin, after the Greek goddess Iris, who acted as the messenger for Zeus. To help her fly between Mount Olympus and the land of mortals, Iris had golden wings (Figure 1). She was also considered the goddess of rainbows and could move along the colored spectrum between the clouds and the earth or sea. By both wings and rainbows, Iris moved swiftly to carry the directions of Zeus to mortals and immortals.
The hormone irisin looks and acts differently from Iris. This messenger is derived from fibronectin type III domain-containing protein 5 (FNDC5), a membrane-spanning protein of 196 aa. Aside from a short signal peptide, FNDC5 predominantly consists of an extracellular region containing the fibronectin type III (FnIII) domain, separated from a small cytoplasmic region by the helical transmembrane section. Irisin is a 112 aa peptide which includes the 91 aa extracellular FnIII domain, cleaved from the carboxy terminus of FNDC5. FnIII domains commonly consist of a combination of beta strands and random coils, as shown in the resolved structure of the FnIII domain of FNDC3 (1X5X.pdb, Figure 1).They are found in thousands of different proteins, usually serving to mediate interactions with other molecules (proteins, DNA, etc.) or cells. Whatever the mechanism, irisin is, like the goddess Iris, a powerful messenger, sending the signal to determine the function of specific cells.
Iris and irisin differ somewhat in their beginnings. While Iris was the daughter of Thaumas, a god of the seas, and Elektra, a nymph of the clouds, irisin is induced by PGC1α, also known as peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator 1-α. As suggested by its name, PGC1α is a transcriptional coactivator; it enhances the activity of nuclear receptors, like PPAR-γ. Predominantly expressed in tissues which are rich in mitochondria, like skeletal muscle, brown adipose tissue, and heart, PGC1α helps regulate transcriptional programs that are important for energy homeostasis by enhancing fatty acid oxidation and stimulating mitochondrial biogenesis. Exercise increases the expression of PGC1α in heart and skeletal muscle, stimulating muscle respiratory capacity. More specifically, contraction of skeletal muscle is initiated by motor neuron-induced calcium signaling (Figure 2). Elevated calcium activates the protein phosphatase calcineurin and the calcium/calmodulin-dependent protein kinases, which then alter the phosphorylation state of several transcription factors and coactivators, including CREB, NFAT, MEF2C, and MEF2D.1 Exercise rapidly and robustly increases the expression of PGC1α, but this effect is transient as both mRNA and protein levels of PGC1α quickly revert to pre-exercise values.2 Exercise also activates AMP-activated protein kinase (AMPK), a master regulator of cellular and organismal metabolism. AMPK directly phosphorylates PGC1α, which is required for PGC1α-dependent induction of the PGC1α promoter.3 While brief training produces only a transient rise in PGC1α, endurance training results in persistent PGC1α elevation.4 Expression of PGC1α in muscle stimulates an increase in FNDC5, as does exercise alone.5 Irisin is then cleaved from the carboxy terminus of FNDC5 and secreted from muscle cells; glycosylated forms of irisin can be detected in the plasma after exercise.5 Thus, myocontraction during exercise drives the expression of PGC1α, which in turn elicits the production of FNDC5 and subsequent secretion of irisin from muscle.
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Perhaps the most interesting things about irisin are its effects and potential applications. One approach to studying the specific effects of elevated levels of irisin in the plasma involves ectopically expressing FNDC5 using adenoviral vectors. When this was done in mice in such a way as to increase plasma levels of irisin 3-4 fold (a modest increase, since basal concentrations are very low), the mRNA levels for UCP1 and Cidea were significantly increased in the subcutaneous fat depot ten days later.5 This was accompanied by a clear increase in the number of UCP1-positive, multilocular adipocytes in that particular adipose tissue. This demonstrated that a moderate increase in circulating irisin can induce browning of white adipose tissues in vivo.
To help clarify, all adipose tissues, and, indeed, all adipocytes, are not identical. Fats are deposited in ‘depots’ or pads in specific sites, which may be identified generally (subcutaneous or visceral) or more specifically by location (e.g., inguinal (groin), epididymal, perirenal). Each site contains a variety of cell types in addition to the adipocytes and has unique features regarding its development and function. More relevant to this article, distinctive types of adipocytes exist. White adipocytes, which contain a single large lipid droplet, populate white adipose tissue. This most familiar form, the bane of dieters, stores excess energy as fat. When other energy sources have been exhausted, white adipocytes hydrolyze triglycerides and export fatty acids to be utilized for energy by other cells. Brown adipocytes, on the other hand, burn fatty acids to generate heat through uncoupled respiration. Cytologically, these cells are described as ‘multilocular’, as they store fat in many small subcellular droplets which appear as empty compartments in histological cross-sections. Brown adipocytes also contain numerous mitochondria, which provide the distinctive color. The mitochondria of brown adipocytes express a unique uncoupling protein, UCP1, a multi-pass inner membrane protein which uncouples oxidative phosphorylation from ATP synthesis so that energy is dissipated in the form of heat. These cells are abundant in brown adipose tissue (BAT), which is most commonly found in newborns and hibernating animals. Functional, classical BAT also occurs in a supraclavicular depot in healthy adult humans.6,7
Recently, a new type of adipocyte which expresses UCP1 and metabolizes, rather than stores, lipids has been described. Like brown adipocytes, these new cells have many mitochondria and locular lipid droplets, albeit fewer than true brown cells. However, they differ in their origin. Brown adipocytes are derived from the same precursor as skeletal muscle, termed a dermomyotome, which expresses the homeobox transcription factor Engrailed 1 (En1) and myogenic factor 5 (Myf5)(Figure 3). Differentiation of dermomyotomes to either myocytes or adipocytes is determined by signaling via bone morphogenetic protein 7 (Bmp7) and Wnt. White adipocytes, on the other hand, differentiate from a different precursor which lacks Myf5, presumably a mesodermal stem cell. Again, adipocyte development is promoted by Bmps and blocked by Wnt. The new type of adipocyte can be induced in vivo in WAT depots by chronic -adrenergic stimulation or by chronic PPARγ-agonist treatment, particularly in the inguinal depot of the mouse.8,9 As this cell type is morphologically and functionally similar to brown cells but shares a precursor with white adipocytes, it has been called a ‘brite’ (brown-in-white) adipocyte.10 Alternatively, it may be referred to as a ‘beige’ adipocyte or a recruitable or inducible brown adipocyte-like cell. More important than the name, this cell type may serve an important role in regulating energy balance, glucose metabolism, and lipid homeostasis.
Iris and irisin differ in their actions. Iris affected the course of the Trojan War, one of the great Greek clashes, by carrying Zeus’ advice to the Trojan leader Hector (although the Trojan Horse ultimately led to the fall of Troy). Irisin, by way of contrast, may alter the course of diseases like diabetes, obesity, and other pathologies that benefit from exercise. ‘Browned’ WAT, produced either by irisin (from FNDC5-expressing adenovirus) or by transgenic expression of Prdm16, protects against diet-induced obesity and diabetes.5,11 Whether irisin can be developed into a deliverable therapeutic that mimics exercise-induced irisin production remains a major hurdle.
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