Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level

Lennart Zabeau, Cathy J. Jensen, Sylvie Seeuws, Koen Venken, Annick Verhee, Dominiek Catteeuw, Geert Van Loo, Hui Chen, Ken Walder, Jacob Hollis, Simon Foote, Margaret J. Morris, José Van Der Heyden, Frank Peelman, Brian J. Oldfield, Justin P. Rubio, Dirk Elewaut, Jan Tavernier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions.

Original languageEnglish
Pages (from-to)629-644
Number of pages16
JournalCellular and Molecular Life Sciences
Issue number3
Publication statusPublished - 2015
Externally publishedYes


  • Antagonist
  • Autoimmune disease
  • Genetic model
  • Leptin receptor
  • Metabolism
  • Nanobody
  • Obesity


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