A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis (original) (raw)
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FNDC5/irisin is not only a myokine but also an adipokine
PloS one, 2013
Exercise provides clear beneficial effects for the prevention of numerous diseases. However, many of the molecular events responsible for the curative and protective role of exercise remain elusive. The recent discovery of FNDC5/irisin protein that is liberated by muscle tissue in response to exercise might be an important finding with regard to this unsolved mechanism. The most striking aspect of this myokine is its alleged capacity to drive brown-fat development of white fat and thermogenesis. However, the nature and secretion form of this new protein is controversial. The present study reveals that rat skeletal muscle secretes a 25 kDa form of FNDC5, while the 12 kDa/irisin theoretical peptide was not detected. More importantly, this study is the first to reveal that white adipose tissue (WAT) also secretes FNDC5; hence, it may also behave as an adipokine. Our data using rat adipose tissue explants secretomes proves that visceral adipose tissue (VAT), and especially subcutaneous ...
Biochemical and Biophysical Research Communications, 1997
in rodents (6-8). However, UCP1 may be of lesser im-Uncoupling proteins (UCPs) are inner mitochonportance in humans in whom the mass of brown adidrial membrane transporters which dissipate the propose tissue is limited. A second uncoupling protein, ton gradient, releasing stored energy as heat. UCP1 is termed UCP2 (9) or UCPH (10) was recently identified. expressed exclusively in brown adipocytes while UCP2 In contrast to UCP1, UCP2 is expressed in many tisis expressed widely. We now report the molecular clonsues, including sites not thought to mediate adaptive ing of a third uncoupling protein homologue, desigthermogenesis. We now report the molecular cloning nated UCP3. At the amino acid level, hUCP3 is 71% of a third uncoupling protein homologue, designated identical to hUCP2 and 57% identical to hUCP1. UCP3 UCP3, which is distinguished from UCP1 and UCP2 is distinguished from UCP1 and UCP2 by its abundant by its preferential expression in skeletal muscle and and preferential expression in skeletal muscle in hubrown adipose tissue, two important sites for regulated mans, and brown adipose tissue and skeletal muscle energy expenditure in humans (11-15) and rodents (8). in rodents. Since skeletal muscle and brown adipose tissue are believed to be important sites for regulated energy expenditure in humans and rodents, respec-MATERIALS AND METHODS tively, UCP3 may be an important mediator of adaptive thermogenesis. Since UCP3 is minimally ex-RACE (rapid amplification of cDNA ends) cloning of UCP3. Fullpressed in human heart and other critical organs, it is length UCP3 cDNA sequences were generated using the Marathon cDNA Amplification Kit, human skeletal muscle Marathon-Ready a promising target for anti-obesity drug development cDNA (both from Clontech Laboratories, Palo Alto, CA) and an antiaimed at increasing thermogenesis. ᭧ 1997 Academic Press sense primer (5 TTC ACC ACG TCC ACC GGG GAT GCC ACC 3). PCR was carried out using ExTaq Polymerase (TaKaRa), Taq Start Antibody (Clontech Laboratories) and the following conditions: 1.5 min. at 94ЊC, 20 sec. at 98ЊC and 4 min. at 68ЊC for 30 cycles. Calories are expended within mitochondria in a Northern blot assays. Human Multiple Tissue Northern Blots highly regulated fashion. Oxidation of fuels generates (#7760-1, #7759-1 and #7767-1) containing approximately 2 mg of a proton electrochemical gradient across the inner mi-polyA RNA per lane were purchased from Clontech Laboratories tochondrial membrane and re-entry of these protons (Palo Alto, CA). All hybridizations, membrane washes and memvia ATP synthase drives conversion of ADP to ATP. brane strippings were performed according to manufacturers specifications. The blots were first hybridized to a hUCP3 probe, washed Uncoupling proteins (UCPs) are inner mitochondrial and exposed to film for 1-18 hours, then stripped, rehybridized to a membrane transporters which dissipate the proton hUCP2 probe and exposed to film for 18 hours. The hUCP3 probe gradient, releasing stored energy as heat (1, 2), and was a 293 bp fragment corresponding to residues #211-308. The are therefore potentially important determinants of hUCP2 probe was a 1125 bp fragment spanning the entire open metabolic efficiency. UCP1, the first uncoupling protein reading frame. The specific activities of both hybridization probes were similar. Mouse Northern blots were generated using total RNA to be identified (3-5), is expressed exclusively in brown isolated from a number of tissues and equal loading of lanes was adipose tissue, an important site of energy expenditure established using ethidium bromide florescence. The mouse Northern blots were hybridized using the hUCP3 probe described above or a 1207 bp mUCP2 probe which spans the entire open reading frame. 1 These three authors contributed equally to this work. 2 To whom correspondence should be addressed at Division of En-RNase protection assays. Partial human UCP-3 and UCP-2 probes were generated by reverse transcriptase-PCR using total RNA docrinology, RN-320,
The energetic implications of uncoupling protein-3 in skeletal muscle
Applied Physiology, Nutrition, and Metabolism, 2007
Despite almost a decade of research since the identification of uncoupling protein-3 (UCP3), the molecular mechanisms and physiological functions of this mitochondrial anion carrier protein are not well understood. Because of its highly selective expression in skeletal muscle and the existence of mitochondrial proton leak in this tissue, early reports proposed that UCP3 caused a basal proton leak and increased thermogenesis. However, gene expression data and results from knockout and overexpression studies indicated that UCP3 does not cause basal proton leak or physiological thermogenesis. UCP3 expression is associated with increases in circulating fatty acids and in fatty acid oxidation (FAO) in muscle. Fatty acids are also well recognized as activators of the prototypic UCP1 in brown adipose tissue. This has led to hypotheses implicating UCP3 in mitochondrial fatty acid translocation. The corresponding hypothesized physiological roles include facilitated FAO and protection from the lipotoxic effects of fatty acids. Recent in vitro studies of physiological increases in UCP3 in muscle cells demonstrate increased FAO, and decreased reactive oxygen species (ROS) production. Detailed mechanistic studies indicate that ROS or lipid by-products of ROS can activate a UCP3-mediated proton leak, which in turn acts in a negative feedback loop to mitigate ROS production. Altogether, UCP3 appears to play roles in muscle FAO and mitigated ROS production. Future studies will need to elucidate the molecular mechanisms underlying increased FAO, as well as the physiological relevance of ROS-activated proton leak.
Impacts of rat hindlimb Fndc5/irisin overexpression on muscle and adipose tissue metabolism
American Journal of Physiology-Endocrinology and Metabolism
Myokines, such as irisin, have been purported to exert physiological effects on skeletal muscle in an autocrine/paracrine fashion. In this study, we aimed to investigate the mechanistic role of in vivo fibronectin type III domain-containing 5 (Fndc5)/irisin upregulation in muscle. Overexpression (OE) of Fndc5 in rat hindlimb muscle was achieved by in vivo electrotransfer, i.e., bilateral injections of Fndc5 harboring vectors for OE rats ( n = 8) and empty vector for control rats ( n = 8). Seven days later, a bolus of D2O (7.2 mL/kg) was administered via oral gavage to quantify muscle protein synthesis. After an overnight fast, on day 9, 2-deoxy-d-glucose-6-phosphate (2-DG6P; 6 mg/kg) was provided during an intraperitoneal glucose tolerance test (2 g/kg) to assess glucose handling. Animals were euthanized, musculus tibialis cranialis muscles and subcutaneous fat (inguinal) were harvested, and metabolic and molecular effects were evaluated. Muscle Fndc5 mRNA increased with OE (~2-fold...
Irisin: A Hope in Understanding and Managing Obesity and Metabolic Syndrome
Frontiers in Endocrinology, 2019
White adipose tissue (WAT) is an endocrine organ highly integrated in homeostasis and capable of establishing ways of communicating and influencing multiple metabolic processes. Brown adipose tissue promotes energy expenditure by incorporating the uncoupling protein 1 (UCP1), also known as thermogenin, which decouples cellular respiration and heat production, in the mitochondrial membranes. Recent data suggest the presence of a thermogenic cell formation from white adipocytes (beige or brite cells) with a potential role in preventing obesity and metabolic syndrome. The formation of these cells is influenced by physical exertion that induces expression of PPARγ coactivator-1 (PGC1) and downstream membrane protein, fibronectin type III domain-containing protein 5 (FNDC5) in skeletal muscle. Irisin, a thermogenic adipomyokine produced by FNDC5 cleavage is involved in the browning of adipose tissue. While animal studies are congruent with regard to the relationship between physical exertion and irisin release, the results from human studies are less than clear. Therefore, this review focuses on recent advances in our understanding of muscle and adipose tissue thermogenesis. Further, it describes the molecular mechanisms by which irisin impacts exercise, glucose homeostasis and obesity. Finally, the review discusses current gaps and controversies related to irisin release, its mode of action and its future potential as a therapeutic tool in managing obesity and metabolic syndrome.