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Inflammatory cytokines such as interleukin (IL)\u20101 trigger inflammatory cascades and may be an important cause for cachexia. We employed genetic and pharmacological approaches to investigate the effects of IL\u20101 blockade in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We generated\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n Il1\u03b2<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice, and we treated\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n and wild\u2010type control mice with IL\u20101 receptor antagonist, anakinra (2.5\u00a0mg\/kg\/day, IP) or saline as vehicle for 6\u00a0weeks. In each of these mouse lines, we characterized the cachexia phenotype consisting of anorexia, loss of weight, fat mass and lean mass, elevation of metabolic rate, and reduced\n in vivo<\/jats:italic>\n muscle function (rotarod activity and grip strength). We quantitated energy homeostasis by measuring the protein content of uncoupling proteins (UCPs) and adenosine triphosphate in adipose tissue and skeletal muscle. We measured skeletal muscle fiber area and intramuscular fatty infiltration. We also studied expression of molecules regulating adipose tissue browning and muscle mass metabolism. Finally, we evaluated the impact of anakinra on the muscle transcriptome in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Skeletal muscle expression of IL\u20101\u03b2 was significantly elevated in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice relative to wild\u2010type control mice. Cachexia was completely normalized in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n Il1\u03b2<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice relative to\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. We showed that anakinra attenuated the cachexia phenotype in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. Anakinra normalized UCPs and adenosine triphosphate content of adipose tissue and muscle in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. Anakinra attenuated aberrant expression of beige adipose cell biomarkers (UCP\u20101, CD137, Tmem26, and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2\/Pgf2\u03b1, Tlr2, Myd88, and Traf6) in inguinal white adipose tissue in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. Moreover, anakinra normalized gastrocnemius weight and fiber size and attenuated muscle fat infiltration in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. This was accompanied by correction of the increased muscle wasting signalling pathways (increased protein content of ERK1\/2, JNK, p38 MAPK, and nuclear factor\u2010\u03baB p65 and mRNA expression of Atrogin\u20101 and Myostatin) and the decreased myogenesis process (decreased mRNA expression of MyoD and Myogenin) in the gastrocnemius muscle of\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. Previously, we identified the top 20 differentially expressed skeletal muscle genes in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice by RNAseq. Aberrant expression of these 20 genes have been implicated in muscle wasting, increased energy expenditure, and lipolysis. We showed that anakinra attenuated 12 of those top 20 differentially expressed muscle genes in\n Ctns<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Anakinra may provide a targeted novel therapy for patients with infantile nephropathic cystinosis.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.12744","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T06:38:14Z","timestamp":1625121494000},"page":"1296-1311","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Targeting interleukin\u20101 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Wai W.","family":"Cheung","sequence":"first","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics, Rady Children's Hospital San Diego University of California, San Diego La Jolla CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Rheumatology, Shanghai Children's Hospital Shanghai Jiao Tong University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronghao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Rheumatology, and Immunology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shanghai General Hospital Shanghai Jiao Tong University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics, Rady Children's Hospital San Diego University of California, San Diego La Jolla CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Zhou","sequence":"additional","affiliation":[{"name":"Sichuan Provincial Hospital for Women and Children Affiliated Women and Children's Hospital of Chengdu Medical College Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hal M.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of California, San Diego La Jolla CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Mak","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics, Rady Children's Hospital San Diego University of California, San Diego La Jolla CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-007-0650-8"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1993.03510180070036"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013060653"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00626.2008"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40635-016-0115-0"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12621"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0155944","article-title":"Effect of the IL\u20101 receptor antagonist Kineret on disease phenotype in mdx mice","volume":"11","author":"Klimek MEB","year":"2016","journal-title":"PLos ONE"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010070760"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12056"},{"key":"e_1_2_9_11_1","first-page":"17.3.1","article-title":"Quantification of creatinine and guanidinoacetate using GC\u2010MS and LC\u2010MS\/MS for the detection of cerebral creatinine deficiency syndromes","author":"Young S","year":"2007","journal-title":"Curr Protoc Hum Genet"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12497"},{"key":"e_1_2_9_13_1","volume-title":"Muscle Biopsy. 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