Selective capacity of metreleptin administration to reconstitute CD4 + T-cell number in females with acquired hypoleptinemia

Giuseppe Matarese, Claudia La Rocca, Hyun-Seuk Moon, Joo Young Huh, Mary T. Brinkoetter, Sharon Chou, Francesco Perna, Dario Greco, Holly P. Kilim, Chuanyun Gao, Kalliope Arampatzi, Zhaoxi Wang, Christos S. Mantzoros

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 methionylhuman 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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number9
DOIs
Publication statusPublished - 2013 Feb 26
Externally publishedYes

    Fingerprint

Keywords

  • CD4 cells
  • Metabolism
  • Nutritional status

ASJC Scopus subject areas

  • General

Cite this

Matarese, G., La Rocca, C., Moon, H-S., Huh, J. Y., Brinkoetter, M. T., Chou, S., Perna, F., Greco, D., Kilim, H. P., Gao, C., Arampatzi, K., Wang, Z., & Mantzoros, C. S. (2013). Selective capacity of metreleptin administration to reconstitute CD4 + T-cell number in females with acquired hypoleptinemia. Proceedings of the National Academy of Sciences of the United States of America, 110(9). https://doi.org/10.1073/pnas.1214554110