Adipocyte1:2,112–115;April/May/June2012;G2012LandesBioscience Role of cardiotrophin-1 in obesity and insulin resistance María J. Moreno-Aliaga,1 M. Asunción Romero-Lozano,2 David Castaño,2 Jesús Prieto2 and Matilde Bustos2,* 1DepartmentofNutrition,FoodSciences,PhysiologyandToxicology;UniversityofNavarra;Pamplona,Spain;2DivisionofHepatologyandGeneTherapy; CenterforAppliedMedicalResearch(CIMA);UniversityofNavarra;Pamplona,Spain Cardiotrophin-1 (CT-1) is a member 130 as a common signal transducer within of the gp130 family of cytokines. their signaling receptor complex. Although In a recent study we examined the there is some cross-talk among the gp130 metabolic features of ct-1 null mice and cytokines, the complex signal transduction the effects on body composition, glucose cascade is not common to all family and lipid metabolism of acute and members. IL-6 and IL-11 first bind to the chronic administration of recombinant IL-6 receptor a and IL-11 receptor a Keywords: gp130 cytokines, IL-6 family CT-1. Our data revealed that CT-1 is a respectively, and then the complex associ- of cytokines, cardiotrophin-1, key regulator of energy metabolism with ateswithagp130homodimerβ(gp130Rβ) adipocytokines, obesity, insulin resistance potential applications in the treatment of complexforsignaling.CNTF,CT-1,CLC obesityandthemetabolicsyndrome.This and NP after binding to their specific a Abbreviations: CT-1, cardiotrophin-1; commentary discusses the significance of receptorsinduceformationofaheterodimer IL, interleukin; LIF, leukemia inhibitory these findings in the context of other key ofthesignal-transducinggp130RβandLIF factor; CNTF, ciliary neurotrophic factor; studies in the field of obesity and insulin receptorβ(LIFRβ).2However,NPhasalso OSM, oncostatin M; CLC, cardiotrophin resistance. been reported to activate signal transducer like cytokine; NP, neuropoietin; STAT, and activator of transcription (STAT)3 signal transducer and activator of in adipocytes independently of LIFRβ.3 transcription; EE, energy expenditure; Obesity is considered to be a worldwide OSM interacts with gp130/OSM receptor rCT-1, recombinant CT-1; WAT, white epidemic disease, the prevalence of which (OSMRβ) complex and has also being adipose tissue; UCP1, uncoupling protein hasdramaticallyincreasedamongchildren, reported to use gp130/LIFRβ.2 In recent 1;Dio2,deiodinaseiodothyroninetypeII; adolescents and adults during the last years,theIL-6familyofcytokineshavebeen TNF-a, tumor necrosis factor-a; PAI-1, decades. It has been, in fact, recognized proposed as potential therapies in obesity plasminogen activator inhibitor-1; ROS, as one of the major global health pro- andinsulinresistance,basedontheirability reactive oxygen species; SOCS, suppressor blems. This health hazard is linked to to modulate metabolic functions in adipo- ofcytokinesignaling;IRS,insulinreceptor increased risk of several types of common cytes and myocytes and because of the substrate;GLP-1,glucagon-like-peptide-1; diseases including cardiovascular dysfunc- efficacy of some of these cytokines in pro- ITT, insulin tolerance test; FFA, tion,insulinresistanceandtype2diabetes moting weight loss and insulin sensitivity.4 free fatty acids; cAMP, cyclic adenosine mellitus, hypertension, dyslipidemia, non- In particular, it has been reported that monophosphate; STZ, streptozotocin alcoholic fatty liver and also various types CNTF decreases fat mass and improves of cancer.1 Progress in understanding the glucose tolerance in humans and rodents Submitted: 01/09/12 regulation of energy metabolism and the acting both centrally and peripherally.5,6 Revised: 02/11/12 pathogenesis of obesity is of paramount However, disappointing results were Accepted: 02/13/12 importance for the design of novel obtained in clinical trials using a therapeutic options. human recombinant variant of CNTF http://dx.doi.org/10.4161/adip.19696 1 The interleukin (IL)-6 family of cyto- (Axokine ).7 On the other hand, there *Correspondenceto:MatildeBustos; kinesincludesIL-6,IL-11,IL-27,leukemia has been considerable debate regarding the Email:[email protected] inhibitoryfactor(LIF),ciliaryneurotrophic effects of IL-6 on insulin sensitivity8,9 but factor (CNTF), cardiotrophin-1 (CT-1), the pro-inflammatory properties of this Commentaryto:Moreno-AliagaMJ,Pérez- oncostatin M (OSM), cardiotrophin like cytokinelimitsitsclinicaluse. EcharriN,Marcos-GómezB,LarequiE,Gil-BeaFJ, ViolletB,etal.Cardiotrophin-1isakeyregulator cytokine (CLC) and neuropoietin (NP). CT-1 is a 21.5 kDa protein that was ofglucoseandlipidmetabolism.CellMetab These cytokines are commonly referred to named by its ability to induce myocyte 2011;14:242–53;PMID:21803294;http://dx.doi. as gp130 ligands/cytokines because all hypertrophy,10 and it is expressed in and org/10.1016/j.cmet.2011.05.013 members of this family utilize glycoprotein released from the heart in response to 112 Adipocyte Volume1Issue2 COMMENTARY stress.11 CT-1 is also expressed in many (TNF)-a and plasminogen activator inhi- mice and when given chronically for 10 d other tissues such as skeletal muscle, liver, bitor-1 (PAI-1). Our data have revealed to ob/ob mice reduced significantly the brain, lungs and kidneys with a broad thatCT-1isacytoadipokinethatcritically levels of glucose and insulin together with spectrum of biological activities, including influences WAT metabolism. an improvement in ITT compared with potent cytoprotective properties.12 A CT-1 mRNA expression levels are both saline and pair-fed groups.13 It has recent publication by our group revealed higher in skeletal muscle, heart and liver beenreportedthatCT-1maycauseinsulin that CT-1 is a master regulator of energy compared with WAT.13 CT-1 lacks signal resistanceinadipocytes.Asothermembers metabolism.13 Mice lacking CT-1 exhi- peptide, but it has been shown that CT-1 of IL-6 family of cytokines, CT-1 induces bited reduced energy expenditure (EE) can be released to extracellular milieu by the expression of suppressor of cytokine and developed adult-onset obesity, hyper- different stimuli such as hypoxia or signaling (SOCS)3,18 a molecule that cholesterolemia and type 2 diabetes, reactive oxygen species (ROS).14 In fact, binds to the insulin receptor inhibiting closely mimicking the human metabolic CT-1 is circulating in plasma and its insulin receptor substrate (IRS)-1 phos- syndrome. Given the fact, that CT-1 concentration is elevated in arterial hyper- phorylation and downstream insulin sig- modulated fat and glucose metabolism tension and coronary artery disease.11,12 naling. In addition, SOCS3 has been weproposed thatthis cytokinemight bea Recently, increased serum CT-1 levels shown to inhibit insulin signaling by potential therapy for obesity and insulin have been found in obesity,15,16 possibly targeting IRS-1 and -2 for proteasomal resistance. Indeed, we observed that as result of augmented secretion by a degradation.19AsSOCS3isupregulatedin recombinant CT-1 (rCT-1) was able to diversity of organs altered in this disease. WAT from different models of obese correct obesity and associated diabetes in The metabolic, cytoprotective and hypo- mice,20 it has been proposed that this animal models ofgenetic(ob/ob mice) and tensor properties described for CT-1 moleculemightpromoteinsulinresistance acquired obesity (high fat diet-fed mice). suggest that the reported overproduction inWAT.However,thestudyoftheroleof Theseeffectswererelatedtoanincreasein of CT-1 observed in subjects with these SOCS3 in WAT by creating fat-specific EE and decreased food intake. The study pathologies could be a protective mech- SOCS3 transgenic mice showed that, alsodemonstratedapotenteffectofrCT-1 anism to counteract the emergence of although overexpression of this molecule onwhiteadiposetissue(WAT),leadingto obesity-related disorders such as type 2 inadipocytesinhibitedlocalinsulinaction, a reduction of fat stores together with a diabetes or cardiovascular dysfunctions. In it improved systemic glucose metabolism dramatic remodeling of WAT, charac- ob/ob mice CT-1 mRNA abundance was in animals subjected to a high-fat diet. It terized by shrinkage of adipocytes and significantly increased in muscle, but not wasfoundthatSOCS3transgenicsshowed upregulationofgenesinvolvedinlipolysis, in WAT, as compared with wild-type increased serum levels of adiponectin and fatty acid oxidation, mitochondrial bio- animals (unpublished observations). decreased WAT mass indicating that the genesis and genes typifying brown-fat Accordingly, it is tempting to speculate reduction of adipocyte size and the phenotype. Analogous metabolic remodel- that the high circulating levels of CT-1 increase of insulin-sensitizing adipokines ing of adipocytes has been described for described in obesity derives more from exertadominanteffectonsystemicinsulin CNTF. However, there are some impor- skeletal muscle than from WAT. It has sensitivity, overcoming local adipocyte tant differences between CNTF and beenshownthatmuscleshavethecapacity insulin resistance.21 In fact, adipose tissue CT-1. In particular, rCT-1 is able to to secrete several myokines which act in a isresponsibleforonly10%ofwhole-body directly upregulate UCP1 (uncoupling hormone-like fashion and exert specific glucose uptake, while muscle accounts for protein 1) and Dio2 (deiodinase iodothyr- endocrine effects on distant organs or 80–90%.22Therefore,insulinresistancein onine type II) in cultured adipocytes, locally via paracrine mechanisms.17 Our WAT may not necessarily cause systemic while CNTF has no comparable effect data showed that rCT-1 markedly stimu- insulinresistance.Furthermore,aprevious on these genes. Moreover, while rCT-1 lates fatty acid oxidation and influences report has shown that CNTF is effective enhances lipolysis in cultured adipocytes glucose homeostasis by acting on skeletal on insulin sensitivity of skeletal muscle by (unpublishedobservations),CNTFfailsto muscle. Indeed, acute rCT-1 administra- bypassing the effects of SOCS3 induction do this. Our findings showed that CT-1 tion activates AKT in this tissue and by high-fat diet.23 Although we did not can activate fat mobilization and fat enhances insulin-induced AKT activation. test the effects of SOCS3 overexpression utilization in WAT, which might explain Interestingly, in vitro incubation of L6E9 on CT-1-induced signaling in WAT, it is the adipose-tissue lowering effect of this myocytes with rCT-1 increases insulin- important to mention that neither acute cytokine. mediated AKT phosphorylation and glu- nor chronic rCT-1 treatment inhibited WAT is no longer considered a passive cose uptake. As the skeletal muscle is the insulin-induced AKT phosphorylation in reservoir for storing lipids, but rather an largest organ in human body, the WAT from obese mice and cultured important organ influencing energy meta- decreased plasma glucose observed after adipocytes,13 suggesting that CT-1 effects bolism, insulin sensitivity and inflam- systemicadministrationofrCT-1couldbe are not impaired by SOCS3. mation by the secretion of a number of explained by the specific effects of rCT-1 Taken into account these effects and signalinghormones(referredtogenerically in muscle. Importantly, chronic rCT-1 the fact that CT-1 mRNA expression as adipokines) including leptin, adiponec- treatment increased insulin-induced AKT increased in skeletal muscle in circum- tin, resistin, visfatin, tumor necrosis factor phosphorylation in muscle of wild-type stances of obesity and insulin resistance, www.landesbioscience.com Adipocyte 113 the overall interpretation could be that significantlyhigherinsubjectswithhyper- metabolism. Previousstudiesofourgroup increased CT-1 mRNA expression in glycemia.15 Our data would argue against have evidenced the hepatoprotective pro- skeletalmusclecouldrepresentaprotective the mentioned hypothesis, since glucose perties of CT-1.14,26-28 Research should be mechanismtocounteractfataccumulation levelstendtodecreaseinfastingwhenCT- also focused in the metabolic effects of and to facilitate glucose uptake by the 1 is upregulated; however, more investi- CT-1 on hepatic glucose and lipid meta- muscle acting in an autocrine or paracrine gations are required to better understand bolism, including the regulation of lipo- manner.Inthiscontext,ithasbeenshown thenutritionalregulationofCT-1.AsCT- genesis, gluconeogenesis as well as hepatic that mRNA levels of IL-6, a prototypic 1isinducedbyfasting,itappearstoplaya insulin sensitivity and glucose production, myokine,increaseafter30minofexercise, roleinthebiologicalresponsetostarvation whichplayimportantrolesinthedevelop- sensitizing myocytes to insulin action,24 by enhancing hydrolysis of triglycerides mentofhyperglycemiaandhyperlipidemia which underscores the fact that proteins and providing FFA to other tissues to be of diabetes. Another issue to be solved is fromskeletalmuscleinfluencelocalmuscle oxidized in situations of energy depletion. the physiological role of CT-1 in the biology. Myokines could also induce In this regard, as mentioned before, we regulation of food intake and EE. We metabolic effects in distant organs such found thatrCT-1 enhancestheexpression clearly demonstrated the anorexigenic asadiposetissue,liverandbrain.Recently, of lipolytic genes in WAT, promotes properties of pharmacological doses of it has been shown that IL-6 secreted by lipolysis in adipocytes and boosts FFA rCT-1,butwealsoobservedthatct-1null skeletalmuscleorWATmediatescrosstalk oxidation in muscle.13 mice represent a model of hypophagic betweeninsulin-sensitivetissues,intestines obesity. We hypothesized that the hypo- and pancreatic islets through glucagon- Future Perspectives phagia of these animals may be a com- like-peptide-1 (GLP-1).25 pensatory mechanism to slow down CT-1 mRNA expression increased Our data point to CT-1 as a promising excessive weight gain as result of low markedly when mice were subjected to therapy for obesity and type 2 diabetes. EE.13 Nevertheless, the underlying bio- 48 h fast and decreased rapidly upon ThisisnotonlybecauseCT-1activatesfat chemical/molecular mechanisms by which refeeding.Thosechangeswereobservedin utilizationand improves insulinsensitivity CT-1 regulates food intake and basal a variety of organs including skeletal acting on WAT and muscle, but also metabolic rate remain to be elucidated. muscle, WAT and liver, indicating that because it possesses anorexigenic pro- Moreover, given the potential of CT-1 to CT-1 is regulated by nutritional status.13 perties. Another hallmark of our study influence energy homeostasis, it is impor- During fasting, circulating glucagon and was the finding that the administration of tant to determine whether variability in glucocorticoidslevelsareelevatedaswellas rCT-1 caused a significant fall in plasma the ct-1 gene is associated with a higher free fatty acids (FFA), all those factors glucose in mice with streptozotocin risk of developing obesity in humans. serveasmediatorsoftheadaptiveresponse (STZ)-induced insulin deficiency, demon- Taking into account the beneficial effects to starvation by inducing changes in gene strating an insulin-independent effect of described for CT-1 in obesity and insulin expression to deal with the new metabolic CT-1 on glucose homeostasis, and sug- resistance in rodents, we may hypothesize conditions. Because CT-1 mRNA is gesting a potential application in type 1 that the reported overproduction of induced during fasting, further investi- diabetes by helping to obtain a better CT-1 in obese subjects with metabolic gations will be needed in order to glycemiccontrolandreducingtherequire- syndrome15,16 could be a protective mech- determinetheroleofcAMP(themediator ments of insulin. Further research is anism opposing the emergence of obesity- of glucagon action), glucocorticoids or needed to determine the actions of CT-1 related disorders. More importantly, the FFA in the regulation of CT-1. It has inpancreaticisletincludingifthecytokine efficacy of safe and well-tolerated doses of been reported that glucose upregulates would be able to preserve the function CT-1 in the treatment of human obesity CT-1 mRNA levels in cultured murine of insulin-producing β cells. 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