Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids

Matteo Fiorenza*, Antonio Checa, Rasmus M. Sandsdal, Simon B.K. Jensen, Christian R. Juhl, Mikkel H. Noer, Nicolai P. Bogh, Julie R. Lundgren, Charlotte Janus, Bente M. Stallknecht, Jens Juul Holst, Sten Madsbad, Craig E. Wheelock, Signe S. Torekov

*Corresponding author for this work

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Abstract

Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.

Original languageEnglish
Article number101629
JournalCell Reports Medicine
Volume5
Issue number7
Number of pages22
ISSN2666-3791
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Keywords

  • adiponectin
  • ceramide
  • cytokines
  • exercise
  • FGF21
  • GDF15
  • GLP-1 receptor agonist
  • leptin
  • obesity
  • sphingolipids

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