title: Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia.
abstract: Leptin is an adipocyte-derived hormone that controls food intake and reproductive and immune functions in rodents. In uncontrolled human studies, low leptin levels are associated with impaired immune responses and reduced T-cell counts; however, the effects of leptin replacement on the adaptive immune system have not yet been reported in the context of randomized, controlled studies and/or in conditions of chronic acquired leptin deficiency. To address these questions, we performed a randomized, double-blinded, placebo-controlled trial of recombinant methionyl-human leptin (metreleptin) administration in replacement doses in women experiencing the female triad (hypothalamic amenorrhea) with acquired chronic hypoleptinemia induced by negative energy balance. Metreleptin restored both CD4(+) T-cell counts and their in vitro proliferative responses in these women. These changes were accompanied by a transcriptional signature in which genes relevant to cell survival and hormonal response were up-regulated, and apoptosis genes were down-regulated in circulating immune cells. We also observed that signaling pathways involved in cell growth/survival/proliferation, such as the STAT3, AMPK, mTOR, ERK1/2, and Akt pathways, were activated directly by acute in vivo metreleptin administration in peripheral blood mononuclear cells and CD4(+) T-cells both from subjects with chronic hypoleptinemia and from normoleptinemic, lean female subjects. Our data show that metreleptin administration, in doses that normalize circulating leptin levels, induces transcriptional changes, activates intracellular signaling pathways, and restores CD4(+) T-cell counts. Thus, metreleptin may prove to be a safe and effective therapy for selective CD4(+) T-cell immune reconstitution in hypoleptinemic states such as tuberculosis and HIV infection in which CD4(+) T cells are reduced.
authors: Dipartimento di Medicina e Chirurgia,  Università degli Studi di Salerno, Baronissi Campus, 84081 Baronissi Salerno,  Italy.
authors: Giuseppe
authors: G
authors: Matarese
authors: Claudia
authors: C
authors: La Rocca
authors: Hyun-Seuk
authors: HS
authors: Moon
authors: Joo Young
authors: JY
authors: Huh
authors: Mary T
authors: MT
authors: Brinkoetter
authors: Sharon
authors: S
authors: Chou
authors: Francesco
authors: F
authors: Perna
authors: Dario
authors: D
authors: Greco
authors: Holly P
authors: HP
authors: Kilim
authors: Chuanyun
authors: C
authors: Gao
authors: Kalliope
authors: K
authors: Arampatzi
authors: Zhaoxi
authors: Z
authors: Wang
authors: Christos S
authors: CS
authors: Mantzoros
mesh_terms: D000293:Adolescent; D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006728:Hormones / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000097:blood; D020738:Leptin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000172:deficiency* / Q000494:pharmacology / Q000627:therapeutic use; D008659:Metabolic Diseases / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D016207:Cytokines; D006728:Hormones; D020738:Leptin; C122136:recombinant methionyl human leptin; C415771:metreleptin
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